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PubMed2005

Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure.

The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of the PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway in mediating insulin's actions in the liver, we employed CRE recombinase/loxP technology to generate L(liver)-PDK1-/- mice, which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver. The L-PDK1-/- mice were not insulin-intolerant, possessed normal levels of blood glucose and insulin under normal feeding conditions, but were markedly glucose-intolerant when injected with glucose. The L-PDK1-/- mice also possessed 10-fold lower levels of hepatic glycogen compared with control littermates, and were unable to normalize their blood glucose levels within 2 h after injection of insulin. The glucose intolerance of the L-PDK1-/- mice may be due to an inability of glucose to suppress hepatic glucose output through the gluconeogenic pathway, since the mRNA encoding hepatic PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase) and SREBP1 (sterol-regulatory-element-binding protein 1), which regulate gluconeogenesis, are no longer controlled by feeding. Furthermore, three other insulin-controlled genes, namely IGFBP1 (insulin-like-growth-factor-binding protein-1), IRS2 (insulin receptor substrate 2) and glucokinase, were regulated abnormally by feeding in the liver of PDK1-deficient mice. Finally, the L-PDK1-/- mice died between 4-16 weeks of age due to liver failure. These results establish that the PDK1 signalling pathway plays an important role in regulating glucose homoeostasis and controlling expression of insulin-regulated genes. They suggest that a deficiency of the PDK1 pathway in the liver could contribute to development of diabetes, as well as to liver failure.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1996

The management of abnormalities of hemostasis in acute liver failure.

The liver is the primary site of synthesis of most coagulation and fibrinolytic proteins, and also plays a role in the clearance of hemostasis factors and their degradation products. In acute liver failure, these functions are severely disturbed, and the risk of hemorrhage is increased. Following a brief summary of the physiology of hemostasis, this review describes the nature and frequency of hemostatic abnormalities in acute liver failure. These abnormalities include quantitative and qualitative platelet defects, impaired synthesis and clearance of the coagulation factors and related inhibitory proteins, and enhanced fibrinolysis. Disseminated intravascular coagulation may also play a role, although this syndrome is difficult to distinguish from changes due to the failure of hepatic synthesis and clearance alone. At present, management options are limited to support with blood products, although pharmacological manipulation of the coagulation and fibrinolytic systems represent a potential area for future study.

Blood Coagulation Disorders↗
PubMed1993

Cerebral metabolic and histological effects of thioacetamide-induced liver failure.

Acute liver failure was induced in rats by successive administrations of thioacetamide over 3 days. At progressing stages of hepatic encephalopathy (HE), brains were fixed with microwave irradiation for analysis of metabolite levels or with formaldehyde for histopathological analysis. Metabolite levels were determined using 1H-nuclear magnetic resonance spectroscopy of perchloric acid extracts of the frontal cortex, parietal or occipital cortex, hippocampus, striatum, brain stem, and cerebellum. After thioacetamide treatment, thioacetamide and its metabolites were detected in the brains at levels that did not correlate with the stage of HE. No changes were observed in the levels of N-acetylaspartate, alanine, gamma-aminobutyric acid, aspartate, or inositol in any brain region after thioacetamide treatment. HE was accompanied by elevated glutamine, glucose, and lactate throughout the brain. At all stages of HE, taurine was decreased in the neocortex and hippocampus, and glutamate and choline compounds were decreased in the frontal cortex. None of the metabolite changes showed progression with the stage of HE. Progressing HE was accompanied by increasing neuronal injury in layer III of the neocortex, in the Purkinje cells of the cerebellum, and in the hippocampus, particularly in the CA4 sector. The similarity of this distribution of injury to that associated with excitotoxic injury suggests that metabolic abnormalities after acute hepatic failure may give rise to adverse effects at excitatory (glutamatergic) neuronal receptors, leading to neuronal injury and clinical symptoms of progressing encephalopathy in this model. However, neuronal injury and the presence of thioacetamide and its metabolites in the brain raise questions about the validity of thioacetamide-induced liver failure as a model for clinical HE.

Animals↗
PubMed2006

Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure.

Acute liver failure (ALF) is consistently accompanied by alterations in brain energy metabolites and recent nuclear magnetic resonance (NMR) studies suggest disturbances in brain oxidative metabolism in experimental ALF. Glucose transport across the blood-brain barrier is essential to sustain brain energy metabolism and is accomplished by the facilitative glucose transporter GLUT1. To investigate alterations in brain glucose uptake in acute liver failure further, GLUT1 expression and [14C]-2-deoxy-D-glucose uptake were measured in the brains of rats with hepatic devascularization. RT-PCR and Western blot analyses showed significant increases in steady-state levels of GLUT1 mRNA and protein in frontal cortex as early as 6 h following hepatic devascularization, (prior to the onset of brain edema and encephalopathy) which remained elevated at coma stages of encephalopathy. Expression of the astrocytic (45-kDa) and endothelial (55-kDa) forms of GLUT1 was increased as a result of hepatic devascularization. Exposure of cultured astrocytes to pathophysiologically relevant concentrations of ammonia resulted in increased GLUT1 expression, suggesting that elevated ammonia levels are responsible for GLUT1 upregulation in ALF. Increased GLUT1 expression in ALF was selective, since expression of the neuronal glucose transporter GLUT3 and other glucose-regulated proteins (GRP-78 and GRP-94) was unaltered. [14C]-2-deoxy-D-glucose autoradiography revealed increases in cerebral glucose uptake following the induction of GLUT1 in ALF. These results suggest that ammonia-induced increases of GLUT1 expression resulting in increased cerebral glucose uptake occur in ALF and could contribute to the pathophysiological mechanisms responsible for the neurological complications of this condition.

Ammonia↗
PubMed1998

[Progress of acute liver failure and indications for liver transplantation].

OBJECTIVE: To analyse the course of acute liver failure and the indications for liver transplantation. PATIENTS AND METHODS: In 16 patients who developed acute liver failure between July 1992 and July 1997 the indications for liver transplantation and total survival time were analysed retrospectively. RESULTS: Intensive medical care (ventilation, dialysis) was necessary in 60% of the patients to bridge organ failure until liver transplantation. In 14 patients liver transplantation was indicated. Eleven of the patients, with a minimal Quick value of less than 10%, presented with the prognostically poorest London criteria. In two patients the combination of three additional criteria of the London classification led to liver transplantation being indicated. In one patient with Wilson's disease the transplantation was undertaken despite good clotting factor synthesis, because an encephalopathy occurred. In two patients liver transplantation was not undertaken even though indicated, in one because liver functions improved, in the other because necrotizing pancreatitis had occurred. In another patient, who had been poisoned by eating the mushroom Amanita phalloides, the attempted transplantation was cut short, because intestinal necrosis had developed, and the patient died during the operation. Nine of the eleven patients who had a transplantation and three of the four treated conservatively survived. CONCLUSION: The 60-day survival rate in this series, achieved in a recently established transplantation programme, is high (12 of 16; 75%), being comparable to those in larger transplantation centres.

Adult↗
PubMedDate not supplied

Systematic analysis of the effects of hepatocyte transplantation on rats with acute liver failure.

BACKGROUND/AIMS: Acute liver failure either after liver resection or as part of underlying liver disease is still associated with high mortality. Hepatocyte transplantation in various forms has attracted attention recently. However, none of those reports have investigated the thorough and systematic analysis of effect of hepatocyte transplantation on acute liver failure induced by 90% hepatectomy. Therefore, we investigated systematic analysis of effect of hepatocyte transplantation on rats with acute liver failure. METHODOLOGY: Male Sprague-Dawley rats were used. Group I rats (n = 26) received intrasplenic injection of 2 x 10(7) hepatocytes in 0.3 mL Dulbecco's modified Eagle's medium (DMEM) 24 hours prior to 90% hepatectomy. Group II rats (n = 24) received intrasplenic injection of DMEM only. Twenty-two rats from group I and 20 from group II were observed for the determination of survival time. The remaining 8 (4/each group) rats were used to assess the liver function and regeneration. RESULTS: The hepatocyte bearing spleen revealed active glucose-6-phosphatase activity. In group I rats, the survival was longer and that group had more long-term survivors than those of group II controls. In group I, there was significant increase in the ratio of weight of remnant liver lobes to body weight. At 24 hours after hepatectomy, group I rats had improved biochemical parameters compared to those of group II rats. CONCLUSIONS: In rats with acute liver failure, intrasplenic hepatocyte transplantation acts as a bridge to support experimental rats from acute liver failure to liver regeneration, prolong survival in rats with acute liver failure and improve biochemical parameters.

Animals↗
PubMed1977

Hepatocellular transplantation in acute liver failure.

Acute liver failure carries a high rate of mortality, but if metabolic support can be maintained for a critical period, liver healing and recovery are possible. Current techniques of temporary hepatic support are cumbersome and inconsistently effective. We studied the ability of dispersed hepatocytes to provide metabolic support when transplanted to rats with liver failure induced by dimethylnitrosamine (DMNA), a rapidly metabolized agent that is selectively toxic to liver cells. DMNA (20 mg/kg) was administered intravenously to 92 Lewis rats. Animals were divided into four groups receiving the following treatments 24 hours after DMNA administration: group I-intraperitoneal transplantation of hepatocytes prepared from 2.0 gm of normal isologous rat liver; group II-infusion into the portal vein of hepatocytes prepared from 1.5 gm of liver; group III-infusion of saline into the portal vein; group IV-no further treatment. The percentages surviving in each group 3 weeks after DMNA administration were 63%, 71%, 17%, and 6%, respectively. Mean serum glutamic oxaloacetic transaminase (SGOT) levels 3 days after DMNA administration were similar in the four groups, indicating that the degree of liver damage was equivalent. A significantly higher proportion of hepatocyte treated rats survived. Liver histology after DMNA administration showed hemorrhagic central lobular necrosis. A return to near-normal architecture occurred by 3 weeks in surviving animals. In group II hepatocytes were seen in portal venules, sinusoids, and central veins. We conclude that dispersed hepatocytes, transplanted either intraperitoneally or via the portal vein, can provide sufficient metabolic support to allow for recovery from drug-induced hepatic necrosis.

Acute Disease↗
PubMed1985

Hepatic Hodgkin's disease simulating cholestatic hepatitis with liver failure.

Fulminant liver failure is an unusual complication that may be seen in patients with hepatic infiltration by non-Hodgkin's lymphomas and leukemias. In such cases, hepatomegaly, marked abnormalities of serum liver function tests, and lactic acidosis may simulate severe viral, alcoholic, or drug hepatitis. We describe the clinical presentation of severe cholestatic hepatitis with liver failure in a patient who was found to have widespread liver involvement by Hodgkin's disease at autopsy. The major histologic findings included extensive portal and periportal Hodgkin's infiltrates, associated loss of periportal liver cells, and variable damage to small bile ducts.

Aged↗
PubMed1984

Fibronectin and factor VIII-related antigen in liver cirrhosis and acute liver failure.

The liver is involved in the turnover of fibronectin in two different ways: hepatic synthesis contributes substantially to the plasma fibronectin pool, while Kupffer-cells, performing an important role of the reticuloendothelial system, remove fibronectin opsonized material from the circulation. In 45 patients with histologically confirmed liver cirrhosis and six patients with acute liver failure due to intoxication we determined fibronectin concentration in plasma by electroimmunoassay and additionally measured factor VIII-related antigen, which is a large glycoprotein not synthesized in the liver. Fibronectin levels in plasma were decreased in liver cirrhosis. This decrease was correlated with the extent of porto-caval collateral circulation. Very low levels were found in patients with acute liver failure. Factor VIII-related antigen levels were greatly increased as a function of the hepatic insufficiency. Between both parameters there was a significant inverse correlation. It is concluded that the simultaneous determination of both proteins provides reliable information about the remaining liver function.

Acute Disease↗
PubMed2002

Serum bile acids in patients with liver failure supported with a bioartificial liver.

BACKGROUND: Serum bile acids are increased in liver failure, but the composition of the bile acid pool in this condition has not been studied in detail. This information is of interest because of dihydroxy bile acid toxicity. METHODS: We measured serum bile acids by gas chromatography-mass spectrometry in 13 patients with fulminant liver failure and five patients with acute-on-chronic liver failure. Furthermore, serum bile acids were analysed in the same patients after 6 h of treatment with a bioartificial liver, consisting of a hollow-fibre cartridge with microcarrier-attached porcine hepatocytes and a charcoal column. RESULTS: Pre-bioartificial liver serum bile acids demonstrated a high dihydroxy/trihydroxy ratio and were higher in patients with acute-on-chronic liver failure than in those with fulminant liver failure (452.8 +/- 98.6 vs. 182.1 +/- 39.7 micro mol/L; P < 0.05). Bioartificial liver treatment decreased significantly serum bile acids in patients with fulminant liver failure (-38.8%) and acute-on-chronic liver failure (-35.8%), with a decreased dihydroxy/trihydroxy ratio. In vitro, porcine hepatocytes in the bioreactor cleared most conjugated bile acid species from pooled patient plasma. CONCLUSIONS: Acute liver failure is associated with very high serum levels of toxic bile acids that could contribute to the pathogenesis of the syndrome. Bioartificial liver treatment reduces both serum bile acid concentrations and the hydrophobicity of the bile acid pool.

Adolescent↗
PubMed2004

[Mechanism of liver failure after hepatectomy].

Liver failure after hepatectomy is caused by many factors such as excessive hepatectomy, ischemic-reperfusion injury, postoperative infection, etc. However, apoptosis of hepatocytes is the most important event in the molecular mechanism of liver failure. Liver failure after excessive hepatectomy is characterized by increased apoptosis of hepatocytes and diminished liver regeneration. The former is induced by hypercytokinemia and hyperendotoxemia, and the latter is caused by cell cycle arrest. In ischemic-reperfusion injury of the liver, the apoptosis of hepatocytes is caused by activation of the MMPT and calpain system that are induced by the intracellular accumulation of Ca. The possible mechanism of liver failure in cases with persistent infection is the inhibition of liver regeneration and the induction of apoptosis of hepatocytes due to transforming growth factor-beta 1. The knowledge of these mechanisms will lead to prompt and appropriate treatments for individual patients.

Animals↗
PubMed2002

Acute fatty liver of pregnancy and acetaminophen toxicity leading to liver failure and postpartum liver transplantation. A case report.

BACKGROUND: Acute fatty liver of pregnancy is a rare entity. A MEDLINE English-language search from 1966 to the present revealed no reports of acetaminophen toxicity and acute fatty liver in pregnancy. CASE: An 18-year-old, African American woman, gravida 1, presented at 33 weeks' gestation with signs and symptoms consistent with acute fatty liver of pregnancy and fetal death. Markedly elevated transaminases prompted a search for other etiologies, and acetaminophen toxicity was diagnosed. Liver biopsy revealed acute fatty liver of pregnancy and toxin-induced injury consistent with acetaminophen use. The patient's condition deteriorated, resulting in fulminant hepatic failure and requiring postpartum orthotopic liver transplantation. CONCLUSION: The combination of acute fatty liver of pregnancy and acetaminophen toxicity resulted in acute liver failure. Attention to clinical and biochemical parameters can lead to diagnosis and management.

Acetaminophen↗
PubMed1998

Review article: the management of acute liver failure.

Acute liver failure (ALF) is a relatively uncommon but dramatic clinical syndrome with high mortality rates, in which a previously normal liver fails within days or weeks. Paracetamol overdose remains the major cause of ALF in the UK, while viral hepatitis is the commonest cause world-wide. Cerebral oedema is the leading cause of death in patients with ALF. Despite advances in intensive care and the development of new treatment modalities, ALF remains a condition of high mortality best managed in specialist centres. Orthotopic liver transplantation is the only new treatment modality that has made a significant impact in improving outcome. Bioartificial liver support systems and hepatocyte transplantation are new promising treatment options that may change the management of ALF in the future.

Animals↗
PubMed2003

[Liver replacement therapy. Reliable indications in acute liver failure].

Extracorporeal liver support devices aim at improving the therapeutical options for liver failure. Numerous artificial and bioartificial devices have been tested to reduce the high mortality of this dynamic disease. In particular, the detoxification function of the liver should be upheld, by means of a number of different procedures, either until liver function is restored or until transplantation. Both purely artificial, machine-based procedures including different forms of dialysis and hemoadsorption as well as bioartificial procedures based on hepatocytes are being tested, as are different types of extracorporeal liver perfusion. This paper provides an overview of the different methods and devices and their clinical evidence in order to give a recommendation for the handling of the expensive devices. There is no current indication for the application of liver support devices outside of clinical studies at specialised centres.

Exchange Transfusion, Whole Blood↗
PubMed2026

Admission Gut and Plasma-Derived Signatures Associated With Severity and 90-day Outcome in Hepatitis A-Related and Drug-Induced Acute Liver Failure.

Acute liver failure (ALF) due to hepatitis A (ALF-A) has high mortality, but admission-day markers associated with disease severity and outcome are unknown. We aimed to define gut microbiome and plasma multi-omics signatures associated with severity and 90-day outcomes in ALF-A, compared to drug-induced ALF (ALF-D) as non-viral ALF group. ALF patients (aged 26&#x2009;&#xb1;&#x2009;9&#x2009;years; 50.7% male, 49.3% female) with IgM HAV positive (ALF-A, n&#x2009;=&#x2009;33), ALF-D (n&#x2009;=&#x2009;38) were recruited along with acute viral hepatitis (AVH-A, n&#x2009;=&#x2009;27) and healthy subjects (HC, n&#x2009;=&#x2009;20). Stool bacteria profiling was done at D0; plasma cytokines, metabolites and barrier markers were analysed at D0, 3, 5, 7. Correlations with clinical severity parameters were assessed. Associations with 90-day mortality were assessed using severity-adjusted association analyses. ALF-A patients were more severe at the time of admission than ALF-D. In ALF-A, 90-day mortality was 33% versus 18.4% with increased severity scores like KCH 21% versus 10.5%, SOFA score 7.97&#x2009;&#xb1;&#x2009;2.89 versus 5.87&#x2009;&#xb1;&#x2009;2.32, SIRS 60.6% versus 18.4%, mechanical ventilation 39% versus 21%. At D0, ALF-A was enriched for lactate/ammonia/bile salt hydrolase/histamine-producing pathobionts like Enterococcus, Ruminococcus gnavus, Flavonifractor, Thomasclavelia correlating positively with severity (|r|&#x2009;>&#x2009;0.4, p&#x2009;<&#x2009;0.05) showing higher baseline abundance in ALF-A non-survivors (NS). At D0 in ALF-A, histamine accumulation, reduced tryptophan, butyrate metabolism inversely correlated with severity and worsened in ALF-A_NS by D7. Pro-inflammatory cytokines, IFABP2 were elevated at Day 0 in ALF-A, correlated positively with severity, and remained increased through Day 7 in ALF-A_NS. In contrast, ALF-D_NS retained commensals, showed increased fatty acid, bile acid biosynthesis with low levels of pro-inflammatory cytokines. In ALF-A, gut and plasma integrated multi-omics features were associated with disease severity, 90-day outcomes and identified candidate biomarkers for future validation.

Humans↗
PubMed2005

Anaplastic T-cell lymphoma presenting as fatal acute liver failure.

Acute liver failure (ALF) is an uncommon manifestation of liver disease and constitutes a medical emergency for which early identification is necessary. Hepatic involvement by hematologic malignancies although frequent, rarely causes severe hepatic dysfunction. Even more, acute hepatic failure as the first manifestation of a hematologic malignancy is extremely uncommon, although some cases have been reported in the literature. We describe the case of a 61 y/o puertorrican veteran who developed acute hepatic failure secondary to massive infiltration of the liver by a recurrent non-Hodgkin's lymphoma.

Fatal Outcome↗