Chronic Liver Failure Consortium Research Articles

Intra-Abdominal Hypertension and Its Prognostic Impact on Mortality in Cirrhotic Patients with Ascites: The Role of Paracentesis.

Elevated intra-abdominal pressure (IAP) can lead to intra-abdominal hypertension (IAH) and, in severe cases, abdominal compartment syndrome (ACS) in patients with cirrhosis and ascites. Paracentesis reduces IAP and improves abdominal perfusion. Intra-abdominal hypertension can also trigger acute-on-chronic liver failure (ACLF) in decompensated cirrhosis. This study evaluates the association between IAH and short-term mortality in patients with cirrhosis and ascites. This prospective, single-center cohort study included 18 patients (7 females, 11 males; median age: 59) scheduled for therapeutic paracentesis. Intra-abdominal pressure was measured using the bladder technique. Patients were grouped based on initial Chronic Liver Failure Consortium Organ Failure (CLIF-C OF) scores as ACLF or non-ACLF and followed up for 3 months. The median model for end-stage liver disease score was 17 (IQR 11-19). The primary etiologies of cirrhosis were viral hepatitis and alcoholic liver disease. Independent risk factors for IAH included advanced liver disease and large-volume ascites. Pre-paracentesis IAP was higher in ACLF patients (22 vs. 18 mm Hg). Post-paracentesis IAP was also higher in ACLF patients (14 vs. 8 mm Hg, P = .007). The 3-month mortality rate was 50%, with worse survival in ACLF patients (24 vs. 76.9 days, P = .002). Pre-paracentesis IAP was significantly higher in patients who died (22 vs. 18 mm Hg, P = .034), and survival was worse in those with IAP ≥18.5 mm Hg (P = .026). Intra-abdominal pressure is elevated in cirrhosis patients with grade 3 ascites. Despite similar paracentesis volumes, IAP remained higher in the ACLF group. Intra-abdominal pressure ≥18.5 mm Hg is associated with significantly reduced survival, indicating that IAH accelerates short-term mortality in these patients.

Liver Dysfunction and Systemic Inflammation Drive Organ Failures in Acute Decompensation of Cirrhosis: A Multicentric Study.

Hospitalized patients with acute decompensation (AD) of cirrhosis are at risk of progressing to acute-on-chronic liver failure (ACLF), significantly increasing their mortality. The aim of this study was to identify key predictors and patient trajectories predisposing to ACLF. In this multicenter, prospective study spanning 2 years, clinical, biochemical, and 90-day survival data were collected from 625 patients with AD (European Association for the Study of the Liver criteria) across North, South, and East India. We divided the cohort into a Derivation cohort (DC: 318 patients) and a Validation cohort (VC: 307 patients). Predictive models for pre-ACLF were derived, validated, and compared with established scores such as model for end-stage liver disease (MELD) 3.0 and chronic liver failure Consortium acute decompensation. Of 625 patients (mean age 49 years, 83% male, 77.5% with alcohol-related liver disease), 32.2% progressed to ACLF. Patients progressing to ACLF showed significantly higher bilirubin (10.9 vs 8.1 mg/dL), leukocyte counts (9,400 vs 8,000 per mm 3 ), international normalized ratio (1.9 vs 1.8), and MELD 3.0 (28 vs 25) but lower sodium (131 vs 134 mEq/L) and survival (62% vs 86%) compared with those without progression ( P < 0.05) in the DC. Consistent results were noted with alcohol-associated hepatitis, infection and hepatic encephalopathy as additional risk factors in VC. Liver failure at presentation (odds ratio: 2.4 [in DC], 6.9 [in VC]) and the 7-day trajectories of bilirubin, international normalized ratio, and MELD 3.0 significantly predicted ACLF progression ( P < 0.001). A new pre-ACLF model showed superior predictive capability (area under the curve of 0.71 in DC and 0.82 in VC) compared with MELD 3.0 and chronic liver failure Consortium acute decompensation scores ( P < 0.05). Approximately one-third of AD patients in this Indian cohort rapidly progressed to ACLF, resulting in high mortality. Early identification of patients at risk can guide targeted interventions to prevent ACLF.

Exploring the predictive value of serum lipids for short‐term prognosis in patients with acute‐on‐chronic liver failure

AbstractAimsAcute‐on‐chronic liver failure (ACLF) is defined as acute liver injury superimposed on chronic liver disease, resulting in a significantly increased short‐term mortality rate. Serum lipids are associated with the severity of liver disease and contribute to the prognostic assessment for cirrhosis and liver failure. However, the presentation of serum lipids varies in different studies, making it difficult to draw definitive conclusions. This study aimed to investigate the predictive value of serum lipids for short‐term prognosis in patients with ACLF.MethodsThis retrospective analysis was conducted using the clinical data of patients hospitalized for ACLF between January 2018 and December 2021. The collected data were subjected to Least Absolute Shrinkage and Selection Operator and logistic regression analyses to identify the independent predictors of 28‐day and 90‐day mortality. Separate regression models were developed for each identified serum lipid. These models were combined with the Model for End‐Stage Liver Disease (MELD), MELD combined with serum sodium concentration (MELD‐Na), Chronic Liver Failure Consortium Acute‐on‐chronic Liver Failure (CLIF‐C ACLF), and Chinese Group on the Study of Severe Hepatitis B‐ACLF (COSSH‐ACLF) scores to construct new models. The performance of these models was evaluated using the area under the receiver operating characteristic curve (AUC), Nagelkerke R2, Brier score, net reclassification index (NRI), and integrated discrimination improvement (IDI) to assess the prognostic ability of serum lipids.ResultsThis study included 266 patients with ACLF, of whom 25.9% (69/266) died within 28 days and 38.5% (102/265, with 1 lost to follow‐up) died within 90 days. The independent predictors of 28‐day mortality were age, the presence of overt hepatic encephalopathy at admission, high‐density lipoprotein cholesterol (HDL‐C) levels, and international normalized ratio (INR). The independent predictors of 90‐day mortality were age, albumin levels, serum creatinine levels, and INR. The comparative analysis revealed that the AUC of all other models exceeded that of HDL‐C (p &lt; 0.001). The COSSH‐ACLF model demonstrated superior predictive ability compared with the MELD and HDL‐MELD models (p = 0.013 and 0.017, respectively). Furthermore, the HDL‐COSSH‐ACLF model exhibited a similar trend in predictive ability compared with the latter two models (p = 0.009). No significant differences were observed in the AUC performances of the other models. A comparison of NRI calculated using the cutoff values assigned by equal assignment revealed that the addition of HDL‐C improved the predictive ability of the MELD score by 4.6% (NRI = 0.0460, p = 0.036). The MELD‐Na score exhibited an 8.4% improvement (NRI = 0.0844, p = 0.047), while the COSSH‐ACLF score demonstrated a 14.4% improvement (NRI = 0.1443, p = 0.015). However, these changes did not significantly impact the capacity of the CLIF‐C ACLF score (NRI = 0.0350, p = 0.141). No significant differences were observed in the IDI comparisons between the models with different cutoff values (all p &gt; 0.050).ConclusionsSerum HDL‐C is an independent predictor of 28‐day mortality in patients with ACLF. Although it has inferior predictive ability when considered alone, HDL‐C enhances the predictive capacity of MELD, MELD‐Na, and COSSH‐ACLF when incorporated into these models.

CLINICAL PATTERNS AND OUTCOMES IN CIRRHOTIC YEMENI PATIENTS WITH ACUTE-ON-CHRONIC LIVER FAILURE

Acute-on-chronic liver failure (ACLF) is a clinical condition of abrupt hepatic decompensation in chronic liver disease patients that is associated with extra-hepatic organ failures and a higher mortality rate. This study aimed to identify the clinical patterns and outcomes in cirrhotic Yemeni patients with ACLF. This prospective cohort study was carried out on 160 cirrhotic patients admitted between May 2023 and May 2024 to the Internal Medicine Department in Al-Sadaqah General Teaching Hospital in Aden governorate, Yemen. Based on the European Association for Study of Liver's Chronic Liver Failure Consortium EASL-CLIF criteria, patients were divided into Group A: 54 patients with ACLF. Group B: 106 patients without ACLF. The prevalence of ACLF is 33.8%. The mean age was 41.54± 8.11 years in ACLF and 39.22± 8.14 years in non-ACLF patients. The proportion of males in ACLF was 51.9% vs. 57.5% in non-ACLF patients. The most common causes of cirrhosis were cryptogenic (58.8%) and autoimmune hepatitis (25.6%). A significant correlation was found between prior hospitalization, decompensation, and the increased risk of developing ACLF. The most common complications were jaundice, hepatic encephalopathy, renal failure, signs of bacterial infection, ascites, and gastrointestinal bleeding, respectively. The main precipitating events for ACLF were bacterial infection, especially SBP (48.1%), GIT bleeding (24.1%), and no identified precipitating events (24.1%). The most common organ failures were renal (70.4%), liver (42.6%), and cerebral (31.5%). ACLF patients showed higher levels of WBCs, bilirubin, and serum creatinine. Mortality rates were significantly higher in ACLF patients compared to non-ACLF at both 28 days (33.3% vs. 5.7%) and 90 days (685% vs. 23.6%). This study demonstrated that ACLF patients have worse prognoses, higher mortality rates, increased ICU admission, lower survival, and higher rates of organ failure than non-ACLF patients.

From prognostication to therapeutics: Four key questions to accelerate the development of therapeutics for patients with acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) has come a long way as a clinical concept within the hepatology and liver transplant communities. Though the term was proposed in 1995, the first recognition of the entity along with a consensus definition emerged in 2009. Subsequently, the entity has sparked great interest, inspired several consensus conferences, and inspired national societies to form professional ACLF affinity groups (eg, special interest group). Multicenter consortia have been established all over the world to study this condition, including the North American Consortium for the Study of End-Stage Liver Disease, Chronic Liver Failure consortium, Asian Pacific Association for the Study of Liver Diseases ACLF Research Consortium, Chronic Liver disease Evolution And Registry for Events and Decompensation, and the LiverHope Consortium. Collectively, these consortia have enrolled tens of thousands of patients with or at risk for ACLF across dozens of countries and characterized in detail the predictors, pathogenesis, and progression of patients with ACLF. Perhaps most importantly, they have produced essential data characterizing the excess morbidity and mortality that patients with ACLF face, making a compelling case for the urgent need for therapeutic strategies for this condition.

Long-term outcome following liver transplantation of patients with ACLF grade 3

Utility, a major principle for allocation in the context of transplantation, is questioned in patients with acute-on-chronic liver failure grade 3 (ACLF-3) who undergo liver transplantation (LT). We aimed to explore long-term outcomes of patients included in a three-centre retrospective French study published in2017. All patients with ACLF-3 (n= 73), as well as their transplanted matched controls with ACLF-2 (n= 145), 1 (n= 119) and no ACLF (n= 292), who participated in the Princeps study published in 2017 were included. We explored 5- and 10-year patient and graft survival rates, causes of death and their predictive factors. Median follow-up of patients with ACLF-3 was 7.5 years. At LT, median MELD was 40. In patients with ACLF-3, 2, 1 and no ACLF, 5-year patient survival rates were 72.6% vs. 69.7% vs. 76.4% vs. 77.0%, respectively (p= 0.31). Ten-year patient survival for ACLF-3 was 56.8% and was not different to other groups (p= 0.37). Leading causes of death in patients with ACLF-3 were infections (33.3%) and cardiovascular events (23.3%). After exclusion of early death, UCLA futility risk score, age-adjusted Charlson comorbidity index and CLIF-C ACLF score were independently associated with 10-year patient survival. Long-term graft survival rates were not different across the groups. Clinical frailty scale and WHO performance status improved over time in patients alive after 5 years. 5- and 10-year patient and graft survival rates were not different in patients with ACLF-3 compared to matched controls. 5-year patient survival is higher than the 50%-70% threshold defining the utility of a liver graft. Efforts should focus on candidate selection based on comorbidities, as well as the prevention of infection and cardiovascular events. While short-term outcomes following liver transplantation in the most severely ill patients with cirrhosis (acute-on-chronic liver failure grade 3 [ACLF-3]) are known, long-term data are limited, raising questions about the utility of graft allocation in the context of scarce medical resources. This study provides a favourable long-term update, confirming no differences in 5- and 10-year patient and graft survival following liver transplantation in patients with ACLF-3 compared to matched patients with ACLF-2, ACLF-1, and no-ACLF. The study highlights the risk of dying from infection and cardiovascular causes in the long-term and identifies scores including comorbidity evaluation, such as the age-adjusted Charlson comorbidity index, as independently associated with long-term survival. Therefore, physicians should consider the cumulative burden of comorbidities when deciding whether to transplant these patients. Additionally, after transplantation, the study encourages mitigating infectious risk with tailored immunosuppressive regimens and tightly managing cardiovascular risk over time.

Development and validation of a new prognostic model for patients with acute-on-chronic liver failure in intensive care unit.

Cirrhotic patients with acute-on-chronic liver failure (ACLF) in the intensive care unit (ICU) have a poor but variable prognoses. Accurate prognosis evaluation can guide the rational management of patients with ACLF. However, existing prognostic scores for ACLF in the ICU environment lack sufficient accuracy. To develop a new prognostic model for patients with ACLF in ICU. Data from 938 ACLF patients in the Medical Information Mart for Intensive Care (MIMIC) database were used to develop a new prognostic model (MIMIC ACLF) for ACLF. Discrimination, calibration and clinical utility of MIMIC ACLF were assessed by area under receiver operating characteristic curve (AUROC), calibration curve and decision curve analysis (DCA), respectively. MIMIC ACLF was then externally validated in a multiple-center cohort, the Electronic Intensive Care Collaborative Research Database and a single-center cohort from the Second Hospital of Hebei Medical University in China. The MIMIC ACLF score was determined using nine variables: ln (age) × 2.2 + ln (white blood cell count) × 0.22 - ln (mean arterial pressure) × 2.7 + respiratory failure × 0.6 + renal failure × 0.51 + cerebral failure × 0.31 + ln (total bilirubin) × 0.44 + ln (internationalized normal ratio) × 0.59 + ln (serum potassium) × 0.59. In MIMIC cohort, the AUROC (0.81/0.79) for MIMIC ACLF for 28/90-day ACLF mortality were significantly greater than those of Chronic Liver Failure Consortium ACLF (0.76/0.74), Model for End-stage Liver Disease (MELD; 0.73/0.71) and MELD-Na (0.72/0.70) (all P < 0.001). The consistency between actual and predicted 28/90-day survival rates of patients according to MIMIC ACLF score was excellent and superior to that of existing scores. The net benefit of MIMIC ACLF was greater than that achieved using existing scores within the 50% threshold probability. The superior predictive accuracy and clinical utility of MIMIC ACLF were validated in the external cohorts. We developed and validated a new prognostic model with satisfactory accuracy for cirrhotic patients with ACLF hospitalized in the ICU. The model-based risk stratification and online calculator might facilitate the rational management of patients with ACLF.

Accuracy of chronic liver failure consortium (CLIF-C) ACLF score compared with meld, MELD-NA and CTP as a mortality predictor in acute on chronic liver failure patients admitted to tertiary rural care hospital

Background Chronic Liver Failure Consortium (CLIF-C) ACLF score, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) are established scoring systems for predicting mortality in Acute on Chronic Liver Failure (ACLF) patients. However, their comparative accuracy, especially in rural care settings, still needs to be explored. This study aims to assess and compare the predictive performance of these scoring systems, providing a nuanced understanding of their applicability in a tertiary rural care hospital. Method This prospective observational cohort study will be conducted at Acharya Vinoba Bhave Rural Hospital, following approval from the institutional ethical committee. ACLF patients aged 18 and above, presenting within one week of onset, will be included. Data collection will involve comprehensive assessments, including scoring system calculations, clinical examinations, and relevant investigations. Statistical analyses, encompassing descriptive statistics, comparative analyses, survival analyses, and multivariate models, will elucidate the accuracy and independent predictors of 28-day mortality. Expected Outcome Anticipated outcomes include a comprehensive understanding of the strengths and limitations of the CLIF-C ACLF score, MELD, MELD-Na, and CTP in predicting mortality among ACLF patients in a rural care context. The study aims to identify potential correlations and independent predictors, offering valuable insights for risk stratification. These findings are expected to guide clinicians in optimising prognostic assessments and decision-making, thereby improving the care and outcomes of ACLF patients in rural healthcare settings.

Outcome of individuals with alcoholic cirrhosis hospitalized with first decompensation and their predictors.

Alcohol is one of most common aetiologies of cirrhosis and decompensated cirrhosis is linked to higher morbidity and death rates. This study looked at the outcomes and mortality associated risk variables of individuals with alcoholic cirrhosis who had hospitalization with their first episode of decompensation. Individuals with alcoholic cirrhosis who were hospitalized with the first episode of decompensation [acute decompensation (AD) or acute-on-chronic liver failure (ACLF)] were included in the study and were prospectively followed up until death or 90 days, whichever was earlier. Of the 227 study participants analyzed, 167 (73.56%) and 60 (26.43%) participants presented as AD and ACLF, respectively. In the ACLF group, the mortality rate at 90 days was higher than in the AD group (48.3 vs 32.3%, P=0.02). In the AD group, participants who initially presented with ascites as opposed to variceal haemorrhage had a greater mortality rate at 90 days (36.4 vs 17.1%, P=0.041). The chronic liver failure-consortium AD score and the lactate-free Asian Pacific Association for the study of the Liver-ACLF research consortium score best-predicted mortality in individuals with AD and ACLF. There is significant heterogeneity in the type of decompensation in individuals with alcoholic cirrhosis. We observed significantly high mortality rate among alcoholic participants hospitalized with initial decompensation; deaths occurring in more than one-third of study participants within 90 days.

The Clinical Courses and Prognosis of Cirrhotic Patients after First Acute Decompensation: Prospective Cohort Study.

The European Foundation for the Study of Chronic Liver Failure (EF-CLIF) consortium suggested that the clinical courses after acute decompensation (AD) stratify the long-term prognosis: stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre acute-on-chronic liver failure (pre ACLF), and ACLF. However, previous studies included patients with a history of previous AD and had limitations associated with identifying the clinical factors related to prognosis after the first AD. The prospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort included cirrhotic patients who were hospitalised with first AD between July 2015 and August 2018. We analysed the factors associated with readmission after the first AD and compared the characteristics and prognosis among each subgroup to evaluate the risk factors for the occurrence of pre ACLF after AD. A total of 746 cirrhotic patients who were hospitalised with first AD were enrolled. The subgroups consisted of SDC (n = 565), UDC (n = 29), pre ACLF (n = 28), and ACLF (n = 124). Of note, pre ACLF showed a poorer prognosis than ACLF. The risk factors associated with readmission within 3 months of first AD were non-variceal gastrointestinal (GI) bleeding, hepatic encephalopathy (HE), and high MELD score. Viral aetiology was associated with the occurrence of pre ACLF compared with alcohol aetiology regardless of baseline liver function status. Cirrhotic patients with first AD who present as non-variceal GI bleeding and HE can easily relapse. Interestingly, the occurrence of AD with organ failure within 3 months of first AD (pre ACLF) has worse prognosis compared with the occurrence of organ failure at first AD (ACLF). In particular, cirrhotic patients with viral hepatitis with/without alcohol consumption showed poor prognosis compared to other aetiologies. Therefore, patients with ACLF after AD within 3 months should be treated more carefully and definitive treatment through LT should be considered.

Thromboelastography characteristics in critically ill patients with liver disease.

The purpose of this study was to determine how thromboelastography (TEG) parameters differ by various clinical conditions that commonly occur in patients with cirrhosis, including sepsis, acute on chronic liver failure (ACLF), alcohol-associated hepatitis (AAH) and portal vein thrombosis (PVT). TEG, a whole blood assay, is used to assess several parameters of coagulation and is becoming increasingly used in clinical practice. This study was a retrospective chart review of 155 patients admitted to the ICU with decompensated cirrhosis from 2017 to 2019. The R time was significantly shorter in patients when they were septic compared to when they were not and longer in patients with vs. without ACLF grade 3. Alpha angle and maximum amplitude was decreased in patients with severe AAH compared to those without severe AAH; and maximum amplitude was increased in patients with acute PVT compared to those with chronic PVT. R time was positively correlated with Chronic Liver Failure Consortium Organ Failure and Chronic Liver Failure Consortium ACLF scores (rho = 0.22, P = 0.020), while alpha angle and maximum amplitude were negatively correlated with MELD-NA. Findings suggest TEG parameters vary in several clinical conditions in patients with decompensated cirrhosis who are admitted to the ICU. Prospective research is needed to confirm our findings and to determine how this knowledge can be used to guide clinical practice, as well as blood product transfusions in the setting of bleeding or prior to invasive procedures.

Neutrophilia is more predictive than increased white blood cell counts for short-term mortality after liver transplantation in patients with acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a life-threatening disease that requires urgent liver transplantation (LT). Accurate identification of high-risk patients is essential for predicting post-LT survival. The chronic liver failure consortium ACLF score is a widely accepted risk-stratification score that includes total white blood cell (WBC) counts as a component. This study aimed to evaluate the predictive value of total and differential WBC counts for short-term mortality following LT in patients with ACLF. A total of 685 patients with ACLF who underwent LT between January 2008 and February 2019 were analyzed. Total and differential WBC counts were examined as a function of the model for end-stage liver disease for sodium (MELD-Na) score. The association between total and differential WBC counts and 90-day post-LT mortality was assessed using multivariable Cox proportional hazards regression analysis. The total WBC counts and neutrophil ratio were higher in patients with ACLF than in those without ACLF. The neutrophil ratio was significantly associated with 90-day post-LT mortality after adjustment (hazard ratio [HR], 1.04; P = 0.001), whereas total WBC counts were not significantly associated with 90-day post-LT mortality in either univariate or multivariate Cox analyses. The neutrophil ratio demonstrated a relatively linear trend with an increasing MELD-Na score and HR for 90-day post-LT mortality, whereas the total WBC counts exhibited a plateaued pattern. Neutrophilia, rather than total WBC counts, is a better prognostic indicator for short-term post-LT mortality in patients with ACLF.

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

Frequency, Clinical Presentation, and Outcome of Acute-on-Chronic Liver Failure among Decompensated Cirrhosis of Liver Patients in a Tertiary Care Hospital

Background: Acute-on-chronic liver failure (ACLF) is characterised by the presence of organ failure in patients with decompensated cirrhosis and is associated with high short-term mortality. Different international entities have taken initiatives to define the condition in different times but recommendations and definitions from The European Association for the Study of the Liver- Chronic Liver Failure (EASL-CLIF) Consortium Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study are most comprehensive and widely accepted till date. Only limited data are available on the prevalence, clinical characteristics, and short-term outcomes of ACLF in Bangladesh. It would be very useful for clinicians to identify patients with ACLF early and initiate focused therapy including referral to transplant centers if these data are available. Objective: To evaluate frequency, clinical presentation, and outcome of acute-on-chronic liver failure among decompensated cirrhosis of liver patients. Materials and Methods: This prospective observational study was carried out at the Department of Gastrointestinal, Hepatobiliary and Pancreatic Disorders (GHPD), BIRDEM General Hospital, Shahbagh, Dhaka, Bangladesh from July, 2019 to September, 2021. Total 175 patients with decompensated cirrhosis of liver were screened, out of which 22 patients were dropped out due to various reasons. Purposive type of non-probability sampling technique was used. Formal ethical clearance was taken from the Institutional Review Board and ethical measures were ensured in concordance with the Declaration of Helsinki. An informed written consent was taken from all participants. Diagnosis of decompensated cirrhosis was based on clinical, biochemical, radiological and endoscopic findings. Laboratory data sent within 24 hours were collected. Oxygen saturation was measured using fingertip pulse oximeter. Investigations for ACLF triggers were done as necessary which included but not limited to urine routine and microscopic examination, urine culture, blood culture, and Anti HEV IgM. Patients’ prognosis and survivability were observed by follow up phone call at 30 days. All data were recorded in a separate case record form and finally, it was analyzed by SPSS 23. Results: Out of 153 patients, 49 patients (32%) had ACLF: grade 1 ACLF in 26 (17%), grade 2 in 18 (11.8%), and grade 3 in 5 (3.3%) patients. Patients had an average age of 59.54±11.55 years with no significant difference between ACLF and no ACLF groups. Most patients in both groups had others (NAFLD, autoimmune hepatitis, secondary biliary cirrhosis, idiopathic) as the main underlying cause of cirrhosis. Bacterial infection, GI bleeding, HEV infection, reactivation of HBV were the precipitating events in 81.6% of patients with ACLF, with bacterial infection being the most common trigger (63.3%). Overall, 44.9% ACLF patients died within 30 days of admission. Older age, male sex, hepatic encephalopathy, GI bleeding, presence of any trigger and higher Child-Turcotte-Pugh (CTP) score were associated with increased risk of death in ACLF. Conclusion: Follow up of 153 patients with decompensated cirrhosis of liver revealed that 1 in 3 patients had ACLF and 44% of them would die in 30 days. Bacterial infection and GI bleeding were the most common triggers of ACLF. Early identification and intervention with multidisciplinary approach and referral to transplant centers are likely to improve survival outcomes in this population. Bangladesh Crit Care J September 2023; 11 (2): 113-120

Plasma S100A8 and S100A9 Are Strong Prognostic Factors for Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

The rapidly evolving organ failure and high short-run mortality of acute-on-chronic liver failure (ACLF) are inseparable from the role of systemic inflammatory response. S100A8 and S100A9 are associated with the excessive cytokine storm and play a decisive part within the process of inflammation. We aimed to clarify the role of them in predicting prognosis of hepatitis B virus-related ACLF (HBV-ACLF). S100A8 and S100A9 levels were analyzed in plasma of 187 transplant-free HBV-ACLF patients, 28 healthy controls and 40 chronic hepatitis B (CHB) patients. S100A8 and S100A9 mRNAs were checked in liver samples from 32 HBV-ACLF patients with liver transplantation, 19 patients undergoing surgery for hepatic hemangioma and 10 CHB patients with needle biopsy. The plasma levels of the S100A8 and S100A9 were higher in HBV-ACLF patients than in CHB patients (S100A8 : P < 0.001 and S100A9 : P < 0.001) and healthy controls (S100A8 : P < 0.001 and S100A9 : P < 0.001), and similar results were obtained for mRNA expression. Moreover, both proteins were related to ACLF grade, different types of organ failure, and infection, and they correlated with other prognostic scoring systems. S100A8 and S100A9 can dependently predict 28/90-day mortality (28-day: S100A8: hazard ratio (HR): 1.027; 95% confidence interval (CI): 1.007-1.048; P=0.026, S100A9 : HR: 1.009; 95% CI: 1.001-1.017; P=0.007, 90-day: S100A8 : HR: 1.023; 95% CI: 1.011-1.035; P=0.004, S100A9 : HR: 1.008; 95% CI: 1.004-1.012; and P < 0.001). Among all of the scoring systems, the combined scoring model (S100A8 and S100A9 jointly with the Chronic Liver Failure-Consortium Organ Failure score (CLIF-C OFs)) displayed the highest area under the receiver operating curve (0.923 (95% CI, 0.887-0.961)) in the prediction of 90-day mortality. S100A8 and S100A9 are promising biomarkers for the analysis of risk stratification and prognosis in ACLF patients. In addition, combining them with the CLIF-C OFs may better predict the prognosis of ACLF.

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure

Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n= 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n= 30). There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p= 0.018) and CLIF-C ACLF scores (p= 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p= 0.036). Biomarkers of systemic inflammation such as IL-8 (p= 0.006), cell death [cytokeratin-18: M30 (p= 0.005) and M65 (p= 0.029)], endothelial function [asymmetric dimethylarginine (p= 0.002)] and, ligands for Toll-like receptor 4 (p= 0.030) and inflammasome (p= 0.002) improved significantly in the DIALIVE group. These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. NCT03065699.

Frequency, Clinical Presentation, and Outcome of Acute-on-chronic Liver Failure among Decompensated Cirrhosis of Liver Patients in a Tertiary Care Hospital

Background: Acute-on-chronic liver failure (ACLF) is characterised by the presence of organ failure in patients with decompensated cirrhosis and is associated with high short-term mortality. Different international entities have taken initiatives to define the condition in different times but recommendations and definitions from The European Association for the Study of the Liver- Chronic Liver Failure (EASL-CLIF) Consortium Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study are most comprehensive and widely accepted till date. Only limited data are available on the prevalence, clinical characteristics, and short-term outcomes of ACLF in Bangladesh. It would be very useful for clinicians to identify patients with ACLF early and initiate focused therapy including referral to transplant centers if these data are available. Objective: To evaluate frequency, clinical presentation, and outcome of acute-on-chronic liver failure among decompensated cirrhosis of liver patients. Methods: This prospective observational study was carried out at the Department of Gastrointestinal, Hepatobiliary and Pancreatic Disorders (GHPD), BIRDEM General Hospital, Shahbagh, Dhaka, Bangladesh from July, 2019 to September, 2021. Total 175 patients with decompensated cirrhosis of liver were screened, out of which 22 patients dropped out due to various reasons. Purposive type of non-probability sampling technique was used. Formal ethical clearance was taken from the IRB and ethical measures were ensured in concordance with the Declaration of Helsinki. An informed written consent was taken from all participants. Diagnosis of decompensated cirrhosis was based on clinical, biochemical, radiological and endoscopic findings. Laboratory data sent within 24 hours were collected. Oxygen saturation was measured using fingertip pulse oximeter. Investigations for ACLF triggers were done as necessary which included but not limited to urine routine and microscopic examination, urine culture, blood culture, and Anti HEV IgM. Patients’ prognosis and survivability were observed by follow up phone call at 30 days. All data were recorded in a separate case record form and finally, it was analyzed by SPSS 23. Results: Out of 153 patients, 49 patients (32%) had ACLF: grade 1 ACLF in 26 (17%), grade 2 in 18 (11.8%), and grade 3 in 5 (3.3%) patients. Patients had an average age of 59.54±11.55 years with no significant difference between ACLF and no ACLF groups. Most patients in both groups had others (NAFLD, autoimmune hepatitis, secondary biliary cirrhosis, none) as the main underlying cause of cirrhosis. Bacterial infection, GI bleeding, HEV infection, reactivation of HBV were the precipitating events in 81.6% of patients with ACLF, with bacterial infection being the most common trigger (63.3%). Overall, 44.9% ACLF patients died within 30 days of admission. Older age, male sex, hepatic encephalopathy, GI bleeding, presence of any trigger and higher CTP score were associated with increased risk of death in ACLF. Conclusion: Follow up of 153 patients with decompensated cirrhosis of liver revealed that 1 in 3 patients had ACLF and 44% of them would die in 30 days. Bacterial infection and GI bleeding were the most common triggers of ACLF. Early identification and intervention with multidisciplinary approach and referral to transplant centers are likely to improve survival outcomes in this population. J Medicine 2023; Vol. 34, No. 2(1) Supplement: 221-222

Validation of the CLIF-C OF Score and CLIF-C ACLF Score to Predict Transplant-Free Survival in Patients with Liver Cirrhosis and Concomitant Need for Intensive Care Unit Treatment.

Both the Chronic Liver Failure Consortium (CLIF-C) organ failure score (OFs) and the CLIF-C acute-on-chronic-liver failure (ACLF) score (ACLFs) were developed for risk stratification and to predict mortality in patients with liver cirrhosis and ACLF. However, studies validating the predictive ability of both scores in patients with liver cirrhosis and concomitant need for intensive care unit (ICU) treatment are scarce. The aim of the present study is to validate the predictive ability of the CLIF-C OFs and CLIF-C ACLFs regarding the rationale of ongoing ICU treatment and to investigate their predictive ability regarding 28-days (short-), 90-days (medium-), and 365-days (long-term) mortality in patients with liver cirrhosis treated in an ICU. Patients with liver cirrhosis and acute decompensation (AD) or ACLF and concomitant need for ICU treatment were retrospectively analyzed. Predictive factors for mortality, defined as transplant-free survival, were identified using multivariable regression analyses and the predictive ability of CLIF-C OFs, CLIF-C ACLFs, MELD score, and AD score (ADs) was assessed by determining the AUROC. Of 136 included patients, 19 patients presented with AD and 117 patients with ACLF at ICU admission. In multivariable regression analyses, CLIF-C OFs as well as CLIF-C ACLFs were independently associated with higher short-, medium-, and long-term mortality after adjusting for confounding variables. The predictive ability of the CLIF-C OFs in the total cohort in short-term was 0.687 (95% CI 0.599-0.774). In the subgroup of patients with ACLF, the respective AUROCs were 0.652 (95% CI 0.554-0.750) and 0.717 (95% CI 0.626-0.809) for the CLIF-C OFs and for the CLIF-C ACLFs, respectively. ADs performed well in the subgroup of patients without ACLF at ICU admission with an AUROC of 0.792 (95% CI 0.560-1.000). In the long-term, the AUROCs were 0.689 (95% Cl 0.581-0.796) and 0.675 (95% Cl 0.550-0.800) for CLIF-C OFs and CLIF-C ACLFs, respectively. The predictive ability of CLIF-C OFs and CLIF-C ACLFs was relatively low to predict short- and long-term mortality in patients with ACLF with concomitant need for ICU treatment. However, the CLIF-C ACLFs may have special merit in judging futility of further ICU treatment.

Serum cytokine and chemokine profiles and disease prognosis in hepatitis B virus-related acute-on-chronic liver failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has significant morbidity and mortality and is associated with the induction of cytokines/chemokines, which might contribute to the pathogenesis of liver injury. This study aimed to explore the cytokine/chemokine profiles of patients with HBV-ACLF and develop a composite clinical prognostic model. We prospectively collected blood samples and the clinical data of 107 patients with HBV-ACLF admitted to the Beijing Ditan Hospital. The concentrations of 40-plex cytokines/chemokines were measured in 86 survivors and 21 non-survivors using the Luminex assay. Discrimination between the cytokine/chemokine profiles in different prognosis groups was analyzed using the multivariate statistical techniques of principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). An immune-clinical prognostic model was obtained using multivariate logistic regression analysis. The PCA and PLS-DA indicated that cytokine/chemokine profiling could clearly distinguish patients with different prognoses. A total of 14 cytokines, namely, IL-1β, IL-6, IL-8, IL-10, TNF-α, IFN-γ, CXCL1, CXCL2, CXCL9, CXCL13, CX3CL1, GM-SCF, CCL21, and CCL23, were significantly correlated with disease prognosis. Multivariate analysis identified CXCL2, IL-8, total bilirubin, and age as independent risk factors that constituted the immune-clinical prognostic model, which showed the strongest predictive value of 0.938 compared with those of the Chronic Liver Failure Consortium (CLIF-C) ACLF (0.785), Model for End-Stage Liver Disease (MELD) (0.669), and MELD-Na (0.723) scores (p<0.05 for all). The serum cytokine/chemokine profiles correlated with the 90-day prognosis of patients with HBV-ACLF. The proposed composite immune-clinical prognostic model resulted in more accurate prognostic estimates than those of the CLIF-C ACLF, MELD, and MELD-Na scores.

Body composition and short-term mortality in patients critically ill with acute-on-chronic liver failure

Body composition is sex dependent and associated with an increased mortality risk in patients with cirrhosis. We evaluated whether it was also associated with short-term mortality in patients critically ill with acute-on-chronic liver failure (ACLF). We retrospectively included all patients with cirrhosis and ACLF hospitalised in the intensive care unit (ICU) of Lausanne University Hospital between 2010 and 2019 for whom an abdominal computed tomography (CT) scan performed ±7 days from admission was available. Patients from the ICU of Paul Brousse University Hospital admitted between 2017 and 2020 served as an external cohort. All body composition parameters at the third lumbar vertebral level (L3) were quantified using a deep learning-based method. In total, 192 patients from Lausanne were included. Median age was 62 years and 28-day survival rate was 58.2%. In males, variables independently associated with 28-day mortality on days 1 and 3 were Chronic Liver Failure Consortium (CLIF-C) ACLF-lactate and sarcopenia. In females, CLIF-C ACLF-lactate on days 1 and 3 was the only predictor of 28-day survival. We derived two scores combining sarcopenia and the CLIF-C ACLF-lactate score on days 1 and 3, with area under the receiver operating characteristic outperforming the CLIF-C ACLF-lactate score alone in male but not in female patients. Comparable results were found in the external cohort of 58 patients and supported the sex specificity of the performance of the model. Patients with sarcopenia had increased risks of invasive fungal infection and renal replacement therapy. Sarcopenia was associated with 28-day mortality in male but not in female patients critically ill with ACLF. Although screening for sarcopenia could impact the management of male patients, further studies are needed in female cohorts to investigate whether other body composition parameters are associated with outcomes. Body composition, easily assessed by CT, is altered in patients with cirrhosis and associated with outcome; it has never been investigated in patients critically ill with ACLF. The results of the present study, underlining the benefit of sarcopenia evaluation to improve prognosis prediction in males critically ill with ACLF, are of importance for physicians managing such patients to optimise the decision-making process toward continued treatment, liver transplantation, or limitation of care. In a wider sense, besides the number and course of organ failures, the results recall the weight of the general condition of males with ACLF at admission to ICU. In females critically ill with ACLF, in analyses limited by the sample size, none of the body composition parameters was associated with short-term mortality independently of organ failures; this suggests that the number and course of organ failures are the main determinant of mortality in these patients.