CLIF-C Acute-on-chronic Liver Failure Research Articles

Validation of prognostic scores to predict short-term mortality in patients with HBV-related acute-on-chronic liver failure: The CLIF-C OF is superior to MELD, CLIF SOFA, and CLIF-C ACLF.

Acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) patients has a high short-term mortality. Identification of effective models to predict the short-term mortality may enable early intervention and improve patients’ prognosis. We aim to assess the performance of the CLIF Consortium Organ Failure score (CLIF-C OFs), CLIF sequential organ failure assessment score (CLIF-SOFAs), CLIF Consortium ACLF score (CLIF-C ACLFs), ACLF grade, and model for end-stage liver disease score (MELDs) in predicting the short-term mortality in CHB patients with ACLF.Among the 155 consecutive adult patients with liver failure as a discharge diagnosis were screened, and all the patients were treated at the Department of Infectious Diseases, Huashan Hospital, Fudan University (Shanghai, China) from January 2010 to February 2016. The diagnosis of ACLF was based on the criteria formalized by the ACLF consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Diagnostic accuracy for predicting short-term (28-day) mortality was calculated for CLIF-C OFs, CLIF-SOFAs, CLIF-C ACLFs, ACLF grade, and MELDs in all patients.One hundred fifty-five consecutive adult liver failure patients were screened and 85 patients including 73 males and 12 females were enrolled. Overall, the 28-day transplant-free mortality was 32% in all patients, and 100% in those with severe early course (ACLF-3). The area under the receiver operating characteristic curve (AUROC) of CLIF-C OFs (AUROC: 0.906, P = .0306, compared with MELDs) was higher than those of CLIF-SOFAs (AUROC: 0.876), CLIF-C ACLFs (AUROC: 0.858), ACLF grade (AUROC: 0.857), and MELDs (AUROC: 0.838) for predicting short-term mortality. The cut-point for baseline CLIF-C OFs in predicting death was 8.5, with 67% sensitivity, 90% specificity, and AUROC of 0.906 (95% CI: 0.8450–0.9679).The results indicate that short-term mortality is high in patients with ACLF and CLIF Consortium Organ Failure score is superior to MELD, CLIF SOFA, and CLIF-C ACLF in predicting its short-term mortality.

PTU-090 Circulating Level of End Product of Apoptosis Caspase-Cleaved Keratin 18 Reflects Clinical Severity in Acute on Chronic Liver Disease and Is A Potential Biomarker for Diagnosis and Therapeutic Monitoring

Introduction Acute on Chronic Liver Failure (ACLF) is characterised by progressive multi-organ failure and an unacceptably high mortality. This distinguishes it clinically and prognostically from Acute Decompensation (AD) of cirrhosis. We have previously demonstrated elevated markers of apoptosis in a rat model of ACLF and a small cohort of human ACLF patients. The aim of this study is to measure plasma levels of caspase-cleaved keratin 18 (cK18), a product of apoptosis, in a well-characterised cohort of subjects with progressive degrees of liver injury, with the aim of confirming our observation of elevated apoptosis in decompensated liver disease and establishing the utility of cK18 as a biomarker of severity of liver injury. Additionally, the correlation of cK18 levels with prognostic clinical scores will be assessed. Methods 78 patients with acutely decompensated liver disease were enrolled and divided into AD (n = 25), ACLF1 (n = 25) and ACLF2 (n = 28) using the CLIF-C ACLF and AD scores. Additionally, 27 stable compensated cirrhotic patients (SC) and 12 healthy volunteers were recruited. Plasma cK18 levels were measured by enzyme linked immunosorbent assay (ELISA) using the M30 antibody for detection. Results were analysed using Prism 6 Software (GraphPad). As the data were not normally distributed, a non-parametric test (Mann-Whitney-Wilcoxon test) was used. Spearman rank test was used for correlation studies. Results cK18 levels rose progressively with the severity of liver injury (median values and interquartile range): healthy 100.5 U/L (IR 76.97–144.7), stable cirrhosis 155.5 U/L (IR 102.5–269.8), AD 341.9 U/L (IR 102.5–489.9), ACLF1 603.6 U/L (IR 342.4–1046) and ACLF2 1028 U/L (IR 513.6–2641), respectively). Statistically significant differences were observed between healthy controls vs SC (p = 0.0232), SC vs AD (p = 0.0054), AD vs ACLF1 and 2 (p = 0.0054 and 0.0006 respectively), ACLF1 and 2 (0.068) (Figure 1). Additionally, cK18 values correlated with model for end-stage liver disease (MELD) score, (r = 0.48, p Conclusion Our data clearly demonstrates a statistically significant, progressive increase in circulating cK18 and apoptosis with increasing clinical severity of decompensated liver disease. These values also correlated with major prognostic scores used in current practice. cK18 is therefore a promising biomarker of severity of liver injury and further studies are needed to assess its role both as a prognostic tool and in monitoring therapeutic response. Disclosure of Interest None Declared

Prognosis and Biomarkers in Acute-on-Chronic Liver Failure.

As formal definitions of acute-on-chronic liver failure (ACLF) have now been established, and given an increased recognition of the dynamic nature of this condition, there is a growing clinical need to assess prognosis and response to interventions. Conventional scoring systems such as Model for End-Stage Liver Disease (MELD) fail to capture the two key prognostic elements in ACLF-namely, extrahepatic organ failure and measures of systemic inflammation-and as such are limited in their prognostic accuracy. Even the best available scoring systems such as the recently described CLIF (Chronic Liver Failure) Consortium ACLF (CLIF-C ACLF) score, are at best 75% accurate and need to be applicable to all etiologies of liver disease. Thus, in the absence of "gold standard" markers of prognosis that render one scoring system superior to another, there is a need to explore other markers of pathophysiology that may better define outcome. This review addresses the evidence for markers of oxidative stress, including those reflecting the inflammasome; elements of cell death such as cytokeratins M30 and M65; and indicators of immune dysfunction, innate immune failure and gut dysbiosis. Finally, evidence for relevance of markers of organ dysfunction, including hemodynamic response, are explored along with associated mediators such as copeptin, dimethylarginines, and renin. It is anticipated that further critique and validation of emerging and relevant biomarkers will facilitate a composite score which, either alone or in combination with existing scoring systems such as CLIF-C, will enable improved prognostication and targeting of therapy in ACLF.

Characteristics, Diagnosis and Prognosis of Acute-on-Chronic Liver Failure in Cirrhosis Associated to Hepatitis B.

The diagnostic and prognostic criteria of acute-on-chronic liver failure (ACLF) were developed in patients with no Hepatitis B virus (HBV) cirrhosis (CANONIC study). The aims of this study were to evaluate whether the diagnostic (CLIF-C organ failure score; CLIF-C OFs) criteria can be used to classify patients; and the prognostic score (CLIF-C ACLF score) could be used to provide prognostic information in HBV cirrhotic patients with ACLF. 890 HBV associated cirrhotic patients with acute decompensation (AD) were enrolled. Using the CLIF-C OFs, 33.7% (300 patients) were diagnosed as ACLF. ACLF was more common in the younger patients and in those with no previous history of decompensation. The most common organ failures were ‘hepatic’ and ‘coagulation’. As in the CANONIC study, 90-day mortality was extremely low in the non-ACLF patients compared with ACLF patients (4.6% vs 50%, p < 0.0001). ACLF grade and white cell count, were independent predictors of mortality. CLIF-C ACLFs accurately predicted short-term mortality, significantly better than the MELDs and a disease specific score generated for the HBV patients. Current study indicates that ACLF is a clinically and pathophysiology distinct even in HBV patients. Consequently, diagnostic criteria, prognostic scores and probably the management of ACLF should base on similar principles.

Characterization of acute-on-chronic liver failure and prediction of mortality in Asian patients with active alcoholism.

Alcoholic liver diseases often evolve to acute-on-chronic liver failure (ACLF), which increases the risk of (multi-)organ failure and death. We investigated the development and characteristics of alcohol-related ACLF and evaluated prognostic scores for prediction of mortality in Asian patients with active alcoholism. A total of 205 patients who were hospitalized with severe alcoholic liver disease were included in this retrospective cohort study, after excluding those with serious cardiovascular diseases, malignancy, or co-existing viral hepatitis. The Chronic Liver Failure (CLIF) Consortium Organ Failure score was used in the diagnosis and grading of ACLF, and the CLIF Consortium ACLF score (CLIF-C ACLFs) was used to predict mortality. Patients with ACLF had higher Maddrey discriminant function, model for end-stage liver disease (MELD), and MELD-sodium scores than those without ACLF. Infections were more frequently documented in patients with ACLF (33.3% vs 53.0%; P = 0.004). Predictive factors for ACLF development were systemic inflammatory response syndrome (odds ratio [OR], 2.239; P < 0.001), serum sodium level (OR, 0.939; P = 0.029), and neutrophil count (OR, 1.000; P = 0.021). For prediction of mortality at predefined time points (28-day and 90-day) in patients with ACLF, areas under the receiver-operating characteristic were significantly greater for the CLIF-C ACLFs than for Child-Pugh, MELD, and MELD-sodium scores. Infection and systemic inflammatory response syndrome play an important role in the development of alcohol-related ACLF in Asian patients with active alcoholism. The CLIF-C ACLFs may be more useful for predicting mortality in ACLF cases than liver-specific scoring systems.

Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF)

Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study. Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade-I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF-scores computed at inclusion. We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57-1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)). The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores.

Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure

Non-selective beta blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation and high mortality. As NSBBs may have beneficial effects on gut motility and permeability and, systemic inflammation, the aims of this prospective, observational study were to determine whether ongoing use of NSBBs reduced 28-day mortality in ACLF patients. The study was performed in 349 patients with ACLF included in the CANONIC study, which is a prospective observational investigation in hospitalized cirrhotic patients with acute deterioration. The data about the use of NSBBs, its type and dosage was specifically recorded. Patient characteristics at enrollment significantly associated with treatment and mortality were taken into account as potential confounders to adjust for treatment effect. A logistic regression model was fitted. 164 (47%) ACLF patients received NSBBs whereas 185 patients did not. Although the CLIF-C ACLF scores were similar at presentation, more patients in the NSBB treated group had lower grades of ACLF (p=0.047) at presentation and significantly more patients improved. Forty patients (24.4%) died in NSBB treated group compared with 63 patients (34.1%) (p=0.048) [estimated risk-reduction 0.596 (95%CI: 0.361-0.985; p=0.0436)]. This improvement in survival was associated with a significantly lower white cell count (NSBB: 8.5 (5.8); no NSBB: 10.8 (6.6); p=0.002). No long-term improvement in survival was observed. This study shows for the first time that ongoing treatment with NSBBs in cirrhosis is safe and reduces the mortality if they develop ACLF. Careful thought should be given before stopping NSBBs in cirrhotic patients.

Clinical Course of acute‐on‐chronic liver failure syndrome and effects on prognosis

Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days. Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.

Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients. Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use. The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis. The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients.