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Acute liver failure (ALF) is a rare condition characterized by the development of encephalopathy in the absence of chronic liver disease. Cerebral edema occurs in up to 80% of patients with Grade IV encephalopathy. In the current prospective randomized controlled clinical trial, we examined the effect of induced hypernatremia on the incidence of intracranial hypertension (IH) in patients with ALF. Thirty patients with ALF and Grade III or IV encephalopathy were randomized. Patients in Group 1 (n = 15) received the normal standard of care. Patients in Group 2 (n = 15) received standard care and hypertonic saline (30%) via infusion to maintain serum sodium levels of 145-155 mmol/L. Intracranial pressure (ICP) was monitored in all patients with a subdural catheter (Camino Systems, San Diego, CA) for up to 72 hours after inclusion. Serum sodium levels became significantly different from the levels observed in the control group at 6 hours (P <.01). Over the first 24 hours, norepinephrine dose increased relative to baseline in the control group (P <.001; 13 patients) but not in the treatment group. ICP decreased significantly relative to baseline over the first 24 hours in the treatment group (P =.003; 13 patients) but not in the control group. The incidence of IH, defined as a sustained increase in ICP to a level of 25 mm Hg or greater, was significantly higher in the control group (P =.04). In conclusion, induction and maintenance of hypernatremia can reduce the incidence and severity of IH in patients presenting with ALF.

SEN virus (SENV) has been tentatively linked to transfusion-associated non-A-E hepatitis. We investigated SENV's role in unexplained hepatitis in other settings. Polymerase chain reaction amplification was used to detect 2 SENV variants (SENV-D and SENV-H) in 1706 patients and control subjects. SENV was detected in 54 (22%) of 248 patients with acute or chronic non-A-E hepatitis, 9 (35%) of 26 patients with hepatitis-associated aplastic anemia, and 0 of 17 patients with cryptogenic acute liver failure, compared with 150 (24%) of 621 control subjects with liver disease and 76 (10%) of 794 healthy control subjects. When controlling for geographic region, the prevalence of SENV among case and control subjects was not significantly different. The severity of acute or chronic hepatitis A, B, or C was not influenced by coexisting SENV infection. No etiological role for SENV in the cause of cryptogenic hepatitis could be demonstrated.

Introduction: Reperfusion injury and hepatic artery thrombosis are major causes of graft failure after liver transplantation. The magnitude of oxidative stress increases after reperfusion and the appearance of an arterial thrombosis presents a higher risk for the graft and patient survival., Aim of the Study: The aim of the study was to detect the level of oxidative stress in the perioperative period of transplantation., Methods: Clinical documentations of 32 patients were investigated and the level of myeloperoxidase (MPO) was measured for the monitoring of the oxidative stress., Results: The mean age of the patients was 43 years and hepatitis C cirrhosis was the most common indication (14 cases, 43%). Two retransplantations were done. In 24 cases (75%) the primary graft functions and patient survival were good. Eight patients died, in two cases because of acute liver failure, in two cases due to primary non function and in four cases due to late complications. The incidence of hepatic artery thrombosis was 11% (4 cases) and the incidence of acute rejection was 35% (12 cases). The level of MPO was higher (65 ng/ml) in all patients before operation. After the first 48 hours this level increased significantly (p < 0.0001) up to the mean level of 123 ng/ml and decreased after one week. In the cases with acute liver failure and hepatic artery thrombosis high levels of MPO were measured., Conclusion: This study provides evidence of increased oxidative stress before liver transplantation. The magnitude of these changes increased after operation, mostly in cases with acute liver failure and hepatic artery thrombosis. Reducing the reperfusion injury and performing an "ideal" arterial supply for the liver-graft present better survival.

Acute liver failure (ALF) is a rare condition in the United Kingdom. Comprehensive supportive intensive care of extra-hepatic organ failure and the early recognition of and use of transplantation for those who will not survive form the cornerstone of its management. Over the last 30 years there has been a reduction in the proportion of cases resulting from viral and seronegative hepatitis, and a progressive rise in those resulting from severe acetaminophen-induced hepatotoxicity. The latter cases mostly result from deliberate self-poisoning and formed the major cause of ALF hospital admissions and indication for emergency liver transplantation. The increasing misuse of acetaminophen has paralleled a rise in sales and greater availability of the drug. Introduction of legislation to restrict sales of acetaminophen has been followed by a fall in hospital admissions resulting from self-poisoning, a 20% reduction in deaths, and a 50% fall in the number of patients undergoing emergency liver transplantation. The reduction in acetaminophen-related ALF has been paralleled by an increase in the number of transplants performed in ALF of nonacetaminophen etiologies.

In the last 5 years the use of a multicenter approach has helped to define acute liver failure (ALF) in the United States. Drug-related hepatotoxicity comprises more than 50% of cases of ALF, including acetaminophen toxicity (40%) and idiosyncratic drugs (approximately 12%). Nearly 20% of cases remain of unknown etiology. Outcome of ALF is determined by etiology; by the degree of hepatic encephalopathy present on admission; and by complications, principally infection. More than 43% survive without a transplant, 28% die, and 29% undergo liver transplantation. Liver support machines have had no impact on this condition to date. A trial of N-acetylcysteine for the treatment of ALF not related to acetaminophen toxicity is underway. Future research in ALF in the United States should focus on limiting the number of cases related to drugs, searching for causes of the indeterminate cases, and developing more effective temporary liver support.

Paracetamol overdose (POD) is a major clinical problem as the commonest cause of fulminant hepatic failure (FHF) in the UK and the USA. While the main loss of liver mass occurs following hepatocyte necrosis, hepatocyte apoptosis has also been reported to occur during paracetamol toxicity in murine liver. Hepatocyte apoptosis has not previously been identified in human liver and the significance of apoptosis in paracetamol toxicity is not known. In this study of paracetamol toxicity in human liver after POD, hepatocyte apoptosis was identified at time of liver transplantation or death and was associated with striking regenerative activity. The biological significance of apoptosis is unclear but the rates of apoptosis found (0.6%) could account for a significant loss of hepatic parenchyma. The stimulus for apoptosis is not known but it is unlikely to be induced directly by paracetamol since it is absent from serum at this time. The possibility that apoptosis may be induced by Kupffer cell activation with cytokine production is raised. Patients who develop FHF after POD have a poor prognosis, with few therapeutic options apart from liver transplantation; an understanding of the dynamics of liver regeneration and ongoing cell loss by apoptosis may allow the development of new therapies in these patients.

Objective: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia., Methodology: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia., Results: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long-term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function., Conclusions: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.

Background: Troglitazone was removed from the U.S. market because its use was associated with an increased risk of liver failure. We evaluated the clinical features of all cases reported to the Food and Drug Administration and estimated the duration and magnitude of the risk of liver failure associated with continued use of the drug., Methods: Data from cases of liver failure associated with troglitazone use were abstracted and analyzed. The extent of troglitazone use was determined from national marketing data, and the duration of use was estimated with data from a large, multistate, health care company. Survival analysis was performed to estimate monthly incidence rates and the cumulative risk of liver failure., Results: Ninety-four cases of liver failure (89 acute, 5 chronic) were reported. Of the acute cases, 58 (67%) were women and only 11 (13%) recovered without liver transplantation. Progression from normal hepatic functioning to irreversible liver injury occurred within 1 month in 19 patients who were indistinguishable clinically from the 70 patients who had an unknown time course to irreversibility, except for the post hoc observation that prior cholecystectomy was less common in those with rapid onset. The incidence of liver failure was elevated from the first through at least the 26th month of troglitazone use. Accounting for case underreporting, the number needed to harm from troglitazone use was between 600 to 1500 patients at 26 months., Conclusion: The progression to irreversible liver injury probably occurred within a 1-month interval in most patients, casting doubt on the value of monthly monitoring of serum aminotransferase levels as a means of preventing troglitazone-induced acute liver failure. The cumulative risk of hepatic failure increased with continued use.

Objectives: Viral hepatitis has previously been the major cause of acute liver failure (ALF) in the United States. We aimed to determine the incidence of viral hepatitis-related ALF and to compare the outcome and clinical and biochemical variables in patients with hepatitis A and B., Methods: A total of 354 patients with ALF from multiple centers were screened for possible acute viral etiology., Results: Forty-three patients (12.1% of all ALF cases) had acute viral hepatitis: hepatitis A (n = 16), hepatitis B (n = 26), and herpes simplex virus infection (n = 1). There was no difference between groups with regard to age, gender, body mass index, admission or peak coma grade, symptom duration, admission mean arterial pressure, temperature, or biochemical liver tests, creatinine, arterial pH, or rate of infections. Platelet count was significantly higher in hepatitis A patients than in hepatitis B patients. The transplantation-free (spontaneous) survival rate was significantly higher for hepatitis A patients (69%) than for hepatitis B patients (19%, p = 0.007), whereas the liver transplantation rate was higher in hepatitis B patients (62%) than in hepatitis A patients (19%, p = 0.017). Spontaneous survivors had significantly higher mean arterial pressure, higher platelet count, and lower AST/ALT ratio than patients who did not survive spontaneously., Conclusions: Viral hepatitis now comprises only one-eighth of all ALF cases in the United States. The marked difference in spontaneous survival between hepatitis A and B cannot be explained by the severity of hepatic dysfunction on admission but may rather be an inherent feature of the infections or a bias toward transplanting patients with hepatitis B.

Objective: Troglitazone, a thiazolidinedione antidiabetic agent, was withdrawn from the U.S. market in March, 2000, after 94 cases of acute liver failure (ALF) were reported with its use. Based on a literature review, the estimated background rate of hospitalization for idiopathic acute liver injury is 22 per million person-years and for idiopathic ALF, less than 1 per million person-years. This study was conducted to estimate the incidence rates of hospitalized idiopathic acute liver injury and ALF among troglitazone-treated patients., Methods: An observational retrospective inception cohort of patients treated with troglitazone was assembled using claims data from a large multistate health care organization. Patients with at least 90 days of health plan enrollment before their first troglitazone prescription between April, 1997 and December, 1998 were enrolled. Hospitalized cases of potential troglitazone-induced acute liver injury or ALF were identified from claims data based on International Classification of Diseases, 9th Revision, coding. Primary medical records were reviewed for case validation, and incidence rates of acute liver injury were calculated using person-years of troglitazone exposure as the denominator., Results: A total of 7568 patients contributed 4020 person-years of troglitazone exposure. Of these, five were hospitalized with acute liver injury attributed to the drug and not explained by other causes. Incidence rates (95% CI) per million person-years of acute idiopathic liver injury were as follows: hospitalization (n = 5), 1244 (404, 2900); hospitalized jaundice (n = 4), 995 (271, 2546); and ALF (n = 1), 240 (6.3, 1385)., Conclusions: Troglitazone use was associated with a marked increase in risk of hospitalized acute idiopathic liver injury and ALF.

Fungal infection is a common, serious and underestimated complication, which contributes significantly to high mortality in patients with acute liver injury. The features accounting for the incidence of fungal infection include defects of immune response, routine use of H2 antagonists, frequent use of broad-spectrum antibiotics and invasive monitoring. Clinical deterioration characterized by increasing coma grade after initial improvement, increasing prothrombin time, pyrexia unresponsive to antibiotics, renal failure and elevated white cell count make up the clinical picture of the disease which suggests coexistence of fungal infection in acute liver injury. Candida albicans is the principal etiological agent of fungal infection and this pathogen is frequently isolated from the respiratory tract within a week of admission. The mortality among untreated patients with acute liver injury complicated with mycotic infection reaches 100%. The early application of the specific treatment in cases suspected of mycotic infection in patients with liver injury could markedly reduce mortality in this group of patients.

Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international registry. One hundred and seventy six patients were analysed, main indications are acute-on-chronic liver failure (56%), acute liver failure (22%), primary graft dysfunction (15%), liver failure post liver surgery (4%) and miscellaneous (3%). The predicted survival within the first group based on a mean MELD score of 30.4 pts. and a mean Child score of 12.6 pts. was quite limited. The data suggest an improved survival accompanied by significant improvements of hepatic encephalopathy, mean arterial pressure, serum bilirubin level, creatinine, urea, albumin, INR, ammonia and MELD score. The results are confirming observations of other trials before which have shown MARS therapy to be an effective and safe extracorporeal liver support in liver failure.

Purpose: Analyze US rates of reported severe liver disease for the oral hypoglycemic agent troglitazone from March 1997 through February 2000 and the possible effects of publicity on reporting., Methods: The number of troglitazone reports with liver failure and or hospitalization with jaundice or hyperbilirubinemia, made to the FDA and/or Parke-Davis are used as numerators. The denominators are numbers of patients and person-time estimates of exposure. Additionally, the amount of publicity about troglitazone during its marketing is quantified., Results: Approximately 1.92 million patients were treated with troglitazone from March 1997 through the end of February 2000 resulting in 1.6 million person-years of exposure. Reports of 83 cases of liver failure associated with troglitazone were received (1 in 23,000 patients or 1 in 20,000 person-years). Of the 83 cases, only 49 (59%) were classified by a hepatologist to be 'possibly' or 'probably' attributed to troglitazone. For the first, second, and third years of marketing, rates of reported hepatic failure per 100,000 person years exposure to troglitazone were 8.3, 5.3, and 2.7 respectively. Rates of reported liver disease involving hospitalizations with mention of jaundice and hyperbilirubinemia per 100,000 person-years were 16.0, 6.1, and 3.6 respectively for these years. During the 3-year marketing history of troglitazone, there were 470 lay press and 158 medical literature articles with mentions of hepatotoxicity for the drug., Conclusions: Rates of reported severe liver disease declined substantially during the second and third years of marketing of troglitazone. The decline followed increasingly stringent requirements for liver function test monitoring and may have been due to improved patient selection and management as a result of the widely publicized association between troglitazone and hepatotoxicity.

The features in 21 patients with childhood hepatic failure studies retrospectively over a seven year period at the University of Calabar Teaching Hospital, Calabar, Nigeria are presented. Of the 21 patients, 71.4 per cent were aged three years nd below. Fulminant hepatic failure occurred in 81.0 per cent of the patients while in 19.0 per cent, the failure resulted from chronic liver disease. Hepatitis B infection alone or in association with other factors was the major cause of the condition, occurring in 76.2 per cent of the cases. The main complications were severe anaemia (23.8%), septicaemia (23.8%) and pneumonia (19.0%), renal failure (9.5%). With only one survival, the case fatality rate was 95.2 per cent. For prevention of the condition in Nigeria, universal mandatory screening of blood and blood products for hepatitis B markers before transfusion and the integration of hepatitis B vaccination into the National Expanded Programme on Immunization are strongly recommended.

In order to ascertain the clinical and epidemiological features of acute liver failure (ALF), we analyzed the clinical histories of 22 patients from La Plata city, with the diagnosis of ALF (prothrombin level or factor V below 50%) seen between November 1996 and November 2000. Age, sex, hepatic encephalopathy, reason for consultation, etiology, hepatic biochemical tests, serum creatinine, glycemia, digestive hemorrhage, course and treatment variables were analyzed. What is remarkable is the high frequency of the toxic etiology and of infection by HDV, as well as the high prevalence of ascites and the low incidence of hepatic encephalopathy. We think that the high survival rate we found is due to the early diagnosis and early referral of the patients to the intensive care unit and to centers with programs for liver transplantation.

Acute liver failure is a rare but potentially fatal disease. Adult definition of fulminant hepatic failure, which includes the development of hepatic necrosis and encephalopathy within 8 weeks of onset of liver disease does not apply to acute liver failure in children particularly if secondary to autoimmune or metabolic liver disease. The etiology of acute liver failure varies with the age of the child. In neonates, infection or an inborn error of metabolism are common, while viral hepatitis and drug induced liver failure are more likely in older children. The clinical presentation of acute liver failure includes jaundice, coagulopathy and encephalopathy. In neonates, encephalopathy may be subclinical. The management of acute liver failure includes assessment of prognosis for liver transplantation; prevention and treatment of complications while awaiting hepatic regeneration or a donor liver and hepatic support. The major complications of acute liver failure are sepsis, gastro-intestinal bleeding, cerebral edema, renal and cardiac failure. Selection for liver transplantation depends on the etiology of the disease, prognostic factors, the presence or absence of multisystem disease and/or reversible brain damage. Prognostic factors for survival are less well established in children than in adults but children with metabolic liver disease, prothrombin time > 50 seconds, rising bilirubin and falling transaminase, grade II or higher grade of hepatic coma indicate poor prognosis. Most children receive a reduced or split liver graft. Living related donations for acute liver failure are also carried out by some centres. Survival post liver transplantation for acute liver failure has improved and most recipients can expect a 70% five year survival.

Background/aims: Ecstasy is a synthetic amphetamine recently identified as a possible cause of acute liver injury. This drug is consumed by young people and has a marked effect on improving sociability. The extent of ecstasy-associated severe hepatic damage is unknown to date., Methods: The clinical histories of 62 patients with acute liver failure admitted to the Intensive Care Liver Unit between January 1994 and December 1996 were reviewed to assess the frequency, the epidemiological, clinical and histological characteristics and the outcome of ecstasy-induced severe hepatitis., Results: Over this period of time, five patients (8%) were admitted because of ecstasy-induced acute liver failure, representing 31% of the cases with drug hepatotoxicity. Ecstasy was the second most common cause of liver injury in patients under the age of 25 years, being 20% in this subset of patients and 36% after ruling out the cases of viral etiology. All the patients had severe liver disease of acute onset, with jaundice, high peak of serum transaminases activity, hypoglycemia and low prothrombin activity, but no hepatic encephalopathy. Full recovery was observed in all cases from 3 to 12 months., Conclusions: Ecstasy is responsible for a relatively high number of cases of acute liver failure in young people. Therefore, the use of this drug should be investigated in all patients with severe hepatitis of unclear origin. Efforts must be made to advise young people of the risks of ecstasy consumption.

Background: Preliminary reports indicate that hepatitis D virus (HDV) infection exists in India. However, its prevalence in patients with different types of liver diseases has not been studied in detail. The aim of this study was to evaluate the status of HDV infection in severe types of liver disease in India., Methods: Using commercial kits for various hepatitis viral markers, the present study was undertaken to determine the serological status of hepatitis B virus (HBV) and hepatitis D virus (HDV) markers in 208 patients with severe liver diseases. This total included 110 cases with fulminant hepatic failure (FHF), 65 cases with subacute hepatic failure (SHF) and 33 cases with chronic active hepatitis (CAH)., Results: The hepatitis B surface antigen (HBsAg) carrier population, indicated by the presence of HBsAg without IgM anti-HBc (hepatitis B core) in serum, was recorded in 23.6%, 24.6% and 60.6% cases of FHF, SHF and CAH groups, respectively. HBV infection, as indicated by serum positivity of IgM anti-HBc in the FHF and SHF groups and HBsAg and/or IgM anti-HBc in the CAH group, was detected in 19.1%, 23.1% and 69.7% of cases from these three groups, respectively. IgM anti-HDV, demonstrating active/recent HDV infection, was found in 8.1% cases of FHF and 9.2% cases of SHF patients. HDV as a superinfection in HBsAg carriers was noted in 4.5% and 4.6% cases, respectively of FHF and SHF groups. Similarly, HDV-HBV coinfection, diagnosed by simultaneous presence of IgM anti-HBc and IgM anti-HDV in the FHF and SHF groups, was recorded in 3.6% and 4.6% of cases from these two groups, respectively. In the CAH group, HDV infection was observed in 9.2% cases., Conclusion: HDV infection, recorded in less than 10% of patients with different liver diseases in India, seems to be an unimportant factor in inducing severe liver diseases in this country.

Infection with an identified hepatotrophic virus accounts for 13-50% of acute liver failure (ALF) in Europe, and an additional 16-17% of cases have non-A non-B or indeterminate hepatitis in whom a viral aetiology is presumed. Hepatitis C is rarely responsible for acute liver failure in Europe and North America but accounts for a higher proportion of cases in Japan, and hepatitis E may lead to ALF, particularly in pregnant women. The survival in cases of acute liver failure associated with hepatitis A is 70%, whereas less than 30% of those with non-A non-B hepatitis survive without a transplant. Management depends on intensive care support and careful selection of patients likely to benefit from transplantation. Recurrence of hepatitis A and non-A non-B hepatitis has been reported following transplantation for ALF, and hepatitis B recurs less frequently in these circumstances than after transplantation for chronic infection.

Objective: oxygen supply dependency at normal or high oxygen delivery rate has been increasingly proposed as a hallmark and a risk factor in critical illnesses. We hypothesized that as far as an adequate oxygen delivery is provided, oxygen consumption, when determined by indirect calorimetry, is not dependent on oxygen delivery in critically ill patients whereas calculated oxygen consumption is associated with artefactual correlation of oxygen consumption and delivery., Design: oxygen delivery, oxygen consumption and their relationship were analyzed prospectively. Metabolic data gained from both measured and calculated methods were obtained simultaneously before and after volume loading., Setting: the study was completed in the intensive care unit as part of the management protocol of the patients., Patients: 32 consecutive patients entered the study and were divided into 3 groups according to a clinical condition known to favour oxygen supply dependency: sepsis syndrome, adult respiratory distress syndrome and acute primary liver failure., Intervention: the rise in oxygen delivery was obtained by colloid infusion (oxygen flux test) performed in hemodynamically and metabolically stable patients. All were mechanically ventilated. No change in therapy was allowed during the test., Measurements and Results: oxygen consumption was simultaneously evaluated by calculation (Fick Principle) and direct measurement using indirect calorimetry. Oxygen delivery was derived from the cardiac output (thermodilution) and arterial content of oxygen. Oxygen supply dependency was considered while observing an increase in oxygen delivery greater than 45 ml/min.m2. Irrespective of patient's clinical diagnosis and outcome, measured oxygen uptake remained unaltered by volume infusion whereas both oxygen delivery and calculated oxygen consumption increased significantly. Arterial lactate level > 2 mmol/l and measured oxygen extraction ratio > 25% failed to identify oxygen supply dependency when measured data were considered., Conclusion: analysis of oxygen uptake, when measured by indirect calorimetry, failed to substantiate oxygen supply dependency in the vast majority of the critically ill patients irrespective of diagnosis and outcome. Mathematical coupling of shared variables accounted for the correlation between oxygen delivery and calculated oxygen consumption.

Liver transplantation has evolved as the therapy of choice in end-stage liver disease. However, liver transplantation for viral liver disease is associated with recurrence of viral hepatitis in the graft. In this paper we discuss the mechanisms of liver cell damage, the clinical impact of recurrent infection and the use of hepatitis-B-specific immunoglobulin (HBIg) to prevent recurrent infection in the allograft. In addition, we propose an HBIg schedule tailored to each individual patient. Based on the excellent survival results published for acute hepatic failure and chronic liver failure with latent hepatitis B virus (HBV) or hepatitis delta infection, we think that no contraindication exists for liver transplantation in these cases. For patients with active viral replication, liver transplantation should only be considered within a scientific frame to prevent reinfection of the allograft.