SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Liver failure is a complication of viral hepatitis, as well as a consequence of acute mushroom or drug poisoning. The different therapies to be employed in a "pre emergency" state, or in case of "emergency" (resistant to medical treatment or starting as "fulminant" hepatic failure) are summarized. The percentage of survival, even by means of sophisticated treatment, does not overcome 30%.
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 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 ± 9 years; 50.7% male, 49.3% female) with IgM HAV positive (ALF-A, n = 33), ALF-D (n = 38) were recruited along with acute viral hepatitis (AVH-A, n = 27) and healthy subjects (HC, n = 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 ± 2.89 versus 5.87 ± 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| > 0.4, p < 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.
Liver failure and hepatic coma present with various clinical and morphological counterparts. While fulminant viral hepatitis is the most common cause of acute liver failure, liver cirrhosis with vascular bypass most often is responsible for the hepatic coma in chronic diseases. Prognosis is mainly determined by the extent of liver cell necrosis and regeneration, provided extrahepatic complications do not cause death. Prognosis can best be judged by stereology of liver biopsies and determination of the alpha-fetoprotein.
A randomised, un-blinded clinical trial of hydrocortisate treatment in acute liver failure was carried out by 17 European centres. During a four year period 40 patients entered the study, 26 in the steroid group and 14 in the control group. The groups were found to be comparable, and the survival was 12 and 14%, respectively. A number of clinical and laboratory data, particularly HBsAg-positivity, appeared to carry some prognostic information, irrespective of treatment, but statistical significance was not achieved. Pooling of the present results with those from relevant published reports indicates a significant negative effect of steroid treatment in acute liver failure (P less than 0.2).
1. The acid-base state of arterial blood and cerebrospinal fluid, and the ventilatory response to CO2, were measured in twelve patients with liver disease. The CO2 response was also measured in eight goats before and after the experimental production of liver failure. Arterial PCO2 and pH, cerebral blood flow and the cerebral metabolic rate for oxygen were also measured in four of the goats while they breathed air and various CO2-enriched gas mixtures. 2. Liver failure was accompanied by a respiratory alkalosis in both the patients and in the goats. Decreased PCO2 and increased pH occurred in the cerebrospinal fluid and in the arterial blood of the patients. 3. The slope of the ventilatory response to CO2 was reduced when liver failure was severe, in patients and goats alike. In addition there was a reduction in the extrapolated PCO2 at zero ventilation, even when liver failure was mild. 4. Cerebral blood flow and metabolic rate were consistently reduced in the goats during liver failure. There was also less cerebral vasodilatation and a greater reduction in cerebral metabolism during experimental hypercapnia when these animals were in liver failure. 5. The decreases in the ventilatory and cerebral circulatory responsiveness to CO2 indicate that the brain is less well defended against hypercapnia in liver failure, and these changes are especially unfavourable as cerebral function deteriorates when the PCO2 is increased.
An evaluation of therapeutic approaches in acute liver failure needs essentially experimental studies. Devascularization of the liver seems to be the superior form of liver damage induced by a variety of toxins. A perfusion circuit for extracorporeal pig liver perfusion was investigated. Oxygen utilization of the livers under experimental conditions proved to be the fastest and most reliable test of organ viability. In therapeutic use in devascularized pigs the survival time could be prolonged. Biochemical parameters were normalized or improved during a 2 hour perfusion. The method was of value in a 59 year old patient perfused for 9 1/2 hours with an isolated baboon liver. Controlled trials, however, seem to be necessary to evaluate each therapeutic method in acute liver failure in man.
Acute liver failure involves disturbances of all major organ systems. The pathophysiology of these disturbances are reviewed and details of management for each system is discussed in clinical work in a special Liver Failure Unit is used to derive principles of treatment, and the use of extracorporeal charcoal haemoperfusion is outlined.
1. The ventilatory responses to transient and steady-state hypoxia were measured in ten patients with hepatic cirrhosis and in ten healthy control subjects. Successive measurements of these responses were also obtained in six goats before and after the experimental production of liver failure. Changes in the effect of steady-state hypoxia on the ventilatory response to hypercapnia were evaluated by successive studies in another goat. 2. In spite of a respiratory alkalosis during liver failure, the response to transient hypoxia was greater in the patients than in the control subjects. This response was increased after the onset of liver failure in all the goats. 3. In healthy humans and goats the responses to transient and steady-state hypoxia were similar in magnitude. During liver failure there was a disparity between the size of these responses, since the ventilatory increment evoked by steady-state hypoxia was unchanged in spite of the increase in response to transient hypoxia. Steady-state hypoxia consistently enhanced the ventilatory response to hypercapnia in a healthy goat, but frequently depressed the response to hypercapnia during liver failure. 4. The findings suggest that liver failure heightens the sensitivity of the peripheral chemoreceptors to the hypoxic stimulus, but may increase the tendency of the medullary centres to become depressed in hypoxia.
The renal and cerebral blood flow was measured in six pigs after total devascularization of the liver. The animals died 21 to 26 h after the operation, with biochemical and electroencephalographic changes compatible with liver failure. The renal blood flow increased slightly, from 2.12 to 2.61 ml.g-1.min-1, throughout the period of observation but did not differ significantly from that of the controls. Conversely, the cerebral blood flow decreased 38%, from 1.30 to 0.80 ml.g-1.min-1, p less than 0.05. The results failed to confirm a simultaneous decrease in cerebral and renal blood flow due to false neurotransmitters in liver failure, as previously suggested. The results do not support the suggested hypothesis that a substance produced by the liver is essential for renal function and perfusion, nor can they confirm that vasoactive material from the gut is responsible for the renal hypoperfusion in liver failure. The absence of renal hypoperfusion in the present preparation might be due to the exclusion of the failing liver from the circulation, giving indirect evidence to the theory that the vasoactive agent(s) responsible for the renal hypoperfusion in liver failure originates in the failing liver itself.
Cerebral edema has now been noted to occur frequently in patients dying of fulminant hepatic failure. In the present study, intracranial pressure was monitored in an animal model of acute liver failure. Acute liver failure was induced surgically by hepatic devascularization. Serial monitoring of the electroencephalogram revealed progressive slowing of the frequency with decreasing amplitude. Elevation of the blood ammonia was also observed from baseline values of 64 +/- 12 SE to 744 +/- 97 mumol/liter. Monitoring of the intracranial pressure with a subdural pressure transducer demonstrated a progressive and reproducible rise from 12.8 +/- 2.5 mm Hg immediately after the operation to a mean value of 51.6 +/- 11.8 mm Hg just before death 6--12 hr later. At autopsy, the brains of the test animals were found to be swollen with flattened cortical gyri. In the control animals, intracranial pressure rose slightly but returned toward normal levels (8.0 +/- 2.5 mm Hg) 8 hr after laparotomy and remained normal until their death. There was a statistically significant difference between intracranial pressure levels of the test animals and those of the controls (P less than 0.01). Intravenous methylprednisolone (2.0 g initially followed by 0.5 g every 2 hr) administered immediately before and after hepatic devascularization prevented rises in intracranial pressure but had no effect when given 4 hr after operation. The early and progressive increase in intracranial pressure was an unexpected finding, and an assessment of such a sequence in patients with fulminant hepatic failure is currently in progress.
In three patients, the first manifestation of Wilson's disease was a syndrome in which acute intravascular hemolysis and acute liver failure were associated. This syndrome developed in three periods; the first, lasting 3 to 14 days, was characterized by fatigue, fever, and jaundice; the second, lasting 1 or 2 days, by severe intravascular hemolysis; and the third, lasting 2 to 6 days, by hepatic encephalopathy. All of the patients died from liver failure 7 to 21 days after the onset of the syndrome. The association of acute intravascular hemolysis and acute live failure is a characteristic manifestation of Wilson's disease; it is rarely associated with other liver diseases. This association might result from hepatic cell necrosis due to accumulation of copper, the consequences being acute liver failure and destruction of erythrocytes by the large amounts of copper released from the necrotic hepatic cells to the plasma.
Clinical experience of some newer methods of hepatic support is described. The results are unpredictable and far from satisfactory. The need for an animal model in which potential therapeutic methods can be studied is emphasized. Such a model based on carefully imposed ischaemic insult to the liver in the absence of portacaval shunting is described. It is suggested that bacterial presence in the bowel together with a depression of the liver reticuloendothelial function plays an important part in the early and rapid mortality of acute liver failure. Temporary auxiliary liver transplantation using an allograft or a closely related primate heterograft seem to be the 2 best available methods of hepatic support for potentially reversible acute liver failure.
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a high short-term mortality rate. Therefore, early and accurate prognostic prediction is crucial for precise clinical management. This study aims to investigate the expression patterns of intercellular adhesion molecule-1 (ICAM-1) and its predictive value for the short-term prognosis of patients with HBV-ACLF. The Methylight method was used to quantitatively detect ICAM-1 promoter methylation level in peripheral blood mononuclear cells (PMBCs) of 286 participants. Meanwhile, the mRNA and plasma expression levels of ICAM-1 were determined using RT-qPCR and ELISA, respectively. The ICAM-1 promoter methylation levels in PBMCs of HBV-ACLF patients were significantly lower than those in chronic hepatitis B (CHB) patients and healthy controls (HCs), whereas the mRNA and plasma expression levels of ICAM-1 were markedly elevated. The ICAM-1 methylation levels in HBV-ACLF patients correlated with specific clinical parameters. Among HBV-ACLF patients, ICAM-1 methylation levels were significantly lower in the non-survivor groups at both 28 and 90 days. The study further revealed that ICAM-1 methylation level serves as an independent influencing factor for the prognosis of HBV-ACLF patients at 28 and 90 days. Based on ROC curve and Kaplan-Meier curves, ICAM-1 methylation levels demonstrated excellent performance in predicting 28- and 90-day mortality in patients with HBV-ACLF. In conclusion, patients with HBV-ACLF exhibit hypomethylation of the ICAM-1 promoter. The combination of ICAM-1 promoter methylation level and MELD score can effectively enhance the predictive ability for the short-term prognosis of HBV-ACLF patients.
BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a poor prognosis. This research aimed to characterize the expression pattern and clinical value of Annexin A3 (ANXA3) in HBV-ACLF patients. METHODS: First of all, ACLF-related datasets were downloaded from the Gene Expression Omnibus (GEO) database to carry out bioinformatics analyses. RT-qPCR, ELISA, and Methylight were used to measure ANXA3 gene expression and promoter methylation levels. A validation cohort was leveraged to further validate the results. RESULTS: Transcriptome analysis showed that ANXA3 was among the most differentially expressed genes when comparing dead patients with HBV-ACLF to those with survivors. The mRNA and serum levels of ANXA3 were elevated, and methylation levels were decreased in HBV-ACLF patients. The PMR value of ANXA3 in patients with HBV-ACLF was negatively correlated with inflammation-related cytokines IL-6, TNF-α, and IL-1β, as well as quantitative clinical parameters AST, TBIL, PT, INR, NEUT%, and MELD score, and positively correlated with PTA (all p < 0.05). In HBV-ACLF patients, ANXA3 was considered to be an independent influence factor for the 90-day mortality. It was also found that ANXA3, especially hypomethylation, was associated with 28- and 90-day overall survival in patients with HBV-ACLF based on receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and Kaplan-Meier curves. CONCLUSIONS: ANXA3 hypomethylation has a prominent predictive value for short-term mortality in patients with HBV-ACLF and may serve as a promising biomarker of HBV-ACLF prognosis.
Two women, aged 41 and 51 years, developed jaundice, encephalopathy, and hypoprothrombinemia during rapid weight loss four and 12 months after jejunoileal bypass for refractory obesity. Both were treated for liver failure and received a prolonged course of nutrition parenterally and orally. Serial liver biopsy specimens demonstrated extensive alcoholic-like hepatitis and cirrhosis that improved with nutritional repletion and reanastomosis. Postoperative biopsy specimens later demonstrated minimal portal fibrosis in one patient and inactive mild cirrhosis in the other. Although previous reports indicate that patients usually die when they develop liver failure of this severity after jejunoileal bypass, prolonged intensive nutritional repletion was associated with sufficient clinical and histologic improvement in these two patients so that intestinal reanastomosis could be performed safely.
Albumin-coated Amberlite XAD-7 has been previously shown to be blood compatible in in vitro hemoperfusion experiments whith human blood. In this study, the preliminary results are reported on single hemoperfusions with albumin-coated XAD-7 resin in four patients with acute liver failure. The mean platelet count was 116+/-SE 16.3% of the initial arterial value and the mean white cell count was 96+/-SE 6.5% of initial at the end of four hours of hemoperfusion. Removal of bilirubin, phenols and substances in the middle molecular weight range by the resin was demonstrated. These preliminary results suggest albumin-coated Amberlite XAD-7 resin to be blood compatible and capable of removing protein-bound and middle molecular weight substances from patients with acute liver failure. Further clinical evaluation of repeated resin hemoperfusion is required to determine whether this treatment will be beneficial to patient survival.
The model of temporary complete liver ischemia was investigated in 60 pigs in order to produce a disease which resembles liver failure in man. The interval of time leading to death in every animal differed in a wide range. A number of biochemical alterations was of no value as for the prognosis of the animal under investigation. The ammonium in the peripheral blood is elevated during shunting of portal blood around the liver only. Microscopic examinations demonstrated that the damage produced is limited to the hepatic tissue. The lesions were less when ischemia was produced after a longer interval after the operation. The role of processes of regeneration and reparation of liver tissue is discussed.