Showing papers on "Model for End-Stage Liver Disease published in 2021"

Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment

Abstract: The term acute-on-chronic liver failure (ACLF) defines an abrupt and life-threatening worsening of clinical conditions in patients with cirrhosis or chronic liver disease. In recent years, different definitions and diagnostic criteria for the syndrome have been proposed by the major international scientific societies. The main controversies relate to the type of acute insult (specifically hepatic or also extrahepatic), the stage of underlying liver disease (cirrhosis or chronic hepatitis) and the concomitant extrahepatic organ failure(s) that should be considered in the definition of ACLF. Therefore, different severity criteria and prognostic scores have been proposed and validated. Current evidence shows that the pathophysiology of ACLF is closely associated with an intense systemic inflammation sustained by circulating pathogen-associated molecular patterns and damage-associated molecular patterns. The development of organ failures may be a result of a combination of tissue hypoperfusion, direct immune-mediated damage and mitochondrial dysfunction. Management of ACLF is currently based on the supportive treatment of organ failures, mainly in an intensive care setting. For selected patients, liver transplantation is an effective treatment that offers a good long-term prognosis. Future studies on potential mechanistic treatments that improve patient survival are eagerly awaited.

Gut dysbiosis as a driver in alcohol-induced liver injury.

Abstract: Alcohol-related liver disease characterises a broad spectrum of hepatic diseases that result from heavy alcohol use, and include alcohol-related steatosis, steatohepatitis, fibrosis, cirrhosis, and alcoholic hepatitis. Amongst heavy drinkers, progression to more severe forms of alcohol-related liver disease is not universal, with only 20% developing cirrhosis and up to one-third developing alcoholic hepatitis. Non-alcohol-related triggers for severe disease are not well understood, but the intestinal microbiome is thought to be a contributing factor. This review examines the role of the microbiome in mild alcohol-related liver disease, cirrhosis, and alcoholic hepatitis. While most of the literature discusses bacterial dysbiosis, we also discuss the available evidence on fungal (mycobiome) and virome alterations in patients with alcohol-related liver disease. Additionally, we explore the mechanisms by which the microbiome contributes to the pathogenesis of alcohol-related liver disease, including effects on intestinal permeability, bile acid dysregulation, and production of hepatotoxic virulence factors.

ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) usually arises in the context of a chronically damaged liver. Liver functional estimation is of paramount importance in clinical decision making. The Child-Pugh score (CPS) can be used to categorise patients into 3 classes (A to C) based on the severity of liver functional impairment according to 5 parameters (albumin, bilirubin, prothrombin time, presence of ascites and hepatic encephalopathy). The albumin-bilirubin (ALBI) grade has emerged as an alternative, reproducible and objective measure of liver functional reserve in patients with HCC, defining worsening liver impairment across 3 grades (I to III). The ALBI score can identify different subgroups of patients with different prognoses across the diverse Barcelona Clinic Liver Cancer stages and CP classes, making it an appealing clinical predictor. In patients treated with potentially curative approaches (resection, transplantation, radiofrequency ablation, microwave ablation), ALBI grade has been shown to correlate with survival, tumour relapse, and post-hepatectomy liver failure. ALBI grade also predicts survival, toxicity and post-procedural liver failure in patients treated with transarterial chemoembolisation, radioembolisation, external beam radiotherapy as well as multi-kinase inhibitors (sorafenib, lenvatinib, cabozantinib, regorafenib) and immune checkpoint inhibitor therapy. In this review, we summarise the body of evidence surrounding the role of ALBI grade as a biomarker capable of optimising patient selection and therapeutic sequencing in HCC.

NAFLD and MAFLD as emerging causes of HCC: A populational study

Abstract: Background & Aims There are conflicting data regarding the epidemiology of hepatocellular carcinoma (HCC) arising in the context of non-alcoholic and metabolic-associated fatty liver disease (NAFLD and MAFLD). We aimed to examine the changing contribution of NAFLD and MAFLD, stratified by sex, in a well-defined geographical area and highly characterised HCC population between 1990 and 2014. Methods We identified all patients with HCC resident in the canton of Geneva, Switzerland, diagnosed between 1990 and 2014 from the prospective Geneva Cancer Registry and assessed aetiology-specific age-standardised incidence. NAFLD-HCC was diagnosed when other causes of liver disease were excluded in cases with type 2 diabetes, metabolic syndrome, or obesity. Criteria for MAFLD included one or more of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. Results A total of 76/920 (8.3%) of patients were diagnosed with NAFLD-HCC in the canton of Geneva between 1990 and 2014. Between the time periods 1990–1994 and 2010–2014, there was a significant increase in HCC incidence in women (standardised incidence ratio [SIR] 1.83, 95% CI 1.08–3.13, p = 0.026) but not in men (SIR 1.10, 95% CI 0.85–1.43, p = 0.468). In the same timeframe, the proportion of NAFLD-HCC increased more in women (0–29%, p = 0.037) than in men (2–12%, p = 0.010) while the proportion of MAFLD increased from 21% to 68% in both sexes and from 7% to 67% in women (p Conclusions In a populational cohort spanning 25 years, the burden of NAFLD and MAFLD associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women. Lay summary Hepatocellular carcinoma (HCC) is the most common type of liver cancer, increasingly arising in patients with liver disease caused by metabolic syndrome, termed non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). We assessed all patients with HCC between 1990 and 2014 in the canton of Geneva (western Switzerland) and found an increase in all HCC cases in this timeframe, particularly in women. In addition, we found that HCC caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall HCC cases.

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

Abstract: Objective Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients. Design This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation. Results After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM. Conclusion The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.

Racial Disparity in Liver Transplantation Listing

Abstract: Background Previous studies have demonstrated disparities in transplantation for women, non-Caucasians, the uninsured or publicly insured, and rural populations. We sought to correlate transplant center characteristics with patient access to the waiting list and liver transplantation. We hypothesized that liver transplant centers vary greatly in providing equitable access to the waiting list and liver transplantation. Study design Center-specific, adult, deceased-donor liver transplant and waitlist data for the years 2013 to 2018 were obtained from the United Network for Organ Sharing. Waitlist race/ethnicity distributions from liver transplant centers performing ≥ 250 transplants over this period (n = 109) were compared with those of their donor service area, as calculated from 5-year US Census Bureau estimates of 2017. Center-specific characteristics correlating with disparities were analyzed using a linear regression model with a log transformed outcome. Results Non-Hispanic Blacks (NHBs) are under-represented in liver transplant listing compared with center donation service area (88/109, 81%), whereas, non-Hispanic Whites are over-represented (65/109, 58%) (p Conclusions Non-Hispanic Blacks are listed for liver transplantation less than would be expected. Once listed, however, racial disparities in transplantation are greatly diminished. Improvements in access to adequate health insurance appear to be essential to diminishing disparities in access to this life-saving care.

Liver resection for hepatocellular carcinoma in patients with clinically significant portal hypertension.

Abstract: Background & Aims Liver resection (LR) in patients with hepatocellular carcinoma (HCC) and clinically significant portal hypertension (CSPH) defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg is not encouraged. Here, we reappraised the outcomes of patients with cirrhosis and CSPH who underwent LR for HCC in highly specialised liver centres. Methods This was a retrospective multicentre study from 1999 to 2019. Predictors for postoperative liver decompensation and textbook outcomes were identified. Results In total, 79 patients with a median age of 65 years were included. The Child-Pugh grade was A in 99% of patients, and the median model for end-stage liver disease (MELD) score was 8. The median HVPG was 12 mmHg. Major hepatectomies and laparoscopies were performed in 28% and 34% of patients, respectively. Ninety-day mortality and severe morbidity rates were 6% and 27%, respectively. Postoperative and persistent liver decompensation occurred in 35% and 10% of patients at 3 months. Predictors of liver decompensation included increased preoperative HVPG (p = 0.004), increased serum total bilirubin (p = 0.02), and open approach (p = 0.03). Of the patients, 34% achieved a textbook outcome, of which the laparoscopic approach was the sole predictor (p = 0.004). The 5-year overall survival and recurrence-free survival rates were 55% and 43%, respectively. Conclusions Patients with cirrhosis, HCC and HVPG ≥10 mmHg can undergo LR with acceptable mortality, morbidity, and liver decompensation rates. The laparoscopic approach was the sole predictor of a textbook outcome. Lay summary Patients with cirrhosis, hepatocellular carcinoma, and clinically significant portal hypertension (defined as a hepatic venous pressure gradient ≥10 mmHg) can undergo resection with acceptable mortality, morbidity, liver decompensation rates, and a textbook outcome. These results can be achieved in selected patients with preserved liver function, good general status, and sufficient remnant liver volume.

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation

Abstract: Background & Aims Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). Methods This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. Results The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. Conclusions The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy. Clinical Trials Registration EudraCT 2016-001177-32. Lay summary Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy.

Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors.

Abstract: Background Combined hepatocellular-cholangiocarcinoma liver tumors (cHCC-CCA) with pathologic differentiation of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma within the same tumor are not traditionally considered for liver transplantation due to perceived poor outcomes. Published results are from small cohorts and single centers. Through a multicenter collaboration, we performed the largest analysis to date of the utility of liver transplantation for cHCC-CCA. Study Design Liver transplant and resection outcomes for HCC (n = 2,998) and cHCC-CCA (n = 208) were compared in a 12-center retrospective review (2009 to 2017). Pathology defined tumor type. Tumor burden was based on radiologic Milan criteria at time of diagnosis and applied to cHCC-CCA for uniform analysis. Kaplan-Meier survival curves and log-rank test were used to determine overall survival and disease-free survival. Cox regression was used for multivariate survival analysis. Results Liver transplantation for cHCC-CCA (n = 67) and HCC (n = 1,814) within Milan had no significant difference in overall survival (5-year cHCC-CCA 70.1%, HCC 73.4%, p = 0.806), despite higher cHCC-CCA recurrence rates (23.1% vs 11.5% 5 years, p Conclusions Regardless of tumor burden, outcomes after liver transplantation are superior to resection for patients with cHCC-CCA. Within Milan criteria, liver transplant for cHCC-CCA and HCC result in similar overall survival, justifying consideration of transplantation due to the higher chance of cure with liver transplantation in this traditionally excluded population.

The Largest Single Center Report on Pediatric Liver Transplantation: Experiences and Lessons Learned.

Abstract: Objective We described our experiences on pediatric liver transplantation (LT) from the largest LT center in the world termed the Shiraz Transplant Center. Background After the first successful pediatric LT in 1967, pediatric LT has become the routine treatment for children with liver failure worldwide. Methods Data on a total of 1141 pediatric cases of LT were collected. Specifics on baseline and anthropometric characteristics, clinicopathology, prognosis of recipients of LT, and donor characteristics are reported. Results Mean age of patients was 7.83 ± 5.55 years old. Most common etiologies for LT were biliary atresia (15.9%), progressive familial intrahepatic cholestasis (13.4%), and Wilson's disease (13.3%), respectively.Whole organs, living donor grafts, and split grafts were used in 47.9%, 41%, and 11.1% of patients, respectively. In-hospital complications were seen among 34.7% of patients and the most common complications were infections (26.8%), bleeding (23.4%), and vascular complications (18%).Median (interquartile range) model for end stage liver disease score was 20 (15, 25). Main causes of death among patients were sepsis (35.2%), followed by post-transplantation lymphoproliferative diseases (10.5%), and primary nonfunction of liver (9%).Patient survival showed improvement over the years (1-year survival of 73.1%, 83.4%, and 84.4%, 2-year survival of 65.2%, 77.1%, and 78.7%, 5-year survival of 58.2%, 72%, and 77.8% for 1997-2007, 2007-2013, and 2013-2019, respectively; P Conclusions This is the largest single-center report on pediatric LT in literature which provides valuable experiences in pediatric LT.

A Comparison of Different Frailty Scores and Impact of Frailty on Outcome in Patients With Cirrhosis

Abstract: Background & aims There is no “gold standard” tool for the assessment of frailty in cirrhosis. This study compares Liver Frailty Index (LFI), Short Physical Performance Battery (SPPB), Fried Frailty Criteria (FFC), and Clinical Frailty Scale (CFS) for frailty assessment and ascertains its impact on predicting mortality and hospitalizations in a cohort of outpatients with cirrhosis. Methods 116 patients were enrolled in this prospective observational cohort study. Frailty assessment was done using LFI, SPPB, FFC, and CFS. All patients were followed up for 6 months. The primary outcome was the first of either all-cause unplanned hospitalization or all-cause mortality occurring within 6 months of the study period. Results 100 (86.2%) males and 16 (13.8%) females with a mean age of 50.2 (48.4–51.9, 95% CI) years were included. The most common cause of cirrhosis was alcoholic liver disease (47.4%) followed by hepatitis C (12.9%) and Nonalcoholic steatohepatitis (NASH) (10.3%). There was no significant difference in prevalence of frailty based on LFI (43.1%), FFC (36.2%), CFS (44%), and SPPB (47.4%) (P > 0.05). Frail patients had worse outcomes compared to the Not frail group. At 6 months, the mortality rate in Frail patients was 42% versus 1.5% for the Not frail; hospitalization in Frail patients occurred in 92% versus 6% in the Not frail. On multivariable analysis, independent predictors of mortality were Frailty [OR 14 (1.4–54.2)], alcohol-related cirrhosis [OR 4.2 (1.1–16.3)], Child-Turcotte-Pugh (CTP) [OR 2.1 (1.4–2.9)] and Chronic liver disease questionnaire (CLDQ) [OR 0.1 (0.1–0.4)] scores. Conclusions LFI, SPPB, FFC, and CFS are comparable in frailty assessment in patients with cirrhosis. Importantly, comparability of the commonly used scores for frailty assessment and prediction of hospitalization and mortality allows flexibility for clinical application.

Early transplantation maximizes survival in severe acute-on-chronic liver failure: Results of a Markov decision process model.

Abstract: Background Uncertainties exist surrounding the timing of liver transplantation (LT) among patients with acute-on-chronic liver failure grade 3 (ACLF-3), regarding whether to accept a marginal quality donor organ to allow for earlier LT or wait for either an optimal organ offer or improvement in the number of organ failures, in order to increase post-LT survival. Methods We created a Markov decision process model to determine the timing of LT among patients with ACLF-3 within 7 days of listing, to maximize overall one-year survival probability. Results We analyzed six groups of candidates with ACLF-3: patients age ≤60 or >60 years, patients with 3 organ failures alone or 4-6 organ failures, and hepatic or extrahepatic ACLF-3. Among all groups, LT yielded significantly greater overall survival probability versus remaining on the waiting list for even 1 additional day (p 60 years or with 4-6 organ failures. Probability of improvement from ACLF-3 to ACLF-2 does not influence these recommendations, as the likelihood of organ recovery was less than 10%. Conclusion During the first week after listing for patients with ACLF-3, earlier LT in general is favored over waiting for an optimal quality donor organ or for recovery of organ failures, with the understanding that the analysis is limited to consideration of only these three variables. Lay summary In the setting of grade three acute-on-chronic liver failure (ACLF-3), questions remain regarding the timing of transplantation in terms of whether to proceed with liver transplantation with a marginal donor organ versus waiting for an optimal liver, and whether to transplant a patient with ACLF-3 or wait until improvement to ACLF-2. In this study, we used a Markov decision process model to demonstrate that earlier transplantation of patients listed with ACLF-3 maximizes overall survival, as opposed to waiting for an optimal donor organ or for improvement in the number of organ failures.

Elevated plasma ICAM1 levels predict 28-day mortality in cirrhotic patients with COVID-19 or bacterial sepsis.

Abstract: Background and Aims: Endothelial injury and dysfunction play a detrimental role in the pathogenesis of infections. Endothelium-related molecules have been reported as potential biomarkers for early diagnosis and/or prognosis of infections. The prognostic value of these biomarkers in patients with liver cirrhosis and infections however remain elusive. Methods: In this study, we investigated the performance of key soluble endothelial injury biomarkers, including intercellular adhesion molecule 1 (ICAM1), von Willebrand Factor (vWF) antigen, vascular endothelial growth factor receptor 1 (vegfr1), angiopoietin 1 and 2 (Ang1, 2) as mortality predictors in liver cirrhosis patients with severe covid-19 or bacterial sepsis. Results: A total of 66 hospitalized patients [admitted in covid-19 ward or liver intensive care unit (ICU)] were included. 22 patients had covid-19 alone while 20 patients had cirrhosis plus covid-19. 24 patients had liver cirrhosis plus bacterial sepsis. Among cirrhosis patients, most common aetiology was alcohol. ICAM1 was increased (p=0.003) while vegfr1 (p<0.0001) and Ang1 (p<0.0001) were reduced in covid-19 patients with cirrhosis, as compared to covid-19 patients alone. Endothelial biomarkers between cirrhosis patients with severe covid-19 or with bacterial sepsis in the ICUs did not differ significantly. In these patients, ICAM1 levels significantly and independently predicted mortality (HR:3.24;1.19-8.86) along with MELD, renal and coagulation failures. The area under the curve for ICAM1 was 0.74, MELD was 0.60 and combined ICAM1 and MELD was 0.70. ICAM1 also positively correlated with the composite organ failure scores recorded 3-5 days post ICU admission (CLIF-OF and SOFA) in this subgroup of patients. Conclusion: The study indicates that in patients with liver cirrhosis, elevated plasma ICAM1 serve as an independent predictor of severe covid-19 or sepsis associated 28-day mortality. Lay Summary: Bacterial sepsis and covid-19 lead to increased mortality in cirrhosis patients. In this study, we demonstrate that high plasma levels of ICAM1, an endothelial injury biomarker is one of the important factors predicting mortality in critically-ill cirrhotic patients having severe covid-19 or bacterial sepsis.