A systems pharmacology-oriented discovery of a new therapeutic use of the TCM formula Liuweiwuling for liver failure.

Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae.

Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study.

BACKGROUND: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF. METHODS: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables. RESULTS: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age ≥70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl. CONCLUSIONS: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data.

What constitutes liver failure after transjugular intrahepatic portosystemic shunt creation? A proposed definition and grading system.

UNLABELLED:  Background and rationale for the study. There is currently no definition of post-transjugular intrahepatic portosystemic shunt (TIPS) liver failure (PTLF), which constitutes a barrier to standardization of TIPS results reporting and limits the ability to compare liver failure incidence across clinical studies. Thisdescriptive study proposes and preliminarily tests the performance of a PTLF definition and grading system. RESULTS: PTLF was defined by ≥ 3-fold bilirubin and/or ≥ 2-fold INR elevation associated with clinical outcomes of prolonged hospitalization/increase in care level (grade 1), TIPS reduction or liver transplantation (grade 2), or death (grade 3) within 30-days of TIPS. PTLF incidence was 20% (grades 1, 2, 3: 10%, 3%, 8%) among 270 TIPS cases, and the scheme identified patients at increased risk for morbidity and mortality with a statistically significant difference in clinical outcomes between PTLF and non-PTLF groups (P<0.0001). CONCLUSIONS: In conclusion, the PTLF definition and classification scheme put forth distributes patients into unique risk groups. PTLF grading may thus be useful for standardization of TIPS results reporting.

The brain in acute on chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a newly defined clinical entity with significant morbidity and mortality (~40-90% at 1 year dependent on need for organ support at presentation). It defines a presentation with acute severe liver injury, often with multiorgan dysfunction, on a background of previously known or unknown cirrhosis. In its severest form, it is almost indistinguishable from acute liver failure, as similarly in around 5% may rapidly progress to intracranial hypertension and cerebral oedema culminating in coma and/or death. Our understanding of such cerebral sequelae is currently limited to clinical observation, though our knowledge base is rapidly expanding since recent consensus clinical definition and guidance. Moreover, there are now animal models of ACLF and imaging modalities to better characterize events in the brain that occur with ACLF. However, as yet there has been little in the way of interventional study of this condition which are much needed. In this review we dissect existing clinical and experimental data to better characterise the manifestations of ACLF on the brain and allow for the development of targeted therapy as currently the plethora of existing interventions were designed to treat either the effects of cirrhosis or acute liver injury independently.

Assessment of ISGLS definition of posthepatectomy liver failure and its effect on outcome in patients with hepatocellular carcinoma.

BACKGROUND: Posthepatectomy liver failure (PHLF) is a major complication after hepatectomy. As there was no standardized definition, the International Study Group of Liver Surgery (ISGLS) defined PHLF as increased international normalized ratio and hyperbilirubinemia on or after postoperative day 5 in 2010. We evaluated the impact of the ISGLS definition of PHLF on hepatocellular carcinoma (HCC) patients. METHODS: We retrospectively analyzed 210 consecutive HCC patients who underwent curative hepatectomy at our facility from 2005 to 2010. The median follow-up period after hepatectomy was 35.2 months. RESULTS: Thirty-nine (18.6%) patients fulfilled the ISGLS definition of PHLF. Overall survival (OS) rates at 1, 3, and 5 years in patients with/without PHLF were 69.1/93.5, 45.1/72.5, and 45.1/57.8%, respectively (P = 0.002). Recurrence-free survival (RFS) rates at 1, 3, and 5 years in patients with/without PHLF were 40.9/65.9, 15.7/38.3, and 15.7/20.3%, respectively (P = 0.003). Multivariate analysis revealed that PHLF was significantly associated with both OS (P = 0.047) and RFS (P = 0.019). Extent of resection (P < 0.001), intraoperative blood loss (P = 0.002), and fibrosis stage (P = 0.040) were identified as independent risk factors for developing PHLF. CONCLUSION: The ISGLS definition of PHLF was associated with OS and RFS in HCC patients, and long-term survival will be improved by reducing the incidence of PHLF.

Risk factors for liver transplant waitlist dropout in patients with hepatocellular carcinoma.

Loco-regional therapy has been developed to reduce waitlist dropout in patients with hepatocellular carcinoma (HCC) awaiting liver transplantation. We evaluated the probability of transplantation and waitlist dropout, and analyzed risk factors for waitlist dropout, in 76 patients with HCC from September 2004 to August 2006. Seventy-three (96.1%) patients received one or more preoperative loco-regional treatments and 55 (72.3%) received an orthotopic liver transplantation with a median wait time of seven months (range, 2-26 months). There were 11 dropouts (14.5%) associated with tumor progression or hepatic decompensation (median waiting time; 5.4 months and range, 0.4-13 months). Cumulative probabilities of transplantation at three, six, nine, 12, 15, and 18 months were 5.4%, 35.4%, 67.5%, 78.8%, 80.7%, and 80.7%, respectively and those of waitlist dropout at three, six, nine, 12, 15, and 18 months were 3.9%, 8.7%, 12.8%, 22.9%, 29.3%, and 29.3%, respectively. A laboratory model for end-stage liver disease (MELD) score >15 or multiple tumors at the time of UNOS listing were significant risk factors for waitlist dropout (p = 0.006 and 0.026, respectively). Patients with HCC being managed with loco-regional therapy who have a laboratory MELD score >15 or multiple tumors should be considered for earlier access to liver transplantation to prevent waitlist dropout.

The influence of laboratory-induced MELD score differences on liver allocation: more reality than myth.

BACKGROUND: Liver allocation in Eurotransplant (ET) is based on the MELD score. Interlaboratory MELD score differences in INR and creatinine determination have been reported. The clinical implication of this observation has not been demonstrated. METHODS: MELD scores were calculated in 66 patients with liver cirrhosis using bilirubin, creatinine, and INR analyzed in six liver transplant centers. Based on allocation results of ET, patients transplanted from December 2006 to June 2007 were divided according to MELD score in four groups. For each group, the influence of the match MELD on the probability of receiving a transplant was studied (Cox proportional hazards model). RESULTS: Laboratory-dependent significant differences in MELD score were demonstrated. Cox proportional hazards model showed a significant association between MELD score and the probability of organ allocation. The unadjusted hazard ratio for receiving a liver transplant was significantly different between group 2 and group 4 (group 2: MELD 19-24; group 4: MELD > 30). CONCLUSION: Laboratory-dependent significant differences in MELD score were observed between the six transplant centers. We demonstrated a significant association between the MELD score and the probability of organ allocation. The observed interlaboratory variation might yield a significant difference in organ allocation in patients with high MELD scores.

Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS).

BACKGROUND: Posthepatectomy liver failure is a feared complication after hepatic resection and a major cause of perioperative mortality. There is currently no standardized definition of posthepatectomy liver failure that allows valid comparison of results from different studies and institutions. The aim of the current article was to propose a definition and grading of severity of posthepatectomy liver failure. METHODS: A literature search on posthepatectomy liver failure after hepatic resection was conducted. Based on the normal course of biochemical liver function tests after hepatic resection, a simple and easily applicable definition of posthepatectomy liver failure was developed by the International Study Group of Liver Surgery. Furthermore, a grading of severity is proposed based on the impact on patients' clinical management. RESULTS: No uniform definition of posthepatectomy liver failure has been established in the literature addressing hepatic surgery. Considering the normal postoperative course of serum bilirubin concentration and International Normalized Ratio, we propose defining posthepatectomy liver failure as the impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased international normalized ratio and concomitant hyperbilirubinemia (according to the normal limits of the local laboratory) on or after postoperative day 5. The severity of posthepatectomy liver failure should be graded based on its impact on clinical management. Grade A posthepatectomy liver failure requires no change of the patient's clinical management. The clinical management of patients with grade B posthepatectomy liver failure deviates from the regular course but does not require invasive therapy. The need for invasive treatment defines grade C posthepatectomy liver failure. CONCLUSION: The current definition of posthepatectomy liver failure is simple and easily applicable in clinical routine. This definition can be used in future studies to allow objective and accurate comparisons of operative interventions in the field of hepatic surgery.

The International Normalized Ratio (INR) in the MELD score: problems and solutions.

The Model for End-Stage Liver Disease (MELD) score is widely used to prioritize patients for liver transplantation. One of the pitfalls of the MELD score is the interlaboratory variability in all three components of the score (INR, bilirubin, creatinine). The interlaboratory variability in the INR has the largest impact on the MELD score, with a mean difference of around 5 MELD points in most studies. During the 3rd conference on Coagulopathy and Liver disease, a multidisciplinary group of scientists and physicians discussed possible solutions for the INR problem in the MELD score with the intention to provide a constructive contribution to the international debate on this issue. Here we will discuss possible solutions and highlight advantages and disadvantages.

Relationship of increased serum brain natriuretic peptide levels with hepatic failure, portal hypertension and treatment in patients with cirrhosis.

BACKGROUND/AIMS: Brain natriuretic peptide is a cardiac neurohormone secreted from ventricles in response to end diastolic pressure and increased volume. It has diuretic, natriuretic and vasodilator effects. In cirrhosis, a hyperdynamic circulation occurs because of hemodynamic and hemostatic alterations. The increase in brain natriuretic peptide concentration shows parallelism with the stage of cirrhosis. The aim of this study is to investigate the relation of increased brain natriuretic peptide level with the pathophysiologic components of cirrhosis and treatment. METHODS: Ninety-five cirrhotic patients in different stages (Child-A: 33; Child-B: 25; Child-C:37) and age and sex matched 86 healthy individuals were recruited for the study. Brain natriuretic peptide concentration was measured with brain natriuretic peptide-Triage test device using fluoresan immune assay method. RESULTS: Brain natriuretic peptide levels of patients with hepatic cirrhosis were significantly higher compared to control group (288.5±329.2/60.2±29.5/p=0.000, respectively). Serum brain natriuretic peptide levels were positively correlated with Child score (Child A-B-C; 201.2±266/258.7±233.6/386.5±407.7, respectively). A negative correlation was observed between brain natriuretic peptide and albumin levels (p=0.002). Brain natriuretic peptide concentration was significantly correlated with the grade of esophagus varices, and presence of ascites and collateral circulation (p=0.006; p=0.001; p=0.002; respectively). Patients receiving with beta-blocker and diuretic treatments had significantly higher brain natriuretic peptide levels. CONCLUSIONS: High brain natriuretic peptide levels in patients with cirrhosis may be due to hepatocellular insufficiency or portal hypertension, but a cardiomyopathy developing insiduously should not be regarded.

Live donor liver transplantation in high MELD score recipients.

BACKGROUND: In 2002, the New York State Committee on Quality Improvement in Living Liver Donation prohibited live liver donation for potential recipients with Model for End-stage Liver Disease (MELD) scores greater than 25. Despite the paucity of evidence to support this recommendation, many centers in North America remain reluctant to offer living donor (LD) to patients with moderate to high MELD scores. METHODS: We analyzed 271 consecutive adult-to-adult right lobe LD liver transplants performed at our institution between 2002 and 2008 to study the relationship, between recipient MELD scores and the outcome of LD liver transplantation. The recipients were categorized according to their MELD score into a low (Low: <25)and high (Hi: >or=25) MELD group. We compared short-term donor morbidity, graft loss within 30 days, length of hospital stay, biochemical markers of hepatocyte injury and graft function, and 90 day posttransplant complications including infection, rejection, bleeding, and renal failure. Long-term posttransplant outcome was measured by graft and patient survival after 1-, 3-, and 5-years. RESULTS: Donor and recipient characteristics were similar between groups. Donor outcomes were similar in both groups. Peak recipient aspartat aminotransferase, alanine aminotransferase, and length of hospital stay were similar between both groups. The proportional decrease in postoperative INR and creatinine within the first week was greater in the high versus low MELD score group. High MELD score recipients had more frequent postoperative pneumonia (Low: 2.2% vs. Hi: 14%, P = 0.003), while no differences were observed in rates of biliary complications, rejection, renal failure, or overall infections. Recipients with a MELD <25 versus >or=25 had a similar 1-year (Low: 92% vs. Hi: 83%), 3-year (Low: 86% vs. Hi: 80%), and 5-year (Low: 78% vs. Hi: 80%) graft survival after LD liver transplantation (P = 0.51). CONCLUSION: LD liver transplantation can provide excellent graft function and survival rates in high MELD score recipients. Thus, when deceased donor organs are scare, a high MELD score alone should not be an absolute contraindication to living liver donation.

Allocation priority in non-urgent liver transplantation: An overview of proposed scoring systems.

Given the lack of donors, a correct organ allocation system for candidates to liver transplantation is essential to increase graft and patient survival. The most used organ allocation tools are Child-Turcotte-Pugh and model for end-stage liver disease. It is generally accepted that model for end-stage liver disease score is superior to the Child-Turcotte-Pugh classification in predicting the short-term survival of cirrhotic patients awaiting liver transplantation. Since 2002, model for end-stage liver disease is widely used for liver allocation. In recent years, to overcome limitations of the consolidated scores, some adjustments to the original model for end-stage liver disease formula and new scoring systems have been proposed. Published data suggest that integrating serum sodium and model for end-stage liver disease may improve the score prognostic accuracy but further studies are necessary to confirm this issue. The updated model for end-stage liver disease, obtained through a revision of traditional model for end-stage liver disease parameters and tested in a large cohort of patients, is of great interest at the moment. In conclusion, several scoring systems have been described for organ allocation, but today, none is definitely able to overcome the limitations of the Child-Turcotte-Pugh and model for end-stage liver disease systems.

Value of MELD and MELD-based indices in surgical risk evaluation of cirrhotic patients: retrospective analysis of 190 cases.

BACKGROUND: Recent studies have suggested that the Model for End-Stage Liver Disease (MELD) may represent a promising alternative to the Child-Turcotte-Pugh classification as a predictive factor of operative mortality and morbidity. This study was designed to evaluate the value of MELD and four MELD-based indices (iMELD: integrated MELD; MESO: MELD to sodium ratio; MELD-Na: MELD with incorporation of sodium; MELD-XI: MELD excluding the International Normalized Ratio) in the quantification of surgical risk for patients with cirrhosis and compare its prognostic value with the Child-Turcotte-Pugh classification and two derived scores (proposed by Huo and Giannini, respectively). METHODS: A retrospective study of 190 patients with cirrhosis, operated on in our department between 1993 and 2008, was undertaken. RESULTS: Forty-three percent of patients were included in Child-Turcotte-Pugh A class, and their mean MELD score was 12.2 +/- 4.9 (range, 6.4-35.2). Mortality and morbidity rates were 13% and 24%, respectively. In global analysis of mortality, MELD-based indices presented an acceptable prognostic performance (auROC = 71-77%), similar to the three analyzed Child-Turcotte-Pugh-derived scores. iMELD demonstrated the highest prognostic capacity (auROC = 77%; 95% confidence interval (CI), 66-88; p = 0.0001); operative death probability was 4% (95% CI, 3.6-4.4) when the score was inferior to 35, 16.1% (95% CI, 14.4-17.9) between 35 and 45, and 50.1% (95% CI, 42.2-58.1) when superior to 45. In elective surgical procedures, iMELD represented a useful prognostic factor of operative mortality (auROC = 80%; 95% CI, 63-97; p = 0.044) with significant correlation and better accuracy then MELD and Child-Turcotte-Pugh-derived indices. CONCLUSIONS: In this study, iMELD was a useful predictive parameter of operative mortality for patients with cirrhosis submitted to elective procedures. Further studies are necessary to define the relevance of MELD-based indices in the individual surgical risk evaluation.

Mammillary body atrophy in acute liver failure and acute-on-chronic liver failure of nonalcoholic etiology.

The most common cause of atrophy of mammillary bodies (MBs) is thiamine deficiency, which is very common in patients with alcoholic liver disease. The purpose of this study was to look for changes in MBs using brain magnetic resonance imaging (MRI) in patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and chronic liver failure (CLF) of non-alcoholic etiology. Volumes of MBs and caudate nuclei (CNs) were quantified in nine patients with ALF, 17 with ACLF, 18 with CLF and in 24 healthy controls. Volume of these structures was quantified again three weeks after clinical recovery in five patients with ALF who had survived their illness. Volume of left, right and both MBs was significantly decreased (p < 0.05) in patients with ALF and ACLF whereas there was no change in patients with CLF, when compared with healthy controls. However CN volumes did not change significantly compared to controls in any of the three patient groups. In the follow-up study significant recovery in volume of MBs was noted compared to baseline values in the ALF patients. We conclude that significant volume loss occurs in MBs in patients with ALF and ACLF of non-alcoholic etiology but not in CLF. This loss of MBs volume recovers substantially in patients with ALF who survive their illness.

Clinically relevant differences in the model for end-stage liver disease and model for end-stage liver disease-sodium scores determined at three university-based laboratories of the same area.

The Model for End-Stage Liver Disease (MELD) score is considered an objective and reliable measure of liver disease severity. However, the use of specific laboratory methodologies may introduce significant and clinically relevant variations into the score. It has been suggested that the incorporation of sodium into MELD (MELD-Na) can provide a more accurate survival prediction than MELD alone. Before implementing organ allocation based on the MELD score in an area with 3 transplant centers, we studied whether there were significant variations in MELD and MELD-Na scores determined at each center. Seventy patients on the waiting list were studied simultaneously. Blood samples for each patient were divided into 3 aliquots and were processed in the 3 laboratories in order to calculate MELD and MELD-Na scores. There were statistical differences between the 3 laboratories in the MELD and MELD-Na scores and their parameters. The MELD score was identical in the 3 laboratories for only 6 of the 70 patients, and the MELD-Na score was identical for only 9. MELD and MELD-Na scores from 2 laboratories differed by 1 point or more in 54% and 47% of cases, respectively. Our study confirms that there is major variability in the MELD score, serum sodium, and MELD-Na score. These differences are clinically relevant, and in order to guarantee equitable organ allocation based on the MELD score, similar laboratory methodologies should be implemented at all centers in the same organ procurement area. Alternatively, the possibility of setting up a central laboratory in each organ procurement area should be considered.

Should liver transplantation in patients with model for end-stage liver disease scores

Studies have shown that liver transplantation offers no survival benefits to patients with Model for End-Stage Liver Disease (MELD) scores or=18 years) listed for or undergoing primary liver transplantation in the United States for chronic liver disease from 1/1/2003 through 12/31/2007 with follow-up until 2/1/2008. The "Rule 14" policy gave a 3% improvement in overall patient survival over the present system at 1, 2, 3, and 4 years and predicted a 13% decrease in overall waitlist time for patients with MELD scores of 15 to 40. Patients with the greatest benefit from a "Rule 14" policy were those with MELD scores of 6 to 10, for whom a 17% survival advantage was predicted from waiting on the list versus undergoing transplantation. Our analysis supports changing the national liver allocation policy to not allow liver transplantation for patients with MELD

Adult living donor liver transplantation: body mass index and MELD score of recipients are independent risk factors for hospital mortality.

BACKGROUND AND AIMS: Adult living donor liver transplantation (LDLT) has been established as elective procedure or urgent procedure to save the life of patients with terminal liver diseases. The outcome of LDLT varies between transplant centers. Here, we aim to evaluate the outcome of LDLT in our center and to identify the risk factors that are associated with hospital mortality of recipients. PATIENTS AND METHODS: A cohort study with 32 consecutive cases of adult living donor liver transplantation was conducted in two cooperated medical centers. Perioperative data, incidence of postoperative complications, and hospital mortality were analyzed. RESULTS: No major surgical complications and no hospital mortality were observed in all 32 donors. All donors were discharged with normal liver function with median intensive care unit (ICU) stay of 1 day and median hospital stay of 10 days. All recipients had normal liver function in early posttransplant period. Eighty-one percent of the recipient survived with normal liver function for more than 1 year. The pretransplant ICU stay, renal failure, international normalized ratio (>1.8), and Model for End-stage Liver Disease (MELD) score (>20) were independent risk factors for hospital mortality of recipients. CONCLUSIONS: Adult living donor liver transplantation should be reserved to less "sick" patients in the era of organ allocation based on MELD score.

A new liver transplant priority for patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Patients with hepatocellular carcinoma on the waiting list for liver transplantation are excluded due to causes related to liver failure and tumor progression. We analyze the various factors to suggest a new liver transplant priority. METHODOLOGY: We evaluated the outcome on the list of 309 patients with hepatocellular carcinoma and causes of drop-out from the list were divided as death, "too sick" and tumor progression. The impact of model for end stage liver disease score, tumor stage and waiting time on the causes of drop-outs was evaluated. RESULTS: During the study period, 197 patients had a liver transplantation, 50 were still on the list and the remaining 62 were removed from the list (28 deaths, 30 tumor progressions, and 4 "too sick"). The receiver operating characteristic curves analysis showed that the model for end stage liver disease score predicted the rate of deaths on the list at 1-year (p<0.001). The waiting time and the tumor stage predicted the rate of drop-outs for tumor progression at 1-year on the list (p<0.05). CONCLUSIONS: Patients with hepatocellular carcinoma on the waiting list should have priority based on their model for end stage liver disease score, waiting time with tumor and tumor stage.