CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

OBJECTIVE: Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. DESIGN: Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. RESULTS: Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. CONCLUSION: Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent

The Royal Free Hospital score: a calibrated prognostic model for patients with cirrhosis admitted to intensive care unit. Comparison with current models and CLIF-SOFA score

Prognosis for patients with cirrhosis admitted to intensive care unit (ICU) is poor. ICU prognostic models are more accurate than liver-specific models. We identified predictors of mortality, developed a novel prognostic score (Royal Free Hospital (RFH) score), and tested it against established prognostic models and the yet unvalidated Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) model

Acute-on-chronic Liver Failure: MELD Score 30-day Mortality Predictability and Etiology in a Pakistani Population

Background: Cirrhosis is a pathological condition that ultimately leads to liver failure. Acute on chronic liver failure (ACLF) has a high short term mortality rate. Viral hepatitis is the most common cause of liver failure in our local population. We carried out this study to identity the 30-day mortality and etiology of patients presenting with ACLF using Model for End-Stage Liver Disease (MELD) score predictability. Methodology: This was a descriptive case series, conducted at Sheikh Zayed Hospital, Lahore, Pakistan from January 31, 2018 to July 30, 2018. One hundred and eighty five patients who met the inclusion criteria were enrolled using 95% confidence level and 4% margin of error. Data was entered and analyzed with SPSS version 23.0. Numerical variables including age was presented by Mean ± S.D. Categorical variables i.e. gender, etiology of acute-on-chronic liver failure and 30-day mortality were presented by frequency and percentage. Data was stratified for age, gender, duration of chronic liver disease and MELD grade to address the effect modifiers. Post-stratification chi-square test was calculated using 95% significance (p≤0.05). Results: Majority of the enrolled patients were male (74.6%) while only 25.4% of the patients were female. One hundred and thirty patients (70.3%) had underlying viral hepatitis while twelve patients (6.5%) and forty three patients (23.2%) presented with alcoholic liver disease and drug-induced ACLF, respectively. Eighty patients (43.2%) died within 30 days of admission.The 30-day mortality with respect to MELD grade was statistically significant (p&lt;0.001) with the highest mortality noted in grade-IV and thirty five patients (43.8%) dying within 30 days of admission (p&lt;0.001). Grade-II and III MELD scores also contributed to the 30-day mortality with twenty three patients (28.8%) and nineteen patients (23.8%) dying within 30 days of admission (p&lt;0.001). Conclusion: MELD scores are able to accurately predict the short-term mortality in patients with ACLF and viral hepatitis was the most common etiology in our population. Early detection and use of appropriate prognostic models may alleviate mortality and morbidity in paitents with ACLF

New Perspectives on Treatment of Hepatitis B Before and After Liver Transplantation

open5noThe hepatitis B virus (HBV) infects more than 260 million people globally, with increasing incidence, especially in developing countries. Despite antiviral therapies, HBV-related end-stage liver disease remains one of the most important indications for liver transplantation worldwide. Although new available treatments have improved the outcome of patients with both compensated and decompensated liver disease in some specific clinical settings as acute-on-chronic liver failure mortality is still high. Moreover, the incidence of HBV-related hepatocellular carcinoma (HCC) seems to be increasing and represents a major challenge for the transplant team. In the post-transplant setting, combination of anti-HBV immunoglobulins and oral nucleos(t)ides provided significant improvement on graft and patient survival. Furthermore, recent data suggested the possibility of personalized therapeutic algorithms based on pre and post-transplant viral and host risk factors. Finally, liver grafts from HBV core antibody (anti-HBc) positive or hepatitis B surface antigen (HBsAg) donors can be safely used in order to expand the donor pool, considering adequate allocation and tailored prophylaxis after LT. In this review we have focused on the evolution of antiviral therapy for HBV, highlighting useful information to aid the transplant hepatologist in clinical practice.ReviewopenZanetto, Alberto; Ferrarese, Alberto; Bortoluzzi, Ilaria; Burra, Patrizia; Russo, Francesco PaoloZanetto, Alberto; Ferrarese, Alberto; Bortoluzzi, Ilaria; Burra, Patrizia; Russo, FRANCESCO PAOL

Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients

Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute-on-Chronic Liver Failure

AIMS: Recent data have demonstrated greater than 80% one-year survival probability after liver transplantation (LT) for patients with severe acute on chronic liver failure (ACLF). However, long term outcomes and complications are still unknown for this population. Our aim was to compare long-term patient and graft survival among patients transplanted across all grades of ACLF. METHODS: We analyzed the UNOS database, years 2004-2017. Patients with ACLF were identified using the EASL-CLIF criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. RESULTS: A total of 75,844 patients were transplanted of which 48,854 (64.4%) had no ACLF, 9,337 (12.3%) had ACLF-1, 9,386 (12.4%) had ACLF-2 and 8,267 (10.9%) had ACLF-3. Patients transplanted without ACLF had a greater proportion of hepatocellular carcinoma within (23.8%) and outside (12.7%) Milan criteria. Five-year patient survival after LT was lower in the ACLF-3 patients compared with the other groups (67.7%, p<0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF-1 (31.1%), ACLF-2 (33.3%) and ACLF-3 (36.7%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (38.5%). Graft survival probability at 5 years was above 90% among all patient groups. CONCLUSION: Patients transplanted with ACLF-3 have lower 5-year survival as compared to ACLF 0-2 but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS)

BACKGROUND AND AIMS: Liver transplantation (LT) has been proposed to be an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to address the current clinical practice and outcomes of ACLF patients wait listed (WL) for LT in Europe. METHODS: Retrospective study including 308 consecutive ACLF patients, listed in 20 centres across 8 European countries, from January 2018 to June 2019. RESULTS: 2677 patients received a LT, 1216 (45.4%) for decompensated cirrhosis (DC). Of these, 234 (19.2%) had ACLF at LT: ACLF-1, 58 (4.8%); ACLF-2, 78 (6.4%); and ACLF-3, 98 (8.1%). Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and Netherlands had medium rates (9-15%); and United Kingdom and Spain had low rates (3-5%) (p 4 mmol/L (HR 3.14, 95% CI 1.37-7.19), recent infection from multi-drug resistant organisms (HR 3.67, 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74, 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the WL. In an intention-to-treat analysis, one-year survival of ACLF patients on the LT WL was 73% for ACLF-1 or -2 and 50% for ACLF-3. CONCLUSION: The results reveal wide variations in listing patients with ACLF in Europe despite favorable post-LT survival. Risk factors for mortality were identified, allowing a more precise prognostic assessment of ACLF patients for potential LT. LAY SUMMARY: Acute on chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonized to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified for selecting patients with favorable outcomes