Acute Liver Failure

Lee, William M.

doi:10.1002/9781118512074.ch98

Cited by 14 publications

(19 citation statements)

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“…Unfortunately, clinical or laboratory biomarkers that predict outcome reliably are not available. As there is evidence of immune or inflammatory dysregulation in acute liver failure (ALF) [3][4][5][6][7] associated with outcome, we hypothesize that markers of immune or inflammatory dysregulation in PALF may be leveraged to predict outcome.…”

Section: Introductionmentioning

confidence: 99%

Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure

Zamora

Vodovotz

et al. 2016

Mol Med

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Absence of early outcome biomarkers for Pediatric Acute Liver Failure (PALF) hinders medical and liver transplant decisions. We sought to define dynamic interactions among circulating inflammatory mediators to gain insights into PALF outcome sub-groups. Serum samples from 101 participants in the PALF study, collected over the first 7 days following enrollment, were assayed for 27 inflammatory mediators.Outcomes (Spontaneous survivors [S, n=61], Non-survivors [NS, n=12], and liver transplant patients [LTx, n=28]) were assessed at 21 days post-enrollment. Dynamic interrelations among mediators were defined using data-driven algorithms. Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all patient sub-groups. The networks in S and LTx were similar, and differed from NS. Dynamic Network Analysis suggested similar dynamic connectivity in S and LTx, but a more highly-interconnected network in NS that increased with time. A Dynamic Robustness Index calculated to quantify how inflammatory network connectivity changes as a function of correlation stringency differentiated all three patient sub-groups. Our results suggest that increasing inflammatory network connectivity is associated with non-survival in PALF, and may ultimately lead to better patient outcome stratification.

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Section: Introductionmentioning

confidence: 99%

Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure

Zamora

Vodovotz

et al. 2016

Mol Med

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“…Chronic inflammation from many causes including alcohol abuse, obesity, and hepatotoxic viruses can lead to cirrhosis while acute liver failure can result from drug overdoses [1]. Inherited disorders such as ornithine transcarbamylase (OTC) enzyme deficiencies can lead to reduced urea output and to hyperammonia toxicity [2].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte-Like Cells Derived from Human Amniotic Epithelial Cells Can Be Encapsulated Without Loss of Viability or Function In Vitro

Vaghjiani

Vaithilingam

Saraswati

et al. 2014

Stem Cells and Development

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Placenta derived human amniotic epithelial cells (hAEC) are an attractive source of stem cells for the generation of hepatocyte-like cells (HLC) for therapeutic applications to treat liver diseases. During hAEC differentiation into HLC, they become increasingly immunogenic, which may result in immune cell-mediated rejection upon transplantation into allogeneic recipients. Placing cells within devices such as alginate microcapsules can prevent immune cell-mediated rejection. The aim of this study was to investigate the characteristics of HLC generated from hAEC and to examine the effects of encapsulation on HLC viability, gene expression, and function. hAEC were differentiated for 4 weeks and evaluated for hepatocyte-specific gene expression and function. Differentiated cells were encapsulated in barium alginate microcapsules and cultured for 7 days and the effect of encapsulation on cell viability, function, and hepatocyte related gene expression was determined. Differentiated cells performed key functions of hepatocytes including urea synthesis, drug-metabolizing cytochrome P450 (CYP)3A4 activity, indocyanine green (ICG) uptake, low-density lipoprotein (LDL) uptake, and exhibited glutathione antioxidant capacity. A number of hepatocyte-related genes involved in fat, cholesterol, bile acid synthesis, and xenobiotic metabolism were also expressed showing that the hAEC had differentiated into HLC. Upon encapsulation, the HLC remained viable for at least 7 days in culture, continued to express genes involved in fat, cholesterol, bile acid, and xenobiotic metabolism and had glutathione antioxidant capacity. CYP3A4 activity and urea synthesis by the encapsulated HLC were higher than that of monolayer HLC cultures. Functional HLC can be derived from hAEC, and HLC can be encapsulated within alginate microcapsules without losing viability or function in vitro.

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“…Cerebral edema and associated increase in intracranial pressure leading to brain herniation are the characteristic features of AHE which occurs in upto 80% of patients with AHE 4-6 and represents the most frequent cause of death in these patients (70% mortality). 4,7 While the basis for the edema in AHE is poorly understood, astroglial swelling (cytotoxic edema) dominates the pathology in experimental animals, [8][9][10][11] as well as in humans. 12 Of interest, no significant or consistent morphologic changes have been identified in neurons or other neural cells.…”

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confidence: 99%

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

Jayakumar

Rao

Norenberg

2015

Journal of Clinical and Experimental Hepatology

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Hepatic encephalopathy (HE) is a major neurological complication of severe liver disease that presents in acute and chronic forms. While elevated brain ammonia level is known to be a major etiological factor in this disorder, recent studies have shown a significant role of neuroinflammation in the pathogenesis of both acute and chronic HE. This review summarizes the involvement of ammonia in the activation of microglia, as well as the means by which ammonia triggers inflammatory responses in these cells. Additionally, the role of ammonia in stimulating inflammatory events in brain endothelial cells (ECs), likely through the activation of the toll-like receptor-4 and the associated production of cytokines, as well as the stimulation of various inflammatory factors in ECs and in astrocytes, are discussed. This review also summarizes the inflammatory mechanisms by which activation of ECs and microglia impact on astrocytes leading to their dysfunction, ultimately contributing to astrocyte swelling/ brain edema in acute HE. The role of microglial activation and its contribution to the progression of neurobehavioral abnormalities in chronic HE are also briefly presented. We posit that a better understanding of the inflammatory events associated with acute and chronic HE will uncover novel therapeutic targets useful in the treatment of patients afflicted with HE. ( J CLIN EXP HEPATOL 2015;5:S21-S28) H epatic encephalopathy (HE) is the major neurological complication of severe liver disease. It presents in two forms, chronic HE and acute HE. Chronic HE (portal-systemic encephalopathy) usually occurs in patients with alcoholic liver cirrhosis and is characterized by impaired neurological function, including changes in personality, altered mood, diminished intellectual capacity, and abnormal muscle tone and tremor. 1 Acute HE (AHE, acute liver failure, ALF; fulminant hepatic failure) generally occurs following massive liver necrosis due to viral hepatitis (hepatitis B and C), hepatic neoplasms, vascular causes, or exposure to acetaminophen and other hepatotoxins. AHE is associated with the abrupt onset of delirium, seizures, and coma.The principal pathological change in chronic HE is characterized by Alzheimer type II astrocytosis, 2,3 which is characterized by astrocytes possessing enlarged, pale nuclei, often occurring in pairs, with the nuclei frequently displaying prominent nucleoli. Cerebral edema and associated increase in intracranial pressure leading to brain herniation are the characteristic features of AHE which occurs in upto 80% of patients with AHE 4-6 and represents the most frequent cause of death in these patients (70% mortality). 4,7 While the basis for the edema in AHE is poorly understood, astroglial swelling (cytotoxic edema) dominates the pathology in experimental animals, [8][9][10][11] as well as in humans. 12 Of interest, no significant or consistent morphologic changes have been identified in neurons or other neural cells. Such findings prompted the suggestion that HE fundamentally represents a pr...

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Acute Liver Failure

Cited by 14 publications

References 100 publications

Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure

Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure

Hepatocyte-Like Cells Derived from Human Amniotic Epithelial Cells Can Be Encapsulated Without Loss of Viability or Function In Vitro

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

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