Prognosis Of Acute-on-chronic Liver Failure Research Articles

Identification of oxidative stress-related biomarkers associated with the development of acute-on-chronic liver failure using bioinformatics

Acute-on-chronic liver failure (ACLF) is a serious stage of chronic liver disease with high short-term mortality and no definitely effective treatment. Oxidative stress (OS) is involved in the development of ACLF. OS-related genes targeted therapy may provide additional assistance for the treatment of ACLF. ACLF related gene sets and oxidative stress-related genes (OSGs) were respectively downloaded from gene expression omnibus (GEO) database and GeneCards database for integrated bioinformatics analyses (functional enrichment, weighted gene co-expression network and immune cells infiltration). Immune-related differentially expressed oxidative stress-related genes (DEOSGs) in ACLF were used for construction of protein–protein interaction (PPI) network in which hub genes were screened out. Hub genes with consistently good diagnostic or prognostic value for ACLF in four gene sets were named as key genes. DEOSGs were significantly enriched in biological process and signaling pathways related to inflammation, immune response and oxidative stress. Six key genes (MPO, CCL5, ITGAM, TLR2, TLR4, and TIMP1) were identified and found to be highly correlated with immune response and metabolic process. This study deepened our understanding of the impact of oxidative stress on the pathogenesis and prognosis of ACLF and provided more insights into the prediction of prognosis and molecular targeted therapy in ACLF.

ABC prognostic classification and MELD 3.0 and COSSH-ACLF Ⅱ prognostic evaluation in acute-on-chronic liver failure

Objective: To investigate the ABC prognostic classification and the updated version of Model for End-stage Liver Disease (MELD) score 3.0 and Chinese Group on the Study of Severe Hepatitis B ACLF Ⅱ score (COSSH-ACLF Ⅱ score) to evaluate the prognostic value in acute-on-chronic liver failure (ACLF). Methods: ABC classification was performed on a 1 409 follow-up cohorts. The area under the receiver operating characteristic curve (AUROC) was used to analyze MELD, MELD 3.0, COSSH-Ⅱ and COSSH-Ⅱ score after 3 days of hospitalization (COSSH-Ⅱ-3d). The prognostic predictive ability of patients were evaluated for 360 days, and the prediction differences of different classifications and different etiologies on the prognosis of ACLF were compared. Results: The survival curve of 1 409 cases with ACLF showed that the difference between class A, B, and C was statistically significant, Log Rank (Mantel-Cox) χ2=80.133, P<0.01. Compared with class A and C, χ2=76.198, P<0.01, the difference between class B and C, was not statistically significant χ2=3.717, P>0.05. AUROC [95% confidence interval (CI)] analyzed MELD, MELD 3.0, COSSH-Ⅱ and COSSH-Ⅱ-3d were 0.644, 0.655, 0.817 and 0.839, respectively (P<0.01). COSSH-Ⅱ had better prognostic predictive ability with class A ACLF and HBV-related ACLF (HBV-ACLF) for 360-days, and AUROC (95% CI) were 0.877 and 0.881, respectively (P<0.01), while MELD 3.0 prognostic predictive value was not better than MELD. Conclusion: ACLF prognosis is closely related to ABC classification. COSSH-Ⅱ score has a high predictive value for the prognostic evaluation of class A ACLF and HBV-ACLF. COSSH-Ⅱ score has a better prognostic evaluation value after 3 days of hospitalization, suggesting that attention should be paid to the treatment of ACLF in the early stage of admission.

Association between plasma level of superoxide dismutase and survival of patients with acute-on-chronic liver failure

BackgroundFewer than 50% of patients with acute-on-chronic liver failure (ACLF) recover spontaneously, and ACLF has high mortality without liver transplantation. Oxidative stress has been shown to mediate hepatic inflammation during acute liver failure (ALF). We wanted to see if a biomarker for oxidative stress might be used to measure the severity and prognosis of ACLF patients.MethodsA retrospective cohort of 124 ACLF patients, as well as healthy individuals, liver cirrhosis and ALF patients, was studied between January 2015 and September 2018. The levels of plasma superoxide dismutase (SOD) were detected using an ELISA commercial kit, and the Kaplan–Meier method was used for survival analysis.ResultsPatients with ACLF had statistically higher plasma SOD levels than the controls did (healthy controls and liver cirrhosis patients); however, the levels did not differ from those in patients with ALF. The plasma SOD level may be an inexpensive, easily accessible, and significant independent prognostic index for mortality on multivariate analysis (HR = 1.201, 95% CI 1.001–1.403, P < 0.01) as well as the model for end-stage liver disease (MELD) score. A level of SOD > 428 U/mL was linked to a statistically significant increase in the likelihood of death or liver transplantation in ACLF patients. Combination of plasma SOD levels and MELD scores improved performance in measuring the severity and prognosis of ACLF patients.ConclusionPatients with ACLF can be classified into high-risk and low-risk groups based on their plasma SOD levels at the time of admission to the hospital. The patient outcome is more closely connected with the combination of SOD level and MELD score than either value alone. This approach might be used to predict patient prognoses and prioritize liver transplant candidates.

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS

The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.

The prognostic value of acute-on-chronic liver failure during the course of severe alcoholic hepatitis

A better identification of factors predicting death is needed in alcoholic hepatitis (AH). Acute-on-chronic liver failure (ACLF) occurs during the course of liver disease and can be identified when AH is diagnosed (prevalent ACLF [pACLF]) or during follow-up (incidental ACLF [iACLF]). This study analyzed the impact of ACLF on outcomes in AH and the role of infection on the onset of ACLF and death. Patients admitted from July 2006 to July 2015 suffering from biopsy-proven severe (s)AH with a Maddrey discriminant function (mDF) ≥32 were included. Infectious episodes, ACLF, and mortality were assessed during a 168-day follow-up period. Results were validated on an independent cohort. One hundred sixty-five patients were included. Mean mDF was 66.3 ± 20.7 and mean model for end-stage liver disease score was 26.8 ± 7.4. The 28-day cumulative incidence of death (CID) was 31% (95% CI 24-39%). Seventy-nine patients (47.9%) had pACLF. The 28-day CID without pACLF and with pACLF-1, pACLF-2, and pACLF-3 were 10.4% (95% CI 5.1-18.0), 30.8% (95% CI 14.3-49.0), 58.3% (95% CI 35.6-75.5), and 72.4% (95% CI 51.3-85.5), respectively, p <0.0001. Twenty-nine patients (17.5%) developed iACLF. The 28-day relative risk of death in patients developing iACLF was 41.87 (95% CI 5.2-335.1; p <0.001). A previous infection was the only independent risk factor for developing iACLF during the follow-up. Prevalence, incidence, and impact on prognosis of ACLF were confirmed in a validation cohort of 97 patients with probable sAH. ACLF is frequent during the course of sAH and is associated with high mortality. Infection strongly predicts the development of ACLF in this setting. In patients with chronic liver disease, an acute deterioration of liver function combined with single or multiple organ failures is known as acute-on-chronic liver failure. This study shows that acute-on-chronic liver failure is frequent during the course of severe alcoholic hepatitis. In severe alcoholic hepatitis, acute-on-chronic liver failure is associated with high mortality and frequently occurs after an infection.

Clinical and virological implications of A1846T and C1913A/G mutations of hepatitis B virus genome in severe liver diseases

Objective: Mutations occurring within different genes of hepatitis B virus (HBV) genome may have different clinical implications. This study aimed to observe the clinical and virological implications of the A1846T and C1913A/G mutations of HBV genome in the development and treatment outcome of severe liver diseases, which has not been previously determined.Materials and methods: A total of 438 cases of patients with liver diseases were retrospectively reviewed, including 146 with mild chronic hepatitis B infection (CHB-M), 146 with severe chronic hepatitis B infection (CHB-S), and 146 with acute-on-chronic liver failure (ACLF). Partial or full-length HBV genome was directly sequenced. Replicons containing A1846T, C1913A or other mutant sequences, or the wild-type counterparts were constructed respectively, and then transfected into HepG2 cells for phenotype analysis.Results: There was significant difference in the detection rates of A1846T (30.82%, 40.41% and 55.48%, respectively) and C1913A/G (15.52%, 28.77%, and 35.62%, respectively) among patients with CHB-M, those with CHB-S, and those with ACLF (p < .01). A1846T was significantly associated with the mortality of ACLF patients within six months after the disease onset (OR 1.704, p = .041). In vitro experiment revealed that A1846T mutant resulted in 3.20-fold and 1.85-fold increase of replication capacity and promoter activity, respectively compared with wild type counterpart (p < .001), while C1913A led to a significant decrease of core protein expression (p < .05).Conclusion: Occurrence of A1846T and C1913A is positively associated with clinical presentations of severe liver disease. A1846T mutation is significantly associated with poor prognosis of ACLF.

Acute-on-Chronic Liver Failure: A Portuguese Single-Center Reference Review

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by an acute deterioration of a patient with cirrhosis, frequently associated with multi-organ failure and a high short-term mortality rate. We present a retrospective study that aims to characterize the presentation, evolution, and outcome of patients diagnosed with ACLF at our center over the last 3 years, with a comparative analysis between the group of patients that had ACLF precipitated by infectious insults of bacterial origin and the group of those with ACLF triggered by a nonbacterial infectious insult; the incidence of acute kidney injury and its impact on the prognosis of ACLF was also analyzed. Twenty-nine patients were enrolled, the majority of them being male (89.6%), and the mean age was 53 years. Fourteen patients (48.3%) developed ACLF due to a bacterial infectious event, and 9 of them died (64.2%, overall mortality rate 31%); however, no statistical significance was found (p < 0.7). Of the remaining 15 patients (51.7%) with noninfectious triggers, 11 died (73.3%, overall mortality rate 37.9%); again there was no statistical significance (p < 0.7). Twenty-four patients (83%) developed acute kidney injury (overall mortality rate 65.5%; p < 0.022) at the 28-day and 90-day follow-up. Twelve patients had acute kidney injury requiring renal replacement therapy (41.37%; overall mortality rate 37.9%; p < 0.043). Hepatic transplant was performed in 3 patients, with a 100% survival at the 28-day and 90-day follow-up (p < 0.023). Higher grades of ACLF were associated with increased mortality (p < 0.02; overall mortality 69%). Conclusions: ACLF is a heterogeneous syndrome with a variety of precipitant factors and different grades of extrahepatic involvement. Most cases will have some degree of renal dysfunction, with an increased risk of mortality. Hepatic transplant is an efficient form of therapy for this syndrome.

The analysis of acute kidney injury in hepatitis B virus related acute-on-chronic liver failure

Objective To investigate the incidence and risk factors of acute kidney injury (AKI) in hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) patients, and to explore the impact of AKI on the prognosis of ACLF. Methods The medical records of 227 patients who were diagnosed with HBV-related ACLF at the Department of Infectious Diseases in the First Affiliated Hospital of Nanchang University from January 2015 to August 2016 were retrospectively reviewed. Patients were divided into AKI group and non-AKI group based on the AKI criteria published by International Club of Ascites in 2015. Demographic and clinical data were compared between groups. The AKI incidence and its impact on patients’ prognosis were analyzed. The comparison of continuous variables was done by t test or rank-sum test. The comparison of categorical variables was done by χ2 test or Fisher exact test. AKI risk factors were analyzed by using logistic regression. Results There were 66 (29.1%) cases were diagnosed with AKI among 227 ACLF patients, among which, 45 patients (68.2%) were stage Ⅰ, 14 (21.2%) were stage Ⅱ and 7 (10.6%) were stage Ⅲ. Age, cirrhosis, concentrations of total bilirubin and albumin, international normalized ratio (INR), percentage of neutrophils, MELD scores and spontaneous peritonitis rate (SBP) were all statistically different between AKI group and non-AKI group (all P<0.05). The binary logistic regression analysis revealed that only INR (OR=3.132, P=0.001) and SBP(OR=4.204, P=0.001) were the independent risk factors of AKI. The optimal cut-off value for INR was 2.025 with AUROC of 0.609 (P=0.01), sensitivity of 59.1% and specificity of 62.1%.The 30-day mortality of AKI group was significantly higher than non-AKI group (χ2=18.324, P<0.01). Conclusions AKI is relatively common in patients with ACLF. The risk factors of AKI are INR and SBP. AKI has significant impact on the short-term survival rate of ACLF. Therefore, physicians should pay attention to patients with INR of ACLF at admissions and SBP during the management so as to prevent the occurrence of AKI and to reduce the fatality of ACLF. Key words: Hepatitis B; Acute on chronic liver failure; Acute kidney injury; Risk factors

Prognostic analysis of acute-on-chronic liver failure after withdrawal of nucleos(t)ide analogues for antiviral treatment of chronic hepatitis B

To investigate the prognostic factors for acute-on-chronic liver failure (ACLF) after the withdrawal of nucleos(t)ide analogues (NAs) for the antiviral treatment of chronic hepatitis B (CHB). The clinical data of 67 hospitalized patients with ACLF after withdrawal of NAs for the antiviral treatment of CHB were analyzed retrospectively. The HBeAg status before initial treatment and after recurrence, course of the antiviral treatment, duration from the withdrawal of NAs to recurrence, and type of NAs before and after withdrawal were not associated with the prognosis of ACLF. The Cox univariate regression analysis showed that serum bilirubin, international normalization ratio, serum creatinine, model of end-stage of liver disease (MELD) score, hepatic encephalopathy, and concurrent infection were associated with the 12-week death. The Cox multivariate regression analysis showed that MELD score and hepatic encephalopathy were independent predictors for 12-week death. The area under the receiver operating characteristic curve for the MELD score to predict 12-week death was 0.906, with an optimal cutoff value of 32, a sensitivity of 82.9%, a specificity of 88.5%, a positive predictive value of 91.9%, and a negative predictive value of 76.7%. MELD score and hepatic encephalopathy are closely associated with the prognosis of patients with ACLF after withdrawal of NAs for the antiviral treatment of CHB.

Influence of variceal bleeding on natural history of ACLF and management options.

Patients with diagnosed and undiagnosed chronic liver diseases experience one or more acute assaults of a hepatic nature and develop a downhill course of liver diseases, a condition regarded as acute-on-chronic liver failure (ACLF). It is a medical emergency, the prognosis of ACLF is extremely bad and considerable numbers of patients with ACLF die even after diagnosis and receiving conservative treatment. ACLF is characterized by jaundice, coagulopathy, ascites and encephalopathy. ACLF patients are very sick and associated with different hemodynamic profiles and have very high 3-month mortality. As these groups of patients have high baseline hepatic venous pressure gradients, the chances of variceal bleed are also high, and the impact is also greater in comparison to stable cirrhosis; however, evidence is lacking to substantiate such effects. The aim of this review is to discuss the natural course of variceal bleeding in ACLF patients and to develop insights into the management of variceal bleeding in ACLF.