Bilirubin Molecular Species Play an Important Role in the Pathophysiology of Acute-on-Chronic Liver Failure.

Bilirubin plays a key role in early diagnosis, prognosis, and prevention of liver diseases. Unconjugated bilirubin (UCB) requires conversion to a water-soluble form through liver glucuronidation, producing monoglucuronide (BMG) or diglucuronide bilirubin (BDG) for bile excretion. This study aimed to assess the roles of bilirubin's molecular species-UCB, BMG, and BDG-in diagnosing and understanding the pathogenesis of liver cirrhosis in patients with acute-on-chronic liver failure (ACLF), compensated liver cirrhosis (LC) patients, and healthy individuals. The study included patients with ACLF and compensated LC of diverse etiologies, along with healthy controls. We collected laboratory and clinical data to determine the severity and assess mortality. We extracted bilirubin from serum samples to measure UCB, BMG, and BDG using liquid chromatography-mass spectrometry (LC-MS). The quantification of bilirubin was performed by monitoring the mass charge (m/z) ratio. Of the 74 patients assessed, 45 had ACLF, 11 had LC, and 18 were healthy individuals. Among ACLF patients, the levels of molecular species of bilirubin were UCB 19.69 µmol/L, BMG 47.71 µmol/L, and BDG 2.120 µmol/L. For compensated cirrhosis patients, the levels were UCB 11.29 µmol/L, BMG 1.49 µmol/L, and BDG 0.055 µmol/L, and in healthy individuals, the levels were UCB 6.42 µmol/L, BMG 0.52 µmol/L, and BDG 0.028 µmol/L. The study revealed marked elevations in the bilirubin species in individuals with ACLF compared to those with compensated cirrhosis and healthy controls, underscoring the progression of liver dysfunction. The correlation of BMG and BDG levels with commonly used inflammatory markers suggests a relationship between bilirubin metabolism and systemic inflammation in ACLF.

Elevated neopterin levels are associated with acute-on-chronic liver failure and mortality in patients with liver cirrhosis.

BACKGROUND: Macrophage activation plays a central role in hepatic and systemic inflammation and is involved in the pathogenesis of acute-on-chronic liver failure (ACLF). AIMS: This study aimed to investigate neopterin levels in patients admitted for acute decompensation (AD) of cirrhosis, evaluating its relationship with ACLF and prognosis. METHODS: This prospective cohort study included 205 adult subjects hospitalized for AD of cirrhosis. Twenty-one healthy subjects and 89 patients with stable cirrhosis were evaluated as controls. RESULTS: Circulating neopterin was higher in AD as compared to stable cirrhosis and healthy controls (p<0.001). ACLF was independently associated with higher neopterin levels (OR 1.015, 95% CI 1.002-1.028, p = 0.025). In the multivariate Cox regression analysis, neopterin levels (HR = 1.002, IC 95% 1.000-1.004, p = 0.041), Child-Pugh class C, and ACLF were predictors of 30-day survival. Among patients with ACLF, the Kaplan-Meier survival probability was 71.4% in those with neopterin levels < 25 nmol/L and 31.0% if neopterin ≥ 25 nmol/L (p<0.001). CONCLUSIONS: Higher circulating neopterin was associated with ACLF in patients hospitalized for AD of cirrhosis. Neopterin levels were also independently predictors of high short-term mortality, especially among patients with ACLF, and could represent a useful biomarker of macrophage activation in clinical practice.

MicroRNA profiles in serum samples from Acute-On-Chronic Liver Failure patients and miR-25-3p as a potential biomarker for survival prediction.

Acute-on-chronic liver failure (ACLF) is a condition characterized by acute decompensation of cirrhosis, associated with organ failure(s), and high short-term mortality. The microRNAs or miRNAs are small non-coding RNA molecules, stable in circulating samples such as biological fluids, and the difference in expression levels may indicate the presence, absence and/or stage of the disease. We analyzed here the miRNA profiling to identify potential diagnostic or prognostic biomarkers for ACLF. The major miRNAs discovered were validated in a cohort of patients with acute decompensation of cirrhosis grouped in no ACLF or ACLF according to EASL-CLIF definition. Relationship between serum miRNAs and variables associated with liver-damage and survival outcomes were verified to identify possible prognostic markers. Our results showed twenty altered miRNAs between no ACLF and ACLF patients, and twenty-seven in patients who died in 30 days compared with who survived. In validation phase, miR-223-3p and miR-25-3p were significantly altered in ACLF patients and in those who died in 30 days. miR-223-3p and miR-25-3p expression were associated with the lowest survival in 30 days. The decrease in miR-223-3p and miR-25-3p expression was associated with the presence of ACLF and poor prognosis. Of these, miR-25-3p was independently related to ACLF and 30-day mortality.

Associations between body mass index and mortality in acute-on-chronic liver failure patients.

INTRODUCTION AND OBJECTIVES: The association between the level of body mass index (BMI) and the mortality of patients with critical liver disease remains unclear. This study aimed to examine the association between BMI and hospital mortality of patients with acute-on-chronic liver failure (ACLF). METHODS: Clinical data from 146 ACLF patients were collected and analyzed. BMI was categorized into three groups: lower BMI (<18.5kg/m2), normal BMI (18.5-24.9kg/m2), and overweight (25.0-32.0kg/m2). BMI and laboratory parameters were measured one day before, or on the day of the start of the treatment. Values of BMI and laboratory parameters were compared between survivors and non-survivors, and then hospital mortality rates were compared among patients with different BMI levels. RESULTS: The prognosis of ACLF patients was significantly correlated with international normalized ratio (INR), albumin and BMI. The ACLF patients with low albumin level and high INR values tend to have a high mortality rate. Also, survival time was significantly shorter in the ACLF patients with lower BMI, while patients with normal and overweight values had longer survival time. CONCLUSIONS: A graded association between BMI and hospital mortality with a strong significant trend was found in ACLF patients in China.

Serum NGAL Is Superior to Cystatin C in Predicting the Prognosis of Acute-on-Chronic Liver Failure.

INTRODUCTION AND AIM: Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality, and predicting the prognosis is challenging. This study aimed to compare the performance of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CysC) in predicting the 90-day mortality in patients with hepatitis B virus (HBV)-associated ACLF (HBV-ACLF). MATERIALS AND METHODS: This prospective, observational study enrolled 54 patients with HBV-ACLF. The serum NGAL and CysC levels were determined. A multivariate logistic regression analysis was used to analyze the independent risk factors of mortality. RESULTS: Serum NGAL, but not CysC, was found to significantly correlate with the total bilirubin, international normalized ratio, and model for end-stage liver disease (MELD). Serum NGAL [odds ratio (OR), 1.008; 95% confidence interval (CI), 1.004-1.012; P < 0.01], but not CysC, was an independent risk factor for developing hepatorenal syndrome. Moreover, NGAL (OR, 1.005; 95% CI, 1.001-1.010; P < 0.01) along with the MELD score was independently associated with the overall survival in patients with HBV-ACLF. Patients with HBV-ACLF were stratified into two groups according to the serum NGAL level at baseline (low risk: <217.11 ng/mL and high risk: ≥ 217.11 ng/mL). The 90-day mortality rate was 22.73% (5/22) in the low-risk group and 71.88% (23/32) in the high-risk group. Moreover, NGAL, but not CysC, significantly improved the MELD score in predicting the prognosis of HBV-ACLF. CONCLUSION: The serum NGAL might be superior to CysC in predicting the prognosis of HBV-ACLF with the normal creatinine level.

Serum sodium, model for end-stage liver disease, and a recent invasive procedure are risk factors for severe acute-on-chronic liver failure and death in cirrhotic patients hospitalized with bacterial infection.

INTRODUCTION: Bacterial infection is present in up to 30% of hospitalized cirrhotic patients. It can lead, even after its resolution, to organ dysfunction and even acute-on-chronic liver failure (ACLF). It is the precipitating factor of ACLF in one third of the cases and is the main cause of mortality in patients with liver cirrhosis. OBJECTIVES: The aim of this study was to evaluate the prevalence and identify early risk factors for severe ACLF and death in hospitalized patients with liver cirrhosis with bacterial infection. PATIENTS AND METHODS: This was a prospective observational study. Hospitalized patients with liver cirrhosis and bacterial infection were included. Clinical and laboratory data and their evolution to organ dysfunction and death were assessed. A statistical analysis were carried out to identify predictors of severe ACLF and in-hospital mortality. RESULTS: This study included 88 patients. ACLF was observed in 62 (70%) patients, with 48 (55%) grade 2 or higher. Of the 27 deaths (31% of all patients), 26 had severe ACLF (54% mortality) (P<0.0001). The independent risk factors for ACLF of at least 2 and death were baseline serum sodium [odds ratio (OR): 0.874; P=0.01, and OR: 0.9, P=0.04], initial MELD (OR: 1.255, P=0.0001, and OR: 1.162, P=0.005), and a recent invasive procedure (OR: 3.169, P=0.01, and OR: 6.648, P=0.003). CONCLUSION: Lower serum sodium values, higher MELD scores at diagnosis of infection, and a recent history of invasive procedures were independent risk factors for severe ACLF and death in patients with cirrhosis and bacterial infection.

Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis.

Acute-on-chronic liver failure (ACLF) develops in acute decompensation (AD) of cirrhosis and shows high mortality. In critically ill patients, early diagnosis of ACLF could be important for therapeutic decisions (eg, renal replacement, artificial liver support, liver transplantation). This study evaluated fibroblast growth factor 21 (FGF21) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals (112 critically patients and 42 healthy controls) divided into a training and a validation cohort. In the training cohort of 42 healthy controls and 34 critically ill patients (of whom 24 were patients with cirrhosis), levels of FGF21, interleukin (IL) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow-up and underwent daily clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, especially in patients with cirrhosis admitted to the intensive care unit (ICU). Moreover, FGF21 as well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the severity of ACLF. Interestingly, in the validation cohort, FGF21 was also elevated in the patients who developed ACLF in the next 7 days. In these patients, FGF21 levels were an independent predictor of ACLF presence and development in multivariate analysis together with Child-Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this study demonstrates that FGF21 levels are of specific diagnostic value regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. Further studies are warranted to address pathophysiological and possible therapeutic implications. Liver Transplantation 24 595-605 2018 AASLD.

Prognostic factors of the short-term outcomes of patients with hepatitis B virus-associated acute-on-chronic liver failure.

OBJECTIVE: To investigate the impact of the baseline status of patients with hepatitis B virus-associated acute-on-chronic liver failure on short-term outcomes. METHODS: A retrospective study was conducted that included a total of 138 patients with hepatitis B virus-associated acute-on-chronic liver failure admitted to the Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, from November 2013 to October 2016. The patients were divided into a poor prognosis group (74 patients) and a good prognosis group (64 patients) based on the disease outcome. General information, clinical indicators and prognostic scores of the patients' baseline status were analyzed, and a prediction model was established accordingly. RESULTS: Elder age, treatment with artificial liver support systems and the frequency of such treatments, high levels of white blood cells, neutrophils, neutrophil count/lymphocyte count ratio, alanine aminotransferase, gamma-glutamyl transferase, total bilirubin, urea, and prognostic scores as well as low levels of albumin and sodium were all significantly associated with the short-term outcomes of hepatitis B virus-associated acute-on-chronic liver failure. The predictive model showed that logit (p) = 3.068 + 1.003 × neutrophil count/lymphocyte count ratio - 0.892 × gamma-glutamyl transferase - 1.138 × albumin - 1.364 × sodium + 1.651 × artificial liver support therapy. CONCLUSION: The neutrophil count/lymphocyte count ratio and serum levels of gamma-glutamyl transferase, albumin and sodium were independent risk factors predicting short-term outcomes of hepatitis B virus-associated acute-on-chronic liver failure, and the administration of multiple treatments with artificial liver support therapy during the early stage is conducive to improved short-term outcomes.

Prognostic factors of the short-term outcomes of patients with hepatitis B virus-associated acute-on-chronic liver failure

OBJECTIVE: To investigate the impact of the baseline status of patients with hepatitis B virus-associated acute-on-chronic liver failure on short-term outcomes. METHODS: A retrospective study was conducted that included a total of 138 patients with hepatitis B virus-associated acute-on-chronic liver failure admitted to the Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, from November 2013 to October 2016. The patients were divided into a poor prognosis group (74 patients) and a good prognosis group (64 patients) based on the disease outcome. General information, clinical indicators and prognostic scores of the patients' baseline status were analyzed, and a prediction model was established accordingly. RESULTS: Elder age, treatment with artificial liver support systems and the frequency of such treatments, high levels of white blood cells, neutrophils, neutrophil count/lymphocyte count ratio, alanine aminotransferase, gamma-glutamyl transferase, total bilirubin, urea, and prognostic scores as well as low levels of albumin and sodium were all significantly associated with the short-term outcomes of hepatitis B virus-associated acute-on-chronic liver failure. The predictive model showed that logit (p) = 3.068 + 1.003 × neutrophil count/lymphocyte count ratio - 0.892 × gamma-glutamyl transferase - 1.138 × albumin - 1.364 × sodium + 1.651 × artificial liver support therapy. CONCLUSION: The neutrophil count/lymphocyte count ratio and serum levels of gamma-glutamyl transferase, albumin and sodium were independent risk factors predicting short-term outcomes of hepatitis B virus-associated acute-on-chronic liver failure, and the administration of multiple treatments with artificial liver support therapy during the early stage is conducive to improved short-term outcomes.

Circulating levels of pentraxin-3 (PTX3) in patients with liver cirrhosis.

BACKGROUND: Despite the circulating levels of PTX3 were related to the severity of various diseases, there are no studies investigating its role in patients with liver cirrhosis. We aimed to study PTX3 levels in patients with liver cirrhosis. MATERIAL AND METHODS: A prospective cohort study included 130 patients hospitalized for acute decompensation of liver cirrhosis, 29 stable cirrhotic outpatients and 32 healthy controls evaluated in a tertiary hospital in Southern Brasil. RESULTS: The median PTX3 level was significantly higher in stable cirrhotic patients compared to controls (2.6 vs. 1.1 ng/mL; p < 0.001), hospitalized cirrhotic patients compared to controls (3.8 vs. 1.1 ng/mL; p < 0.001), and hospitalized cirrhotic patients compared to stable cirrhotic patients (3.8 vs. 2.6 ng/mL; p = 0.001). A positive correlation was found between PTX3 and serum creatinine (r = 0.220; p = 0.012), Chronic Liver Failure - Sequential Organ Failure Assessment score (CLIF-SOFA) (r = 0.220; p = 0.010), MELD (r = 0.279; p = 0.001) and Child-Pugh score (r = 0.224; p = 0.010). Significantly higher levels of PTX3 were observed in patients on admission with ACLF (8.9 vs. 3.1 ng/mL; p < 0.001) and MELD score ≥ 20 (6.6 vs. 3.4 ng/mL; p = 0.002). Death within 90 days occurred in 30.8% of patients and was associated with higher levels of PTX3 (5.3 vs. 3.4 ng/mL; p = 0.009). The probability of Kaplan-Meier survival was 77.0% in patients with PTX-3 < 5.3 ng mL (upper tercile) and 53.5% in those with PTX3 ≥ 5.3 ng/mL (p = 0.002). CONCLUSION: These results indicate the potential for use of PTX3 as an inflammatory biomarker for the prognosis of patients with hepatic cirrhosis.

From stable disease to acute-on-chronic liver failure: Circulating cytokines are related to prognosis in different stages of cirrhosis.

INTRODUCTION: Although both pro- and anti-inflammatory circulating cytokines are known to be elevated in liver cirrhosis, its clinical significance is not completely recognized. Our aim was to evaluate the prognostic significance of circulating cytokines interleukin (IL)-6, IL-17 and IL-10 in different stages of cirrhosis. METHODS: This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n=118), and (2) subjects hospitalized for acute decompensation (AD) (n=130). Thirty healthy subjects served as control group. RESULTS: Patients with cirrhosis exhibited higher levels of cytokines as compared to controls. In stable cirrhosis, during a median follow-up of 17months, liver-related events occurred in 26 patients. Higher IL-10 levels and Child-Pugh B/C were independently associated with reduced event-free survival. In AD cohort, death after 90days of follow-up occurred in 39 patients and was independently associated with ascites, higher IL-6 and model for end-stage liver disease. IL-6 levels also showed higher AUROC than CRP for predicting bacterial infection in the AD cohort (0.831±0.043vs. 0.763±0.048, respectively). IL-17 decreased at third day of hospitalization only in patients who progressed to death. Higher IL-6 levels were observed in acute-on-chronic liver failure (ACLF) patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Higher IL-10 and IL-17 levels were associated with progression to death in ACLF. CONCLUSIONS: The pattern of immune response seems to vary according to the phase of cirrhosis and is related to prognosis, from stable disease to ACLF.

External validation and comparison of six prognostic models in a prospective cohort of HBV-ACLF in China.

UNLABELLED:  Background. Acute-on-chronic liver failure has high mortality. Currently, robust models for predicting the outcome of hepatitis B virus (HBV)-associated ACLF are lacking. AIM: To assess and compare the performance of six prevalent models for short- and longterm prognosis in patients with HBV-ACLF. MATERIAL AND METHODS: The model for end-stage liver disease (MELD), MELD sodium (MELD-Na), MELD to sodium ratio (MESO), integrated MELD, Child-Turcotte-Pugh (CTP), and modified CTP (mCTP) were validated in a prospective cohort of 232 HBV-ACLF patients. The six models were evaluated by determining discrimination, calibration and overall performance at 3 months and 5 years. RESULTS: According to the Hosmer-Lemeshow tests and calibration plots, all models could adequately describe the data except CTP at 3 months. Discrimination analysis showed that the iMELD score had the highest AUC of 0.76 with sensitivity of 62.6% and specificity of 80.2% for an optimal cut-off value of 52 at 3 months. It also had the highest AUC of 0.80 with sensitivity of 89.9% and specificity of 48.2% for an optimal cut-off value of 43 at 5 years. The overall performance of iMELD, assessed with Nagelkerke's R2 and the Brier score, was also the best among the six models. CONCLUSION: Integrated MELD may be the best model to predict short- and long-term prognosis in patients with HBV-ACLF.

Usefulness of serum thyroid-stimulation hormone (TSH) as a prognostic indicator for acute-on-chronic liver failure.

UNLABELLED: BACKGROUND AND RATIONALE FOR THE STUDY: To investigate thyroid function in patients with acute-on-chronic liver failure (ACLF) caused by hepatitis B virus infection and to determine whether thyroid hormone levels can be used as prognostic markers for assessing severity and prognosis of ACLF patients. We enrolled 75 patients with ACLF and70 patients with chronic hepatitis B (CHB). Continual serum samples were collected during hospitalization from the ACLF patients. The serum thyroid hormone levels (triiodothyronine [T3], thyroxine [T4], free (F)-T3, FT4, and thyroid stimulation hormone [TSH]) were measured by chemiluminescence. The Model for End-stage Liver Disease (MELD) score was used to assess severity. RESULTS: ACLF patients showed significantly (p < 0.001) lower values of serum T3, T4, FT3/FT4 and TSH than CHB patients. The T3, T4, and TSH levels in ACLF patients were negatively correlated with the MELD score (T3: r = -0.495, p < 0.001; T4: r = -0.281, p < 0.001; TSH: r = -0.498, p < 0.001), suggesting that serum thyroid hormone levels reflect disease severity. At 1 year, 31 patients died. The T3 (p = 0.016), T4 (p = 0.008), and TSH (p = 0.003) levels in non-survivors were significantly lower than in survivors. The serum TSH level was a significant factor for predicting mortality in ACLF patients (optimal cutoff value = 0.38 IU/mL). The cumulative survival rate was decreased significantly when the serum TSH level was < 0.38 IU/mL (39.2%, p < 0.001). CONCLUSION: Serum TSH level may be a useful indicator for assessing severity and prognosis in ACLF patients.