sTREM-1 as promising prognostic biomarker for acute-on-chronic liver failure and mortality in patients with acute decompensation of cirrhosis

BACKGROUND Acute decompensation(AD)of cirrhosis is associated with high short-term mortality,mainly due to the development of acute-on-chronic liver failure(ACLF).Thus,there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality.Soluble triggering receptor expressed on myeloid cells-1(sTREM-1)is released from activated innate immune cells and correlated with various inflammatory processes.AIM To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis.METHODS A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort(n=309)and validation cohort(n=133).Demographic and clinical data were collected,and serum sTREM-1 was measured at admission.All enrolled patients were followed-up for at least 1 year.RESULTS In patients with AD and cirrhosis,serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver,coagulation,cerebral and kidney failure.A new prognostic model of AD(P-AD)incorporating sTREM-1,blood urea nitrogen(BUN),total bilirubin(TBil),international normalized ratio(INR)and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease(MELD),MELD-sodium(MELD-Na),chronic liver failure-consortium(CLIF-C)ACLF and CLIF-C AD scores.Additionally,sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up.The ACLF risk score incorporating serum sTREM-1,BUN,INR,TBil and aspartate aminotransferase levels was established and significantly superior to MELD,MELD-Na,CLIF-C ACLF,CLIF-C AD and P-AD in predicting risk of ACLF development.CONCLUSION Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.

Therapeutic possibilities of gut microbiota modulation in acute decompensation of liver cirrhosis

The formation of liver cirrhosis(LC) is an unfavorable event in the natural history of chronic liver diseases and with the development of portal hypertension and/or impaired liver function can cause a fatal outcome. Decompensation of LC is considered the most important stratification variable for the risk of death. It is currently postulated that decompensation of LC occurs through an acute(including acute-on-chronic liver failure) and non-acute pathway. Acute decompensation of LC is accompanied by the development of life-threatening complications, characterized by an unfavorable prognosis and high mortality.Progress in understanding the underlying molecular mechanisms has led to the search for new interventions, drugs, and biological substances that can affect key links in the pathogenesis of acute decompensation in LC, for example the impaired gut-liver axis and associated systemic inflammation. Given that particular alterations in the composition and function of gut microbiota play a crucial role here, the study of the therapeutic possibilities of its modulation has emerged as one of the top concerns in modern hepatology. This review summarized the investigations that describe the theoretical foundations and therapeutic potential of gut microbiota modulation in acute decompensation of LC. Despite the encouraging preliminary data, the majority of the suggested strategies have only been tested in animal models or in preliminary clinical trials;additional multicenter randomized controlled trials must demonstrate their efficacy in larger patient populations.

Chronic liver failure-consortium acute-on-chronic liver failure and acute decompensation scores predict mortality in Brazilian cirrhotic patients

To validate prognostic scores for acute decompensation of cirrhosis and acute-on-chronic liver failure in Brazilian patients.METHODSThis is a prospective cohort study designed to assess the prognostic performance of the chronic liver failure-consortium (CLIF-C) acute decompensation score (CLIF-C AD) and CLIF-C acute-on-chronic liver failure score (CLIF-C ACLF), regarding 28-d and 90-d mortality, as well as to compare them to other prognostic models, such as Model for End-Stage Liver Disease (MELD), MELD Sodium (MELD-Na), Child-Pugh (CP) score, and the CLIF-C Organ Failure score (CLIF-C OF). All participants were adults with acute decompensation of cirrhosis admitted to the Emergency Department of a tertiary hospital in southern Brazil. Prognostic performances were evaluated by means of the receiver operating characteristic (ROC) curves, area under the curves (AUC) and 95%CI.RESULTSOne hundred and thirteen cirrhotic patients were included. At admission, 18 patients had acute-on-chronic liver failure (ACLF) and 95 individuals had acute decompensation (AD) without ACLF, of which 24 eventually developed ACLF during the course of hospitalization (AD evolving to ACLF group). The AD group had significantly lower 28-d (9.0%) and 90-d (18.3%) mortality as compared to the AD evolving to ACLF group and to the ACLF group (both P < 0.001). On the other hand, 28-d and 90-d mortalities were not significantly different between AD evolving to ACLF group and ACLF group (P = 0.542 and P = 0.708, respectively). Among patients with ACLF, at 28 d from the diagnosis, CLIF-C ACLF was the only score able to predict mortality significantly better than the reference line, with an AUC (95%CI) of 0.71 (95%CI: 0.54-0.88, P = 0.021). Among patients with AD, all prognostic scores performed significantly better than the reference line regarding 28-d mortality, presenting with similar AUCs: CLIF-C AD score 0.75 (95%CI: 0.63-0.88), CP score 0.72 (95%CI: 0.59-0.85), MELD score 0.75 (95%CI: 0.61-0.90), MELD-Na score 0.76 (95%CI: 0.61-0.90), and CLIF-C OF score 0.74 (95%CI: 0.60-0.88). The same occurred concerning AUCs for 90-d mortality: CLIF-C AD score 0.70 (95%CI: 0.57-0.82), CP score 0.73 (95%CI: 0.62-0.84), MELD score 0.71 (95%CI: 0.59-0.83), MELD-Na score 0.73 (95%CI: 0.62-0.84), and CLIF-C OF score 0.65 (95%CI: 0.52-0.78).CONCLUSIONThis study demonstrated that CLIF-C ACLF is the best available score for the prediction of 28-d mortality among patients with ACLF. CLIF-C AD score is also useful for the prediction of mortality among cirrhotic patients with AD not fulfilling diagnostic criteria for ACLF, but it was not superior to other well-established prognostic scores.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China

BACKGROUND Autoimmune liver disease(AILD)has been considered a relatively uncommon disease in China,epidemiological data for AILD in patients with cirrhosis and acute decompensation(AD)is sparse.AIM To investigate the prevalence,outcome and risk factors for AILD in cirrhotic patients complicated with AD in China.METHODS We collected data from patients with cirrhosis and AD from two prospective,multicenter cohorts in hepatitis B virus endemic areas.Patients were regularly followed up at the end of 28-d,90-d and 365-d,or until death or liver transplantation(LT).The primary outcome in this study was 90-d LTfree mortality.Acute-on-chronic liver failure(ACLF)was assessed on admission and during 28-d hospitalization,according to the diagnostic criteria of the European Association for the Study of the Liver(EASL).Risk factors for death were analyzed with logistic regression model.RESULTS In patients with cirrhosis and AD,the overall prevalence of AILD was 9.3%(242/2597).Prevalence of ACLF was significantly lower in AILD cases(14%)than those with all etiology groups with cirrhosis and AD(22.8%)(P<0.001).Among 242 enrolled AILD patients,the prevalence rates of primary biliary cirrhosis(PBC),autoimmune hepatitis(AIH)and PBC-AIH overlap syndrome(PBC/AIH)were 50.8%,28.5%and 12.0%,respectively.In ACLF patients,the proportions of PBC,AIH and PBC/AIH were 41.2%,29.4% and 20.6%.28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF.The etiology of AILD had no significant impact on 28-d,90-d or 365-d LTfree mortality in patients with cirrhosis and AD in both univariate and multivariate analysis.Total bilirubin(TB),hepatic encephalopathy(HE)and blood urea nitrogen(BUN)were independent risk factors for 90-d LT-free mortality in multivariate analysis.The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio.CONCLUSION AILD was not rare in hospitalized patients with cirrhosis and AD in China,among which PBC was the most common etiology.90-d LT-free mortality were independently associated with TB,HE and BUN.

Fecal cytolysin does not predict disease severity in acutely decompensated cirrhosis and acute-on-chronic liver failure

Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.

Chronic Liver Failure-Sequential Organ Failure Assessment is better than the Asia-Pacific Association for the Study of Liver criteria for defining acute-on-chronic liver failure and predicting outcome

AIM: To compare the utility of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) and Asia-Pacific Association for the Study of Liver (APASL) definitions of acute-on-chronic liver failure (ACLF) in predicting short-term prognosis of patients with ACLF.

Acute-on-chronic liver failure：recent update

Acute on chronic liver failure（ACLF） was first described in 1995 as a clinical syndrome distinct to classic acute decompensation.Characterized by complications of decompensation,ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between45%and 90%.Despite the clinical relevance of the condition,it still remains largely undefined with continued disagreement regarding its precise etiological factors,clinical course,prognostic criteria and management pathways.It is concerning that,despite our relative lack of understanding of the condition,the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%.This paper highlights our current understanding of ACLF,including its etiology,diagnostic and prognostic criteria and pathophysiology.It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates.The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters,while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

Definition and classification of acute-on-chronic liver diseases

Patients with chronic liver diseases(CLDs)develop acute liver injury and/or acute decompensation under the attack of various precipitants and present with significantly elevated alanine aminotransferase and/or total bilirubin levels,liver failure,or acute decompensation of liver cirrhosis,which is called acute-on-CLD(AoCLD).AoCLD accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases.AoCLD is complicated by various clinical types,the severity of the disease,and may pose a high risk of death.To date,the definition of AoCLD is still vague,and a consensus concept of the clinical classification is lacking.This review aimed to define the concept and clinical types of AoCLD based on related studies and the literature.

Prevalence and risk factors of acute-on-chronic liver failure in a single center from Argentina

AIMTo study the prevalence, characteristics, risk factors and mortality at 28 d of acute-on-chronic liver failure (ACLF). METHODSA total of 100 cirrhotic patients admitted to our hospital for more than one day were included during the period between June 2013 and December 2015. We used the European Association for the Study of the Liver-Chronic Liver Failure-Consortium diagnostic criteria for ACLF, considering it as the acute decompensation of cirrhosis associated with the presence of one or more organ failure. For the diagnosis of organic failure the Chronic Liver Failure-Sequential Organ Failure Assessment score was used. Our population was divided into patients with and without ACLF. Clinical characteristics, presence of precipitating events, potential risk factors for developing ACLF and causes of mortality were analyzed. Mortality at 28 d was evaluated. RESULTSTwenty-nine patients (29%) developed ACLF criteria. Alcoholism, detected in 58 patients (58%), was the major etiological agent of cirrhosis. Bacterial infections were recognized as a precipitating event in 41.3% of cases and gastrointestinal bleeding in 27.5%. No precipitating event was identifiable in 27.5% of patients with ACLF. Comparing patients with and without ACLF, statistically significant risk factors were: Child Pugh score 10.2 &plusmn; 2.1 vs 8.4 &plusmn; 1.6 (P ˂ 0.0001), MELD score 20.7 &plusmn; 8.5 vs 12.3 &plusmn; 4 (P ˂ 0.0001), presence of ascites 27 (93%) vs 43 (60.5%) (P = 0.001), leukocytosis 15300 &plusmn; 8033 per cubic millimeter vs 10770 &plusmn; 5601 per cubic millimeter (P ˂ 0.0001), and high plasma levels of C reactive protein values 50.9 &plusmn; 46.4 mg/L vs 28.6 &plusmn; 23.4 mg/L (P ˂ 0.0019). Mortality rate was 62% (18 patients) vs 5.6% (4 patients), respectively (P CONCLUSIONWe observed that the ACLF is a frequent entity in this group of patients and has a significantly higher mortality rate.

Animal models applied to acute-on-chronic liver failure:Are new models required to understand the human condition?

The liver is a multifaceted organ;its location and detoxifying function expose this organ to countless injuries.Acute-on-chronic failure liver(ACLF)is a severe syndrome that affects the liver due to acute decompensation in patients with chronic liver disease.An infection environment,ascites,increased liver enzymes and prothrombin time,encephalopathy and fast-evolving multiorgan failure,leading to death,usually accompany this.The pathophysiology remains poorly understand.In this context,animal models become a very useful tool in this regard,as understanding;the disease may be helpful in developing novel therapeutic methodologies for ACLF.However,although animal models display several similarities to the human condition,they do not represent all ACLF manifestations,resulting in significant challenges.An initial liver cirrhosis framework followed by the induction of an acute decompensation by administering lipopolysaccharide and D-Ga IN,potentiating liver damage supports the methodologies applied to induce experimental ACLF.The entire methodology has been described mostly for rats.Nevertheless,a quick Pub Med database search indicates about 30 studies concerning ACFL models and over 1000 regarding acute liver failure models.These findings demonstrate the clear need to establish easily reproducible ACFL models to elucidate questions about this quickly established and often fatal syndrome.

Correlation of Ceruloplasmin with Biomarkers of Cardiac Remodelling and Myofibrosis in Patients with Acute Decompensated Heart Failure Referred to a Tertiary Nurse Lead Heart Failure Clinic

Background: Ceruloplasmin is an acute phase protein with plasma copper binding properties, and is a potent extracellular antioxidative enzyme. Inflammation and oxidative stress might explain the role of ceruloplasmin in the pathophysiology of heart failure. Study objective: The objective is to assess the correlation of ceruloplasmin levels with biomarkers of cardiac remodelling and myofibrosis in patients with acute decompensated heart failure. Patients and methods: Blood samples were taken and serum levels of soluble ST2, galectin-3, NT-proBNP and ceruloplasmin were analysed in 31 consecutive patients with systolic HF referred to tertiary care nurse lead heart failure clinic with acute decompensated CHF requiring i.v. diuretics. The mean patients’ age was 68 years, mean left ventricular ejection fraction (LV EF) was 29%, 66% patients had ischemic aetilogy of CHF and 33% had atrial fibrillation. Results: The mean ceruloplasmin level was 0.243 g/l, mean galectin-3 level was 1.26 ng/ml, mean sST2 level was 38.15 ng/ml, and mean NT-proBNP was 1927 pg/ml. The ceruloplasmin level correlated with NT-proBNP (r = 0.58, p < 0.05) and with sST2 (r = 0.77, p < 0.001), sST2 levels correlated significantly with NT-proBNP (r = 0.66, p < 0.01). The ceruloplasmin level did not correlate with galectin-3 concentration. Conclusion: The ceruloplasmin level correlates with the biomarkers of cardiac remodelling (NT-proBNP, sST2), but not with the biomarker of myofibrosis (galectin-3). This finding supports the hypothesis of inflammatory response in acute decompensated heart failure.

Effi cacy and Renal Tolerability of Ultrafi ltration in Acute Decompensated Heart Failure: A Meta-analysis and Systematic Review of 19 Randomized Controlled Trials

Background:Acute decompensated heart failure(ADHF)is a life-threatening and costly disease.Controversy re-mains regarding the effi cacy and renal tolerability of ultrafi ltration for treating ADHF.We therefore performed this meta-analysis to evaluate this clinical issue.Methods:A search of PubMed,EMBASE,and the Cochrane database of controlled trials was performed from in-ception to March 2021 for relevant randomized controlled trials.The quality of the included trials and outcomes was evaluated with the use of the risk of bias assessment tool and the Grading of Recommendations,Assessment,Develop-ment and Evaluation(GRADE)approach,respectively.The risk ratio and the standardized mean difference(SMD)or weighted mean difference(WMD)were computed and pooled with fi xed-effects or random-effects models.Results:This meta-analysis included 19 studies involving 1281 patients.Ultrafi ltration was superior to the control treatments for weight loss(WMD 1.24 kg,95%confi dence interval[CI]0.38-2.09 kg,P=0.004)and fl uid removal(WMD 1.55 L,95%CI 0.51-2.59 l,P=0.003)and was associated with a signifi cant increase in serum creatinine level compared with the control treatments(SMD 0.15 mg/dL,95%CI 0.00-0.30 mg/dL,P=0.04).However,no signifi cant effects were found for serum N-terminal prohormone of brain natriuretic peptide level,length of hospital stay,all-cause mortality,or all-cause rehospitalization in the ultrafi ltration group.Conclusions:The use of ultrafi ltration in patients with ADHF is superior to the use of the control treatments for weight loss and fl uid removal,but has adverse renal effects and lacks signifi cant effects on long-term prognosis,in-dicating that this approach to decongestion in ADHF patients is effi cient for fl uid management but less safe renally.

Effect of Angiotensin Receptor-neprilysin Inhibitor on Acute Kidney Injury in Patients With Acute Decompensated Heart Failure

Objective:The risk of acute kidney injury(AKI)is high in patients with acute decompensated heart failure(ADHF).The aim of this study is to analyze the role of urinary neutrophil gelatinase-associated lipocalin(uNGAL)in diagnosing AKI in patients with ADHF and evaluate the therapeutic effect of angiotensin receptor-neprilysin inhibitor(ARNI)on AKI.Method:Sixty patients with ADHF were enrolled at the First Affiliated Hospital of Kangda College of Nanjing Medical University from January 2020 to June 2021,and randomized into 2 groups(ARNI group:30 patients treated with tablets of sacubitril valsartan sodium;and angiotensin-converting enzyme inhibitor(ACEI)group:30 patients treated with benazepril).The uNGAL level was measured immediately after as well as 1,2,3,and 7 d after hospital admission.The serum creatinine(sCr)level and estimated glomerular filtration rate(eGFR)were measured immediately as well as 2 and 7 d after hospital admission.The urine volume,dose of loop diuretics,and duration of hospital stay(DoHS)were recorded.Result:The most valuable diagnostic metric for AKI in patients with ADHF was the uNGAL level 1 d after hospital admission,which had a sensitivity of 0.94,specificity of 0.84,and optimal cutoff of 125.62μg/L.In the presence of AKI,during the first 2 d,patients in the ARNI-AKI and ACEI-AKI groups showed an increase in the sCr level and a reduction in the eGFR level,but there was no significant difference between the 2 groups(P>0.05).After 7 d of treatment,the sCr level decreased and the eGFR level increased in both groups,with a significantly greater changes being observed in the ARNI-AKI group than in the ACEI-AKI group(P<0.05,respectively).In the absence of AKI,the difference in the sCr level and eGFR between the 2 groups was not significant.The DoHS((11.25±2.38)d vs.(14.11±2.89)d),urinary microalbumin level((22.95±6.04)mg/L vs.(31.91±2.18)mg/L),and daily dose of loop diuretics((19.03±3.04)mg/d vs.(23.62±4.46)mg/d)were significantly lower in patients with AKI in the ARNI group than in the ACEI group(P<0.05,respectively).Conclusion:In patients with ADHF,uNGAL measurement enables the diagnosis of AKI earlier than that using the sCr level by 1 to 2 d.ARNI treatment reduced the sCr level,facilitated eGFR recovery,reduced the daily dose of loop diuretics,and decreased the DoHS compared with that in patients receive ACEI treatment.

Circulating insulin-like growth factor-binding protein 3 as prognostic biomarker in liver cirrhosis

AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.