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Andres T Blei

Publications and source records attributed to Andres T Blei.

32 records · Page 2Linked to original sources
PubMed2004

Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture.

Apoptosis occurs during the isolation and even short-term storage and culture of hepatocytes, and in the pathogenesis of liver diseases, such as hepatic failure and hepatitis. Therapeutic hypothermia has beneficial effects in experimental models of fulminant hepatic failure. The mechanisms underlying the potential benefits of mild hypothermia on the liver have not been well investigated. We examined the effects of temperature on soluble Fas ligand-induced apoptosis in freshly isolated mouse hepatocytes. Decreasing the culture temperature from 37 degrees C to 32 degrees C produced significant suppression of Fas-mediated apoptosis in cultured hepatocytes over a 12-h period. This observation was supported by cell morphology, flow cytometry analysis of cellular DNA content, and Annexin V-FITC staining of membrane phosphatidylserine translocation. In hypothermic conditions, Fas-mediated cytochrome c release from mitochondria of hepatocytes and the proximate downstream activation of caspase-9 were suppressed under mild hypothermic conditions. Effector caspase-7 activity was also inhibited at 32 degrees C. In contrast, the activation of initiator caspase-8 and cleavage of Bid were not affected after Fas-ligand stimulation. These findings suggest that mild hypothermia suppresses Fas-mediated apoptosis of liver cells by the partial inhibition of signaling events including mitochondrial damage, cytochrome c release, and subsequent apoptosome formation and effector caspase activation.

Animals↗
PubMed2003

Etiology and management of fulminant hepatic failure.

Fulminant hepatic failure (FHF) remains a rare but devastating disease. Viruses and drug-induced hepatotoxicity are the most common causes of the syndrome, but the relevance of each differs depending on the geographic area. In a large proportion of patients no cause for FHF can be identified. Good intensive care is critical for patient survival. Orthotopic liver transplantation (OLT) remains a definitive therapeutic option. Prognostic indices have helped to optimize patient selection and timing for performance of OLT. However, the accuracy of these prognostic indices decreases when they are applied to different populations, probably because of regional differences in etiology and peculiar native host factors. More accurate prognostic criteria and new therapeutic alternatives to OLT are required.

Humans↗
PubMed2003

Infection and the progression of hepatic encephalopathy in acute liver failure.

BACKGROUND & AIMS: Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection. METHODS: We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies. RESULTS: On multivariate analysis, acquisition of infection during stage I-II HE (P < 0.01), increased leukocyte levels at admission (P < 0.01), and decreased platelet count (P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (P < 0.05) and AST levels (P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and >or=2 components of SIRS, P < 0.05). CONCLUSIONA: This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.

Acetaminophen↗
PubMed2003

Vasopressin accelerates experimental ammonia-induced brain edema in rats after portacaval anastomosis.

BACKGROUND/AIMS: Cerebral hyperemia is an important contributor to the development of brain edema in fulminant hepatic failure. Rats receiving an ammonia infusion after portacaval anastomosis (PCA) demonstrate a rise in cerebral blood flow (CBF) with brain edema at 180 min. Vasopressin (VP), a systemic vasoconstrictor which in the rat dilates cerebral vessels through V(2) receptors, was used to ascertain the effects of increasing CBF. METHODS: Changes in CBF were measured with Laser Doppler flowmetry (LDF). Absolute CBF was measured with radioactive microspheres to calculate oxygen and ammonia uptake. RESULTS: Compared to the NH(3)+Vehicle group, VP+NH(3) infusion accelerated the rise in CBF (117+/-21 vs. -6+/-12%, P<0.01), and the development of brain edema (81.09+/-0.17 vs. 80.29+/-0.06%, P<0.01). Radioactive microspheres confirmed these results (254+/-44 vs. 106+/-9.5 ml/min/100 g, P<0.01). Oxygen uptake was similar. Ammonia uptake was more than twofold higher in the VP+NH(3) group. A V(1) antagonist negated the higher mean arterial pressure (MAP) that occurs with VP but cerebral hyperemia still occurred. A V(2) antagonist resulted in similar systemic pressures, CBF and brain water compared to the VP+NH(3) group. CONCLUSIONS: In this model, an increase in CBF with VP hastens the development of brain edema while increasing ammonia delivery to the brain.

Ammonia↗
PubMed2003

A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial.

Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V(2) receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V(2) receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P <.05) and serum sodium (P <.05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use.

Aldosterone↗
PubMed2003

Dual-echo, chemical shift gradient-echo magnetic resonance imaging to quantify hepatic steatosis: Implications for living liver donation.

In living liver donation, a fatty liver poses risks for both recipient and donor. Currently, liver biopsy is the standard for assessing the presence and extent of steatosis. The goals of this study were to correlate a steatosis index derived from magnetic resonance imaging (MRI) to the histologic grade on biopsy as well as to determine the topographic distribution of steatosis within the liver. We examined the ability of dual-echo, chemical shift gradient-echo MRI to predict the degree of steatosis on liver biopsy. A total of 22 subjects received both a liver biopsy and detailed MRI evaluation. These individuals included 15 potential living donors and 7 patients with nonalcoholic fatty liver disease. MRI steatosis index was then compared with histologic grade on liver biopsy. The topographic distribution of hepatic steatosis was determined from those subjects in whom MRI detected hepatic steatosis. The steatosis index had a positive correlation with grade of steatosis on liver biopsy (correlation coefficient, 0.84). There was no significant variation in the degree of steatosis among segments. A steatosis index of >0.2 had good positive and negative predictive value for the presence of significant steatosis (>15%) on biopsy. Our quantitative MRI protocol can predict the degree of hepatic steatosis when it is minimal to moderate, and may obviate the need for liver biopsy for the purpose of quantification of steatosis in living donors. Fat saturation added to the MRI protocol may further improve diagnostic accuracy. This technique may be applicable to the larger population with hepatic steatosis.

Adult↗
PubMed2003

Pathogenesis of hepatic encephalopathy in acute liver failure.

Hepatic encephalopathy (HE) in acute liver injury signifies a serious prognosis. Brain edema and intracranial hypertension are major causes of death in this syndrome. Comparison of HE in acute liver failure (ALF) with that of cirrhosis allows recognition of important differences and similarities. A key role for ammonia in the pathogenesis of both HE and brain edema is now firmly supported by clinical and experimental data. Additional factors, such as infection, products of the necrotic liver, and synergistic toxins, may contribute to an altered mental state. A low plasma osmolarity, high temperature, and both high and low arterial pressure may affect brain water content. A combined derangement of cellular osmolarity coupled with cerebral hyperemia can explain the development of brain edema in ALF. Increasingly, study of the mechanisms responsible for brain swelling provides critical information for understanding the pathogenesis of HE.

Ammonia↗
PubMed2002

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.

BACKGROUND: Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition. OBJECTIVE: To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure. DESIGN: Prospective cohort study. SETTING: 17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group. PATIENTS: 308 consecutive patients with acute liver failure, admitted over a 41-month period. MEASUREMENTS: Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission. RESULTS: 73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not. CONCLUSIONS: Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.

Acetaminophen↗
PubMed2002

GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of portacaval shunted rats.

Identifying the gene expression changes induced by hepatic encephalopathy (HE) leads to a better understanding of the molecular mechanisms of HE-induced neurological dysfunction. Using GeneChip and real-time PCR, the present study evaluated the gene expression profile of rat cerebral cortex at 4 weeks after portacaval shunting. Among 1,263 transcripts represented on the chip, mRNA levels of 31 transcripts were altered (greater than twofold; 16 increased and 15 decreased) in the portacaval shunted (PCS) rat compared to sham control. Changes observed by GeneChip analysis were confirmed for 20 transcripts (8 increased, 7 decreased, and 5 unchanged in PCS rat brain) by real-time PCR. Neurotransmitter receptors, transporters, and members of the second messenger signal transduction are the major groups of genes altered in PCS rat brain. Of importance was that the increased heme oxygenase-1 and decreased Cu,Zn-superoxide dismutase expression observed raise the possibility of oxidative stress playing a pathogenic role in chronic HE.

Animals↗
PubMed2002

Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.

Research on hepatic encephalopathy is hampered by the imprecise definition of this disabling complication of liver disease. Under this light, the Organisation Mondiale de Gastroentérologie commissioned a Working Party to reach a consensus in this area and to present it at the 11th World Congress of Gastroenterology in Vienna (1998). The Working Party continued its work thereafter and now present their final report. In summary, the Working Party has suggested a modification of current nomenclature for clinical diagnosis of hepatic encephalopathy; proposed guidelines for the performance of future clinical trials in hepatic encephalopathy; and felt the need for a large study to redefine neuropsychiatric abnormalities in liver disease, which would allow the diagnosis of minimal (subclinical) encephalopathy to be made on firm statistical grounds. In the interim, it proposes the use of a psychometric hepatic encephalopathy score, based on the result of 5 neuropsychologic tests. Finally, the need for a careful evaluation of the newer neuroimaging modalities for the diagnosis of hepatic encephalopathy was stressed.

Clinical Trials as Topic↗
PubMedDate not supplied

Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy and brain edema are important complications in the course of a patient with acute liver failure. Presumed unrelated for many years, increasing evidence suggests that an increase in brain water is seen in all forms of hepatic encephalopathy. Ammonia, traditionally linked to the pathogenesis of hepatic encephalopathy, plays an important role in the increase in brain water. In acute liver failure, an osmotic disturbance in the astrocyte, in combination with an alteration of cerebral blood flow results in overt brain edema and intracranial hypertension. In cirrhosis, magnetic resonance techniques indicate the presence of a brain osmotic disturbance. Several clinical factors modulate the development of brain swelling.

Ammonia↗