Experimental models of hepatic encephalopathy: ISHEN guidelines.

Objectives of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Commission were to identify well-characterized animal models of hepatic encephalopathy (HE) and to highlight areas of animal modelling of the disorder that are in need of development. Features essential to HE modelling were identified. The best-characterized animal models of HE in acute liver failure, the so-called Type A HE, were found to be the hepatic devascularized rat and the rat with thioacetamide-induced toxic liver injury. In case of chronic liver failure, surgical models in the rat involving end-to-side portacaval anastomosis or bile duct ligation were considered to best model minimal/mild (Type B) HE. Unfortunately, at this time, there are no satisfactory animal models of Type C HE resulting from end-stage alcoholic liver disease or viral hepatitis, the most common aetiologies encountered in patients. The commission highlighted the urgent need for such models and of improved models of HE in chronic liver failure in general as well as a need for models of post-transplant neuropsychiatric disorders. Studies of HE pathophysiology at the cellular and molecular level continue to benefit from in vitro and or ex vivo models involving brain slices or exposure of cultured cells (principally cultured astrocytes) to toxins such as ammonia, manganese and pro-inflammatory cytokines. More attention could be paid in the future to in vitro models involving the neurovascular unit, microglia and neuronal co-cultures in relation to HE pathogenesis.

Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy.

OBJECTIVES: The grading of hepatic encephalopathy (HE) is based on a combination of indicators that reflect the state of consciousness, intellectual function, changes in behavior, and neuromuscular alterations seen in patients with liver failure. METHODS: We modified the traditional West Haven criteria (WHC) to provide an objective assessment of the cognitive parameters to complement the subjective clinical ratings for the performance of extracorporeal albumin dialysis (ECAD) using a molecular adsorption recirculating system in patients with cirrhosis and severe (grade III / IV) encephalopathy. The HE Scoring Algorithm (HESA) combined clinical indicators with those derived from simple neuropsychological tests,the latter more often used in milder grades of HE (I / II). The performance of each indicator was compared across grades and sites. RESULTS: Results of HESA were also compared with the Glasgow Coma Scale. A total of 597 evaluations were performed in patients randomized to ECAD plus standard medical therapy or the latter only. Most parameters exhibited significant separation between grades; the most effective indicators were lack of verbal, eye, and motor response (grade IV), somnolence and disorientation to place (grade III), and lethargy and disorientation to time (grade II). Two clinical and four neuropsychological indicators were useful to classify patients as grade I. The Glasgow Coma Scale differed among the four stages of the WHC, but the differences between grades I and II were small and not clinically useful. CONCLUSION: HESA extends the traditional WHC for grading HE. In the absence of a "gold" standard, the most useful indicators noted in this trial should be further validated.

The role of etiology in the hyperamylasemia of acute liver failure.

OBJECTIVES: Hyperamylasemia (HA) is often reported in patients with acute liver failure (ALF). Direct toxic effects of acetaminophen on the pancreas have been postulated, but the occurrence of HA in other etiologies raises the question of whether multiorgan failure is part of the pathogenesis of HA in this setting. Our main aim was to describe and analyze the incidence, clinical characteristics, and outcomes of HA in ALF of different etiologies. METHODS: Patients enrolled in the Acute Liver Failure Study Group registry with an admission amylase value available were included. For the purpose of this analysis, HA was defined as > or =3x upper limits of normal. Patients were classified as having acetaminophen (APAP)- or non-APAP-induced ALF, and by amylase group: normal (<115), mildly elevated (115-345), or HA (>345). Significant variables identified by univariate analysis were added to a multiple linear regression model. The primary outcome was overall survival. RESULTS: In total, 622 eligible patients were identified in the database, including 287 (46%) with APAP-induced ALF; 76 (12%) patients met the criteria for HA. Among patients with HA, 7 (9%) had documented clinical pancreatitis. The incidence of HA was similar among APAP (13%) and non-APAP (12%) patients. Although HA was associated with renal failure and greater Model for End-stage Liver Disease scores for both groups, HA was not an independent predictor of mortality in multivariate analysis. CONCLUSIONS: Although not an independent predictor of mortality, HA in ALF was present in all etiologies and was associated with diminished overall survival. HA appeared to be related to renal dysfunction in both groups and multiorgan failure in non-APAP ALF.

Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.

In the current Model for End-Stage Liver Disease allocation system, patients are at risk of suffering repeated episodes of hepatic encephalopathy (HE) while waiting for an orthotopic liver transplantation (OLT); the posttransplantation impact of these episodes has not been well explored. We evaluated the cognitive function and quality of life in a group of OLT recipients (n = 25) who had suffered from overt HE prior to their procedure (HE-PreLT group) and compared their performance to that of a similar group of patients (n = 14) without overt HE (No HE-PreLT group) as well as to controls. Patients were selected from a cohort of 280 patients who underwent OLT during this period; the presence of clinical confounders excluded many of the remaining subjects. Demographic and clinical characteristics were balanced among groups. At an average of 18 months after OLT, we administered 2 neuropsychological batteries [Psychometric Hepatic Encephalopathy Score (PHES) test battery and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]; a pyschophysiological test (critical flicker frequency); and the SF-36 quality of life score. The HE-PreLT group scored below controls in 5 of 6 cognitive domains tested by RBANS, 3 of 6 PHES subtests, as well as the critical flicker frequency test. The No HE-PreLT group scored below the controls in 1 of the 6 cognitive domains tested by RBANS. The more severe neurocognitive abnormalities seen in the HE-PreLT group did not appear to affect quality of life, as lower values than normative data were only found in 1 of the 8 SF-36 scales. In conclusion, neurocognitive abnormalities were more severe in liver transplant recipients that had suffered from overt HE prior to OLT. Prospective studies of neurocognitive function pre-OLT and post-OLT are needed to fully determine the impact of such abnormalities.

Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure.

Disseminated herpes simplex virus (HSV) infection may lead to acute liver failure (ALF) and the need for emergency liver transplantation (LT). The primary aim of this study was to determine the utility of HSV serological testing and HSV DNA testing by polymerase chain reaction (PCR) in the diagnosis and management of indeterminate, pregnancy-related, and known HSV-related ALF. Stored sera obtained on study day 1 or 2 from patients enrolled in the United States ALF Study Group with indeterminate (n = 51), pregnancy-related (n = 12), and HSV-related (n = 4) ALF were screened for HSV DNA by PCR and serology. While 7 of the indeterminate and pregnant patients had positive anti-HSV immunoglobulin M, none had detectable HSV DNA. The 4 known HSV cases all had high-titer HSV DNA on presentation (range: 3.5 to 36 x 10(8) copies/mL). Two HSV patients underwent LT but developed posttransplant extrahepatic HSV infection despite suppression of HSV DNA with acyclovir treatment, and one of them eventually died. The 2 other fulminant HSV patients died within 48 hours of presentation. In conclusion, serum HSV DNA indicative of occult HSV infection was not detected in 51 indeterminate and 12 pregnancy-related ALF patients. The 4 patients with known HSV-related ALF all had high HSV DNA levels at presentation, and despite the rapid use of antiviral therapy and emergency LT, substantial morbidity and mortality were encountered, highlighting the poor prognosis with severe disseminated HSV infection.

Outcomes of living donor liver transplantation for acute liver failure: the adult-to-adult living donor liver transplantation cohort study.

For acute liver failure (ALF), living donor liver transplantation (LDLT) may reduce waiting time and provide better timing compared to deceased donor liver transplantation (DDLT). However, there are concerns that a partial graft would result in reduced survival of critically ill LDLT recipients and that the rapid evolution of ALF would lead to selection of inappropriate donors. We report outcomes for ALF patients (and their donors) evaluated for LDLT between 1998 and April 2007 from the Adult-to-Adult Living Donor Liver Transplantation Cohort. Of the 1201 potential LDLT recipients, 14 had ALF, only 6 of whom had an identified cause. The median time from listing to first donor evaluation was 1.5 days, and the median time from evaluation to transplantation was 1 day. One patient recovered without liver transplant, 3 of 10 LDLT recipients died, and 1 of 3 DDLT recipients died. Five of the 10 living donors had a total of 7 posttransplant complications. In conclusion, LDLT is rarely performed for ALF, but in selected patients it may be associated with acceptable recipient mortality and donor morbidity.

Therapeutic hypothermia for acute liver failure: toward a randomized, controlled trial in patients with advanced hepatic encephalopathy.

Acute liver failure (ALF), the abrupt loss of liver function in a patient without previous liver disease, remains a highly mortal condition. Patients with ALF often succumb to their liver injury after the development of cerebral edema, resulting in intracranial hypertension and brain herniation. While the management of cerebral edema in ALF always includes the administration of osmotically active agents, osmotherapy often reduces intracranial pressure (ICP) insufficiently, such that herniation may be delayed but not prevented. Therapeutic hypothermia, the intentional reduction of body core temperature, has been increasingly used to treat cerebral edema in patients with traumatic and hypoxic brain injury. Data in animal models of ALF also suggest that hypothermia is effective in the prevention and treatment of cerebral edema, and case reports in humans have suggested that hypothermia is an effective bridge to orthotopic liver transplantation. A randomized, controlled trial comparing the management of ALF patients under normothermic and hypothermic conditions is a logical extension of these preliminary observations. Herein, we consider the many difficulties which will be encountered in the design of such a trial in patients with ALF at high risk of developing cerebral edema.

Brain edema in acute liver failure.

Acute liver failure (ALF) is a syndrome of rapidly deteriorating liver function that manifests as coagulopathy and encephalopathy in a previously healthy individual. This article analyzes the repercussions of ALF on the brain through a discussion of special features of this syndrome, important for the interpretation of neurologic findings. Of particular interest within the context of ALF are hepatic encephalopathy and the pathogenesis of brain edema in acute liver failure as well as its clinical and therapeutic aspects.

Hemodynamic evaluation before liver transplantation: insights into the portal hypertensive syndrome.

The cardiac hemodynamics of patients awaiting liver transplantation is complex. Coronary atherosclerosis, a hyperdynamic circulatory state and cirrhotic cardiomyopathy are present to a variable degree in this population. In this contribution to the Symposium on Portal Hypertension, we expand on our published experience with coronary angiography and cardiac hemodynamics at the time of evaluation of candidacy for liver transplantation in a cohort of 161 patients. Although we confirmed the relation of systemic hemodynamics with the degree of liver failure, we noted a higher prevalence of high output heart failure, defined as an increased left ventricular end-diastolic pressure in the setting of an elevated cardiac output, most notably in patients classified as Child C. Most patients with high pulmonary artery pressure also exhibited evidence of elevated left ventricle filling pressures. A low systemic vascular resistance, a marker of arterial vasodilatation, was similar in the presence of atherosclerosis, a condition where impaired vasorelaxation occurs as a result of endothelial dysfunction. The high prevalence of coronary artery disease in this series supports the observations that atherosclerosis is a major issue in the current population with cirrhosis awaiting liver transplantation. A lower sensitivity of noninvasive screening tools for the detection of coronary atherosclerosis is likely the result of the interaction of the hyperdynamic circulation with the performance of these tests.

Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.

UNLABELLED: Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non-protein-bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2-grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end-stage liver disease (MELD) 32 (11-50) and CPT 13 (10-15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P = 0.044) and was reached faster and more frequently than in the SMT group (P = 0.045). Subjects receiving ECAD tolerated treatment well with no unexpected adverse events. CONCLUSION: The use of ECAD may be associated with an earlier and more frequent improvement of HE (grade 3/4). Because this 5-day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials.

Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group.

OBJECTIVE: To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within participating centers. METHODS: In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of > or =25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145-155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation. CONCLUSIONS: The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.

Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.

Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation (LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-treated patients as compared to 88% in the untreated subjects (P=0.03). Variables on presentation associated with death or need for LT compared to spontaneous survival: male gender, age>40 yr, immunocompromised state, ALT>5,000 U/L, platelet count<75x10(3)/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded.

Portal hypertension and its complications.

PURPOSE OF REVIEW: Portal hypertension is responsible for most of the complications associated with cirrhosis, specifically variceal hemorrhage, ascites and hepatic encephalopathy. Progress in understanding the pathophysiology of portal hypertension and improvements in the diagnosis and management of its complications that have occurred over the last year are discussed. RECENT FINDINGS: Endothelial dysfunction contributes to the pathogenesis of portal hypertension and may represent a novel therapeutic target. Hepatic venous pressure gradient measurements, when properly performed, are useful in the management of patients with cirrhosis. Hyponatremia in cirrhosis has prognostic value and novel aquaretic and other agents may provide alternative approaches to the management of chronic liver disease. The mechanisms for bacterial translocation in cirrhosis that predisposes patients to infectious complications, such as spontaneous bacterial peritionitis, are being explored. Adrenal insufficiency is common in septic patients with advanced cirrhosis and corticosteroids may provide a survival benefit. Pulmonary disease complicates the management of patients with advanced liver disease. SUMMARY: Significant advances continue to be made in the diagnosis and management of the complications of portal hypertension in the face of an increasing burden of chronic liver disease.

Mild hypothermia attenuates liver injury and improves survival in mice with acetaminophen toxicity.

BACKGROUND & AIMS: Body temperature may critically affect mechanisms of liver injury in acetaminophen (APAP) hepatotoxicity. In addition, mild hypothermia is used to treat intracranial hypertension in human liver failure without detailed information on its effects on the injured liver itself. Therefore, we investigated the effects of body temperature on the progression of APAP-induced liver injury in mice. METHODS: Male C57BL6 mice treated with saline or APAP (300 mg/kg intraperitoneally) were maintained at normothermia (35.5-37.5 degrees C) by external warming or were allowed to develop mild hypothermia (32.0-35.0 degrees C) after 2 hours from APAP administration. RESULTS: Mild hypothermia resulted in improved survival after APAP intoxication. Liver damage was reduced, as assessed histologically and by plasma alanine aminotransferase levels. Early effects of hypothermia included a reduction of hepatic congestion and improved recovery of glycogen stores. At later time points (8-12 hours), APAP-treated mice that were maintained at normothermia manifested increased hepatocyte apoptosis, as assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining and cleavage of poly(adenosine diphosphate-ribose) polymerase. Mild hypothermia did not affect the formation of APAP-protein adducts or the depletion of glutathione, nor did it abrogate hepatocyte DNA synthesis. CONCLUSIONS: Mild hypothermia improved survival and attenuated liver injury and apoptosis in APAP-treated mice by reducing hepatic congestion and improving glycogen recovery without affecting hepatic regeneration. Results of the study underscore the need for a strict control of body temperature in animal models of liver failure and suggest that the benefits of mild hypothermia in liver failure may extend beyond those related to reduced cerebral complications.

Surgically restoring portal blood flow to the liver in children with primary extrahepatic portal vein thrombosis improves fluid neurocognitive ability.

OBJECTIVES: Children with primary extrahepatic portal vein thrombosis (EHPVT) have portal-systemic shunting, which may lead to disturbed neurocognitive function similar to portal-systemic encephalopathy (PSE) seen with chronic liver disease and cirrhosis. The functions most affected are those involving fluid cognitive ability, which comprise neurocognitive domains such as attention, processing speed, and short-term memory, that are particularly vulnerable to systemic illness or diffuse neurologic insult. We determined the fluid cognitive ability of children with EHPVT and whether surgically restoring portal blood flow by mesenteric left portal vein bypass (MLPVB) improved it. DESIGN: Twelve children with EHPVT and no overt PSE underwent comprehensive neurocognitive testing before and 1 year after undergoing surgery with intent to perform MLPVB. The evaluations sampled 4 functional domains at both time points: (1) neurobehavioral (behavior, emotional, executive functioning); (2) broad cognitive (intelligence, achievement); (3) fluid ability (attention, mental speed, working memory, memory encoding); and (4) visual motor (drawing, fine motor). Tasks in the fluid-ability and visual-motor domains were expected to be especially sensitive to adverse effects of EHPVT and to be most likely to show improvement with MLPVB. The test group consisted of 8 subjects who underwent successful MLPVB, and the comparison group was composed of 3 patients who received distal splenorenal shunts and one whose MLPVB failed. RESULTS: Both groups demonstrated similar fluid cognitive ability at initial evaluation. Successful MLPVB resulted in significantly improved fluid cognitive function: in the fluid cognitive domain, significant improvements were seen for the hit reaction time variability in the Conner's Continuous Performance Test, the attention scale of the Cognitive Assessment System, and immediate verbal memory in the Children's Memory Scale. In the visual-motor domain, z scores on the Grooved Pegboard Test improved. No improvement was observed in the comparison group. DISCUSSION: The results show that surgically restoring portal flow to the liver in children with primary EHPVT results in improved fluid cognitive ability. Subjects showed some neurocognitive abnormalities involving mainly fluid cognitive ability consistent with minimal PSE seen in adults with chronic liver disease. Cognitive defects in patients with minimal PSE seem to relate primarily to attention and fine motor skill, and although affected patients can function in everyday life, they are at risk for performance deficits in educational and vocational situations requiring the ability to pay close attention and react quickly (eg, driving, employment in manufacturing). The tests we administered in these domains are pediatric equivalents to measures used to detect minimal PSE in adults and should detect abnormalities in the same functional domains. Our results suggest that a narrow battery of tests could be used to detect minimal PSE in children in a manner similar to the 5-test battery used in adults, eliminating the need for the comprehensive and broad testing we performed. Our findings suggest that shunting of portal blood from the liver in primary EHPVT can result in PSE and question whether it is as benign a disease as previously thought. The importance of our findings is twofold. For understanding the pathophysiology of PSE, we have shown that restoring blood flow to the liver improves cognitive function in children with EHPVT. For therapy for EHPVT, it becomes clear that MLPVB is an excellent treatment option. It is effective for treating the complications of portal hypertension and provides effective portal blood flow that other medical and surgical therapies do not. The findings provide additional evidence that primary EHPVT should be considered curable by MLPVB. However, comparison of overall risks and benefits of MLPVB with those of other therapeutic options and longer-term outcome studies must be completed before MLPVB can be fully endorsed as the best treatment for EHPVT in children. CONCLUSIONS: Surgical restoration of portal venous flow to the liver in children with primary EHPVT by MLPVB improves fluid cognitive ability. MLPVB should be considered in treating primary EHPVT, because it corrects portal blood flow and could optimize learning potential.

Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy.

Monitoring of intracranial pressure (ICP) in acute liver failure (ALF) is controversial as a result of the reported complication risk (approximately 20%) and limited therapeutic options for intracranial hypertension. Using prospectively collected information from 332 patients with ALF and severe encephalopathy, we evaluated a recent experience with ICP monitoring in the 24 centers constituting the U.S. ALF Study Group. Special attention was given to the rate of complications, changes in management, and outcome after liver transplantation (LT). ICP monitoring was used in 92 patients (28% of the cohort), but the frequency of monitoring differed between centers (P < 0.001). ICP monitoring was strongly associated with the indication of LT (P < 0.001). A survey performed in a subset of 58 patients with ICP monitoring revealed intracranial hemorrhage in 10.3% of the cohort, half of the complications being incidental radiological findings. However, intracranial bleeding could have contributed to the demise of 2 patients. In subjects listed for LT, ICP monitoring was associated with a higher proportion of subjects receiving vasopressors and ICP-related medications. The 30-day survival post-LT was similar in both monitored and nonmonitored groups (85% vs. 85%). In conclusion, the risk of intracranial hemorrhage following ICP monitoring may have decreased in the last decade, but major complications are still present. In the absence of ICP monitoring, however, patients listed for LT appear to be treated less aggressively for intracranial hypertension. In view of the high 30-day survival rate after LT, future studies of the impact of intracranial hypertension should also focus on long-term neurological recovery from ALF.