Brain edema : a valid endpoint for measuring hepatic encephalopathy?

Hepatic encephalopathy (HE) is a major complication of liver failure/disease which frequently develops during the progression of end-stage liver disease. This metabolic neuropsychiatric syndrome involves a spectrum of symptoms, including cognition impairment, attention deficits and motor dysfunction which eventually can progress to coma and death. Pathologically, HE is characterized by swelling of the astrocytes which consequently leads to brain edema, a common feature found in patients with acute liver failure (ALF) as well as in cirrhotic patients suffering from HE. The pathogenic factors involved in the onset of astrocyte swelling and brain edema in HE are unresolved. However, the role of astrocyte swelling/brain edema in the development of HE remains ambiguous and therefore measuring brain edema as an endpoint to evaluate HE is questioned. The following review will determine the effect of astrocyte swelling and brain edema on neurological function, discuss the various possible techniques to measure brain edema and lastly to propose a number of neurobehavioral tests to evaluate HE

Clinical features of alcoholic hepatitis in latinos and caucasians: A single center experience.

AimTo study differences of presentation, management, and prognosis of alcoholic hepatitis in Latinos compared to Caucasians.MethodsWe retrospectively screened 876 charts of Caucasian and Latino patients who were evaluated at University of California Davis Medical Center between 1/1/2002-12/31/2014 with the diagnosis of alcoholic liver disease. We identified and collected data on 137 Caucasians and 64 Latinos who met criteria for alcoholic hepatitis, including chronic history of heavy alcohol use, at least one episode of jaundice with bilirubin ≥ 3.0 or coagulopathy, new onset of liver decompensation or acute liver decompensation in known cirrhosis within 12 wk of last drink.ResultsThe mean age at presentation of alcoholic hepatitis was not significantly different between Latinos and Caucasians. There was significant lower rate of overall substance abuse in Caucasians compared to Latinos and Latinos had a higher rate of methamphetamine abuse (12.5% vs 0.7%) compared to Caucasians. Latinos had a higher mean number of hospitalizations (5.3 ± 5.6 vs 2.7 ± 2.7, P = 0.001) and mean Emergency Department visits (9.5 ± 10.8 vs 4.5 ± 4.1, P = 0.017) for alcohol related issues and complications compared to Caucasians. There was significantly higher rate of complications of portal hypertension including gastrointestinal bleeding (79.7% vs 45.3%, P < 0.001), spontaneous bacterial peritonitis (26.6% vs 9.5%, P = 0.003), and encephalopathy (81.2% vs 55.5%, P = 0.001) in Latinos compared to Caucasians.ConclusionLatinos have significant higher rates of utilization of acute care services for manifestations alcoholic hepatitis and complications suggesting poor access to outpatient care

Specific issues concerning the management of patients on the waiting list and after liver transplantation

The present document is a second contribution collecting the recommendations of an expert panel of transplant hepatologists appointed by the Italian Association for the Study of the Liver (AISF) concerning the management of certain aspects of liver transplantation, including: the issue of prompt referral; the management of difficult candidates; malnutrition; living related liver transplants; hepatocellular carcinoma; and the role of direct acting antiviral agents before and after transplantation. The statements on each topic were approved by participants at the AISF Transplant Hepatology Expert Meeting organized by the Permanent Liver Transplant Commission in Mondello on 12-13 May 2017. They are graded according to the GRADE grading system

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability

Influence of selected patient variables and operative blood loss on six-month survival following liver transplantation.

A group of 118 adults who underwent primary, orthotopic transplantation of the liver over a 4-year period served as the subjects of a detailed examination of their ability to survive the first 6 months as a function of their preoperative condition. As a result, a scoring system was developed empirically in an attempt to separate very high-risk from relatively low-risk patients. The scoring method is based on the high degree of correlation between survival probability and various patient characteristics. It allows for additional scoring to account for the dramatic effect of operative blood loss on the eventual outcome. The curve that best describes the relationship between patient scores and survival probability is sigmoidal in shape. Many patients will have scores located on the curve between the inflection points. They represent a group whose relative risk is difficult to estimate but for whom operative blood loss or the occurrence of surgical complications may prove particularly telling

Sarcopenia from mechanism to diagnosis and treatment in liver disease

Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition and is a frequent complication in cirrhosis that adversely affects clinical outcomes. These include survival, quality of life, development of other complications and post liver transplantation survival. Radiological image analysis is currently utilized to diagnose sarcopenia in cirrhosis. Nutrient supplementation and physical activity are used to counter sarcopenia but have not been consistently effective because the underlying molecular and metabolic abnormalities persist or are not influenced by these treatments. Even though alterations in food intake, hypermetabolism, alterations in amino acid profiles, endotoxemia, accelerated starvation and decreased mobility may all contribute to sarcopenia in cirrhosis, hyperammonemia has recently gained attention as a possible mediator of the liver-muscle axis. Increased muscle ammonia causes: cataplerosis of α-ketoglutarate, increased transport of leucine in exchange for glutamine, impaired signaling by leucine, increased expression of myostatin (a transforming growth factor beta superfamily member) and an increased phosphorylation of eukaryotic initiation factor 2α. In addition, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy mediated proteolysis, also play a role. These molecular and metabolic alterations may contribute to the anabolic resistance and inadequate response to nutrient supplementation in cirrhosis. Central and skeletal muscle fatigue contributes to impaired exercise capacity and responses. Use of proteins with low ammoniagenic potential, leucine enriched amino acid supplementation, long-term ammonia lowering strategies and a combination of resistance and endurance exercise to increase muscle mass and function may target the molecular abnormalities in the muscle. Strategies targeting endotoxemia and the gut microbiome need further evaluatio

Bile duct ligation of C57BL/6 mice as a model of hepatic encephalopathy

Background: Bile duct ligation (BDL) has been used for experimental research on hepatic encephalopathy (HE) caused by chronic liver disease. However, little research has been done on a BDL model in C57BL/6 mouse. Therefore, we evaluated the suitability of a BDL model in C57BL/6 mouse for the study of HE and determined which behavioral tests are appropriate for the identification of HE in this model. Methods: Twelve to fourteen-week-old male C57BL/6 mice were randomly assigned to either sham group or BDL group. Histological changes in liver were confirmed by hematoxylin/ eosin and Masson’s trichrome staining. Liver function alterations were detected by alanine aminotransferase (ALT) and ammonia levels. To identify behavioral changes, open field, elevated plus maze, novel object recognition, and passive avoidance tests were performed. Results: Inflammatory liver injury and fibrosis were observed 14 days after BDL. ALT and ammonia levels were significantly higher in BDL group than in sham group. There were no differences in general locomotor activity or anxiety between the groups. No difference was observed between these two groups in the novel object recognition test, but BDL group showed significant learning/memory impairment in the passive avoidance test compared to sham group. Conclusions: Fourteen days of BDL in 12–14-week-old male C57BL/6 mice is a clinically relevant model for HE, as these mice have liver fibrosis with impaired liver function, hyperammonemia, and learning/memory impairment. Passive avoidance can be used as the major behavioral test in this model of HE.ope