Hematological ratios in patients with acute decompensation and acute-on-chronic liver failure: prognostic factors.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated cirrhosis and is characterized by the presence of intense systemic inflammation. Leucocyte quantification can serve as an indirect indicator of systemic inflammation. In our study, we investigated the predictive value of hematological ratios (neutrophils to lymphocytes, monocyte to lymphocytes, platelets to lymphocytes, lymphocytes to C-reactive protein, and neutrophils to lymphocytes and platelets) in acute decompensation (AD) and ACLF patients and their relation to disease severity and early mortality. PATIENTS AND METHODS: We included 60 patients with ACLF and AD, and 30 cirrhotic controls. Clinical data were collected, and survival was followed for 1 and 6 months. Blood samples were analyzed at admission for differential leucocytes and assessed for liver and renal function tests. The leukocyte ratios were calculated and compared, and their correlation with liver function indicators and prognosis was assessed. RESULTS: All ratios were significantly higher in AD and ACLF patients compared to control (except for lymphocyte to C-reactive protein ratio which was significantly lower), and were positively correlated with Child-Pugh score, model for end-stage liver disease (MELD)-Na, and ACLF severity scores. Multivariate regression revealed that neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, and MELD-Na were independent prognostic factors of 1-month and 6-month mortality. A unique prognostic nomogram incorporating MELD-Na, neutrophil to lymphocyte ratio, and monocyte to lymphocyte ratio could be proposed for predicting prognosis in AD and ACLF patients. CONCLUSIONS: Cheap, easy, and noninvasive hematological ratios are introduced as a tool for early identification and risk stratification of AD and ACLF patients.

Alpha-fetoprotein and APRI as predictive markers for patients with Type C hepatitis B-related acute-on-chronic liver failure: a retrospective study.

BACKGROUND: Type C hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), which is based on decompensated cirrhosis, has different laboratory tests, precipitating events, organ failure and clinical outcomes. The predictors of prognosis for type C HBV-ACLF patients are different from those for other subgroups. This study aimed to construct a novel, short-term prognostic score that applied serological indicators of hepatic regeneration and noninvasive assessment of liver fibrosis to predict outcomes in patients with type C HBV-ACLF. METHOD: Patients with type C HBV-ACLF were observed for 90 days. Demographic information, clinical examination, and laboratory test results of the enrolled patients were collected. Univariate and multivariate logistic regression were performed to identify independent prognostic factors and develop a novel prognostic scoring system. A receiver operating characteristic (ROC) curve was used to analyse the performance of the model. RESULTS: A total of 224 patients with type C HBV-ACLF were finally included. The overall survival rate within 90 days was 47.77%. Age, total bilirubin (TBil), international normalized ratio (INR), alpha-fetoprotein (AFP), white blood cell (WBC), serum sodium (Na), and aspartate aminotransferase/platelet ratio index (APRI) were found to be independent prognostic factors. According to the results of the logistic regression analysis, a new prognostic model (named the A3Twin score) was established. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.851 [95% CI (0.801-0.901)], the sensitivity was 78.8%, and the specificity was 71.8%, which were significantly higher than those of the MELD, IMELD, MELD-Na, TACIA and COSSH-ACLF II scores (all P < 0.001). Patients with lower A3Twin scores (<-9.07) survived longer. CONCLUSIONS: A new prognostic scoring system for patients with type C HBV-ACLF based on seven routine indices was established in our study and can accurately predict short-term mortality and might be used to guide clinical management.

Blood Testing for Phosphatidylethanol.

A 36-year-old man with obesity and dyslipidemia presented with elevated liver enzymes following a liver transplant to treat acute-on-chronic liver failure due to alcohol-associated hepatitis. What would you do next?

The value of dynamic changes in FT3 level for predicting 90-day prognosis of HBV-ACLF patients.

OBJECTIVE: To explore the effect of dynamic changes in free triiodothyronine (FT3) level for predicting the 90 day prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). METHODS: The clinical data of 122 hospitalised patients with HBV-ACLF between September 2018 and January 2020 were collected and divided into a survival group (77 cases) and a death group (45 cases) according to the 90 day prognosis. We statistically analysed the characteristics of FT3 changes in the two groups of patients. Binary logistic regression one-way analysis was used to assess the degree of influence of each factor. The Kaplan-Meier survival curve and receiver operating characteristic curve were used to evaluate the effect of a single change in FT3 level difference (single △FT3) and the FT3 level change range (△FT3 range) in predicting the 90-day prognosis of patients. RESULTS: There were only three types of changes in FT3 levels, which included 19 (15.6%) cases of continuous normal type, 35 (28.7%) cases of continuous decrease type and 68 (55.7%) cases of U-shaped change type. The difference in survival curves between the three types of patients was statistically significant (P < 0.001). CONCLUSION: The dynamic change type of FT3 is related to the disease severity and 90-day prognosis of patients with HBV-ACLF. The single FT3 value and FT3 range could be used as a predictive factor for the 90-day prognosis of patients with HBV-ACLF. These results have a degree of research value and are worth further exploration in the future.

Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure.

CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8 days (IQR: 3-13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7 mg/dL to median post-treatment: 10.8 mg/dL; - 47.8%; p < 0.001), procalcitonin (1.34 to 0.74 pg/mL; - 44.6%; p < 0.001), interleukin-6 (385 to 131 ng/mL; - 66.0%; p = 0.0182)-but also of platelets (72 to 31 G/L; - 56.9%; p = 0.0014) and fibrinogen (230 to 154 mg/dL; - 33.0%; p = 0.0297) were detected. ICU survivors had a trend towards a stronger relative decrease in bilirubin (- 76.1% vs. - 48.2%), procalcitonin (- 90.6% vs. - 23.5%), and IL-6 (- 54.6% vs. - 17.8%) upon CytoSorb treatment. Moreover, no serious CytoSorb-attributed complications were detected. In conclusion, use of CytoSorb adsorber in ACLF patients results in a significant decrease in bilirubin and proinflammatory cytokines, while platelets and fibrinogen were also lowered. Prospective trials are warranted to investigate the impact of CytoSorb on clinical outcomes of ACLF patients with high proinflammatory cytokine levels.

Citrate pharmacokinetics in critically ill liver failure patients receiving CRRT.

Citrate has been proposed as anticoagulation of choice in continuous renal replacement therapy (CRRT). However, little is known about the pharmacokinetics (PK) and metabolism of citrate in liver failure patients who require CRRT with regional citrate anticoagulation (RCA). This prospective clinical PK study was conducted at King Chulalongkorn Memorial Hospital between July 2019 to April 2021, evaluating seven acute liver failure (ALF) and seven acute-on-chronic liver failure (ACLF) patients who received CRRT support utilizing RCA as an anticoagulant at a citrate dose of 3 mmol/L. For evaluation of the citrate PK, we delivered citrate for 120 min and then stopped for a further 120 min. Total body clearance of citrate was 152.5 ± 50.9 and 195.6 ± 174.3 mL/min in ALF and ACLF, respectively. The ionized calcium, ionized magnesium, and pH slightly decreased after starting citrate infusion and gradually increased to baseline after stopping citrate infusion. Two of the ACLF patients displayed citrate toxicity during citrate infusion, while, no ALF patient had citrate toxicity. In summary, citrate clearance was significantly decreased in critically ill ALF and ACLF patients receiving CRRT. Citrate use as an anticoagulation in these patients is of concern for the risk of citrate toxicity.

Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC. METHODS: A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison. RESULTS: Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis. CONCLUSIONS: Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC. LAY SUMMARY: Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis.

Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

Low hemoglobin levels are associated with direct antiglobulin test positivity in patients with acute-on-chronic liver failure.

BACKGROUND: Multiple factors contribute to anemia in patients with Hepatitis B virus (HBV)related acute-on-chronic liver failure (ACLF); however, the mechanism is unclear. The purpose of this study was to evaluate the clinical significance of the direct antiglobulin test (DAT) in patients with HBV related ACLF. METHODS: DAT was used to detect immunoglobulins and/or complement proteins on the surface of erythrocytes. RESULTS: We recruited 78 HBV-associated ACLF patients, 30 chronic hepatitis B(CHB)patients and 40 healthy people between October 2015 and May 2016. In HBV related ACLF patients, the hemoglobin concentration, number of erythrocytes, and hematocrit value were significantly lower, while the erythrocyte distribution width was significantly higher, compared to patients with CHB and healthy controls (HCs) (P < 0.001). The rates of DAT positivity in HBV related ACLF patients, CHB patients, and HCs were 62.8 %, 13.3 %, and 0%, respectively. DAT-positive ACLF patients exhibited lower Hb levels, older average age, as well as higher total bilirubin, alanine aminotransferase, and complement component 3 levels compared to DAT-negative patients. CONCLUSIONS: HBV related ACLF patients showed significant alterations in erythrocyte parameters, possibly reflecting disease development and severity. The high presence of erythrocyte autoantibodies suggested that immunologic clearance of erythrocytes contributed to multifactorial anemia in HBV related ACLF patients.

Role of Bacterial Infection in the Development of Acute Liver Failure in Patients with Decompensated Alcoholic Liver Cirrhosis.

We examined 74 patients with acute decompensation of alcoholic liver cirrhosis: 34 (45.9%) with bacterial infection (group 1) and 40 (54.1%) without bacterial infection (group 2). The degree and index of acute-on-chronic liver failure (ACLF) were determined using an on-line CLIF-C ACLF Calculator and the levels of cytokeratin-18 fragments, TNFα, IL-1ß, IL-4, IL-6, and IL-8. In group 1, AST, cytokeratin-18, TNFα, IL-1ß, IL-6, degree and score of ACLF were significantly higher than in group 2. ACLF developed in 18 (52.9%) patients in group 1 and in 11 (27.5%) (p<0.05) patients in group 2. Within 1 month, 10 (29.4%) patients of group 1 and 2 (5%) patients of group 2 died (p<0.05). Patients with bacterial infection showed a more severe course of alcoholic liver cirrhosis and ACLF than those without bacterial infection.

Aberrant methylation of UBE2Q1 promoter is associated with poor prognosis of acute-on-chronic hepatitis B pre-liver failure.

ABSTRACT: Acute-on-chronic hepatitis B liver failure (ACHBLF) is one severe liver disease with rapid progression and high mortality. Identification of specific markers for the prediction of ACHBLF has important clinical significance. We explored the feasibility of UBE2Q1 gene promoter methylation as an early prediction and prognosis biomarker of ACHBLF.UBE2Q1 promoter methylation frequency was detected in 60 patients with acute-on-chronic hepatitis B pre-liver failure (Pre-ACHBLF), 40 patients with chronic hepatitis B and 20 cases of healthy control (HC). The UBE2Q1 mRNA was detected by quantitative real-time polymerase chain reaction.The methylation frequency of the UBE2Q1 promoter in pre-ACHBLF patients was 38.33%, which was significantly lower than that in chronic hepatitis B patients (60.00%) and HCs (65.00%). The UBE2Q1 mRNA expression in pre-ACHBLF patients with UBE1Q1 non-methylation was significantly higher than that in patients with UBE1Q1 promoter methylation. Further analysis showed that hypomethylation of the UBE2Q1 promoter was positively correlated with total bilirubin and international normalized ratio levels in patients with pre-ACHBLF, but negatively correlated with PTA level. COX multivariate analysis showed that the model for end-stage liver disease score and UBE2Q1 promoter hypomethylation status were potential early warning factors that can predict the progression of pre-ACHBLF to ACHBLF. The sensitivity and specificity of UBE2Q1 promoter methylation status combined with the model for end-stage liver disease score for early diagnosis of ACHBLF were 92.9% and 75.0%, respectively. The area under the receiver-operating characteristic curve was 0.895.The hypomethylation of UBE2Q1 promoter is associated with severity of Pre-ACHBLF, which could serve as a potential prognostic biomarker for pre-ACHBLF.

Increased Circulating T Follicular Helper Cells Induced via IL-12/21 in Patients With Acute on Chronic Hepatitis B Liver Failure.

Objectives: T Follicular helper (Tfh) cells, recognized as a distinct CD4+ T cell subset, mediate the development of long-lived humoral immunity via B cell activation/differentiation. Tfh cells play an important role during hepatic viral infection, but its role in hepatitis B virus-related acute on chronic liver failure (HBV-ACLF) remains to be explored. Materials and Methods: The frequency of Tfh cells, serum pro-inflammatory cytokine (IL-12, IL-21, IL-17 and TNF) levels and IgG/M levels were investigated in HBV-ACLF (n = 36), serious chronic hepatitis B (n = 21), moderate chronic hepatitis B patients (n = 32) and healthy control (HC) subjects (n = 10). Results: Circulating Tfh cells were significantly increased in HBV-ACLF patients compared to other groups, correlating well with MELD score. However, the frequency of Tfh cells decreased in ameliorated HBV-ACLF patients. Furthermore, serum IL-12 and IL-21 levels were higher in HBV-ACLF patients, compared to other groups. Naïve CD4+ T cells from HC subjects differentiate into Tfh cells following treatment with HBV-ACLF patients' serum, a process that can be blocked by IL-12/21 neutralizing antibodies. Tfh cells induced by HBV-ACLF patient's serum promoted the proliferation and IgG production of B cells in vitro. Moreover, circulating CD19+ B cells, serum and liver IgG/M levels were significantly higher in HBV-ACLF patients, compared to other groups. Conclusions: Our data demonstrated that there was a high frequency of Tfh cells and high levels of serum IL-12/21 in HBV-ACLF patients. Naïve CD4+ T cells differentiate into Tfh cells in the presence of HBV-ACLF patients' serum rich in IL-12/21, which can be blocked by neutralizing IL-12/21 antibodies. These data may provide useful insights for both clinical and basic research in the treatment of HBV-ACLF.

Determination of Effective Albumin in Patients With Decompensated Cirrhosis: Clinical and Prognostic Implications.

BACKGROUND AND AIMS: Circulating albumin in cirrhosis can be dysfunctional because of accumulating structural damages, leading to the concept of effective albumin concentration (eAlb), referring to the albumin portion presenting structural and functional integrity. We aimed to estimate eAlb in patients with decompensated cirrhosis and analyze its relationships with albumin function and clinical outcomes as compared to total albumin concentration (tAlb). APPROACH AND RESULTS: We evaluated 319 patients with cirrhosis hospitalized for acute decompensation (AD) with and without acute-on-chronic liver failure (ACLF) and 18 age- and sex-comparable outpatients with compensated cirrhosis. tAlb was quantified by standard assay, whereas eAlb was estimated combining liquid chromatography/electrospray ionization/mass spectrometry and standard methods. Albumin binding and detoxification efficiency were evaluated by electron paramagnetic resonance analysis. Circulating albumin in patients with decompensated cirrhosis displayed multiple structural abnormalities, with reversible oxidation and glycation being the most frequent. As a result, eAlb progressively declined with the worsening of cirrhosis and was superior to tAlb in stratifying patients between compensated cirrhosis, AD, and ACLF, as well as patients with and without complications. Moreover, eAlb, but not tAlb, was closely associated with binding capacities in ACLF. Finally, eAlb at admission predicted the occurrence of ACLF within 30 days and mortality at 90 days better than tAlb. CONCLUSIONS: This large, observational study provides the evidence in patients with decompensated cirrhosis that eAlb can be quantified and differentiated from tAlb routinely measured in clinical practice. As compared to tAlb, eAlb is more closely associated with disease severity and albumin dysfunction and carries a greater prognostic power. These results prompt future research assessing eAlb as a biomarker for predicting prognosis and treatment response.

Albumin in Advanced Liver Diseases: The Good and Bad of a Drug!

Human serum albumin is the most abundant plasma protein, and it regulates diverse body functions. In patients with advanced and decompensated cirrhosis, serum albumin levels are low because of a reduction in the hepatocyte mass due to disease per se and multiple therapeutic interventions. Because of their oncotic and nononcotic properties, administration of human albumin solutions (HAS) have been found to be beneficial in patients undergoing large-volume paracentesis or who have hepatorenal syndrome or spontaneous bacterial peritonitis. Albumin also improves the functionality of the immune cells and mitigates the severity and risk of infections in advanced cirrhosis. Its long-term administration can modify the course of decompensated cirrhosis patients by reducing the onset of new complications, improving the quality of life, and probably providing survival benefits. There is, however, a need to rationalize the dose, duration, and frequency of albumin therapy in different liver diseases and stages of cirrhosis. In patients with acute-on-chronic liver failure, potentially toxic oxidized isoforms of albumin increase substantially, especially human nonmercaptalbumin and 2, and nitrosoalbumin. The role of administration of HAS in such patients is unclear. Determining whether removal of the pathological and dysfunctional albumin forms in these patients by "albumin dialysis" is helpful, requires additional studies. Use of albumin is not without adverse events. These mainly include allergic and transfusion reactions, volume overload, antibody formation and coagulation derangements. Considering their cost, limited availability, need for a health care setting for their administration, and potential adverse effects, judicious use of HAS in liver diseases is advocated. There is a need for new albumin molecules and economic alternatives in hepatologic practice.

Peripheral T lymphocytes predict the severity and prognosis in patients with HBV-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening syndrome with high mortality. Biomarkers are urgently needed to predict the prognosis of HBV-ACLF. Recent evidence suggests a key role for immune system in the pathology of HBV-ACLF. Here, we analyzed the correlation between peripheral blood T lymphocytes and the severity and prognosis in HBV-ACLF patients. METHOD: Sixty-six patients with HBV-ACLF received conventional medical treatments for 4 weeks. Twenty-five healthy subjects and 20 HBV patients were enrolled for comparison. We determined white blood cell count, lymphocytes, CD3+, CD4+ and CD8+ T cells, and CD4+CD25+ Treg cells in the blood of all subjects. Their associations with laboratory parameters before or after treatments were statistically analyzed. RESULT: The results showed that compare normal subjects and chronic hepatitis B patients, HBV-ACLF patients had significantly increased white blood count, CD4+ T cells and decreased lymphocytes, CD3+ T cells, and Treg cells. Correlation analysis showed that white blood cell, lymphocytes, and peripheral T lymphocytes were correlated with prothrombin activity (PTA) and model for end-stage liver disease (MELD) scores. After treatment, white blood cell, lymphocytes, and peripheral T lymphocytes were also correlated with PTA and MELD scores. Additionally, total bilirubin (TBIL), alanine aminotransferase (ALT), international standard ratio (INR), MELD, and white blood cell count were potential prognostic criteria for HBV-ACLF patients. CONCLUSION: HBV-ACLF patients had depletion and dysfunction of immune system. Changes of peripheral T lymphocytes were closely related to the pathogenesis and prognosis of disease. Our results may contribute to predict the severity of HBV-ACLF, and provide a prognosis response to improve the treatment of HBV-ACLF.

Hyperkalemia influences the outcome of patients with cirrhosis with acute decompensation (AD) and acute-on-chronic liver failure (ACLF).

INTRODUCTION: The presence of hyperkalemia in different clinical scenarios has been described as a risk factor for mortality. Information about this electrolyte disorder in patients with cirrhosis is limited and there are no data in patients with acute-on-chronic liver failure (ACLF). AIM: The aim of this study was to investigate whether hyperkalemia is a risk factor for mortality in patients with cirrhosis and acute decompensation (AD) with and without ACLF. METHODS: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,314 consecutive patients admitted to 29 European centers with AD both with and without associated ACLF (294 and 1020 respectively). Hyperkalemia was defined as serum potassium ≥ 5.0 mEq/L. All patients had at least one valid measure of serum potassium from admission and/or through the whole hospitalization. RESULTS: 1314 patients were admitted with AD and 294 of them had ACLF at admission. Prevalence of hyperkalemia was significantly higher in ACLF versus AD (22.4% and 8.6% respectively, p<0.001). Hyperkalemia was associated with an increased 90, 180 and 360-day mortality risk in ACLF compared to AD (HR 10 vs 2.3 at 90-day p<0.001, 8.9 vs 3.1 at 180-day, p<0.001 and 5.8 vs 3.8 at 360-day, p<0.001). In a multivariate analysis, the presence of hyperkalemia during admission was independently associated with 90-day mortality [HR 2.4 (1.7 - 3.4)]. Variability of potassium between two valid measures ≥ 0.9 mg/dl was always also associated with a higher mortality rate. Addition of hyperkalemia to MELD score (MELD-K model) improved the accuracy to predict 90-day mortality risk. CONCLUSIONS: Hyperkalemia is an independent risk factor of mortality in patients with AD and ACLF. Addition of hyperkalemia to the MELD score improves diagnostic accuracy to predict 90-day mortality in patients with AD and ACLF.

Determinants of mortality in patients with cirrhosis and uncontrolled variceal bleeding.

BACKGROUND & AIMS: Failure to control oesophago-gastric variceal bleeding (OGVB) and acute-on-chronic liver failure (ACLF) are both important prognostic factors in cirrhosis. The aims of this study were to determine whether ACLF and its severity define the risk of death in OGVB and whether insertion of rescue transjugular intrahepatic shunt (TIPS) improves survival in patients with failure to control OGVB and ACLF. METHODS: Data on 174 consecutive eligible patients, with failure to control OGVB between 2005 and 2015, were collected from a prospectively maintained intensive care unit registry. Rescue TIPS was defined as technically successful TIPS within 72 hours of presentation with failure to control OGVB. Cox-proportional hazards regression analyses were applied to explore the impact of ACLF and TIPS on survival in patients with failure to control OGVB. RESULTS: Patients with ACLF (n = 119) were significantly older, had organ failures and higher white cell count than patients with acute decompensation (AD, n = 55). Mortality at 42-days and 1-year was significantly higher in patients with ACLF (47.9% and 61.3%) than in those with AD (9.1% and 12.7%, p <0.001), whereas there was no difference in the number of endoscopies and transfusion requirements between these groups. TIPS was inserted in 78 patients (AD 21 [38.2%]; ACLF 57 [47.8%]; p = 0.41). In ACLF, rescue TIPS insertion was an independent favourable prognostic factor for 42-day mortality. In contrast, rescue TIPS did not impact on the outcome of patients with AD. CONCLUSIONS: This study shows that in patients with failure to control OGVB, the presence and severity of ACLF determines the risk of 42-day and 1-year mortality. Rescue TIPS is associated with improved survival in patients with ACLF. LAY SUMMARY: Variceal bleeding that is not controlled by initial endoscopy is associated with high risk of death. The results of this study showed that in the occurrence of failure of the liver and other organs defines the risk of death. In these patients, insertion of a shunt inside the liver to drain the portal vein improves survival.

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

Artificial liver support systems.

Artificial liver systems are used to bridge between transplantation or to allow a patient's liver to recover. They are used in patients with acute liver failure (ALF) and acute-on-chronic liver failure. There are five artificial systems currently in use: molecular adsorbent recirculating system (MARS), single-pass albumin dialysis (SPAD), Prometheus, selective plasma filtration therapy, and hemodiafiltration. The aim is to compare existing data on the efficiency of these devices. A literature search was conducted using online libraries. Inclusion criteria included randomized control trials or comparative human studies published after the year 2000. A systematic review was conducted for the five individual devices with a more detailed comparison of the biochemistry for the SPAD and MARS systems. Eighty-nine patients were involved in the review comparing SPAD and MARS. Results showed that there was an average reduction in bilirubin (-53 µmol/L in MARS and -50 µmol/L in SPAD), creatinine (-19.5 µmol/L in MARS and -7.5 µmol/L in SPAD), urea (-0.9 mmol/L in MARS and -0.75 mmol/L in SPAD), and gamma-glutamyl transferase (-0.215 µmol/L·s in MARS and -0.295 µmol/L·s in SPAD) in both SPAD and MARS. However, there was no significant difference between the changes in the two systems. This review demonstrated that both MARS and SPAD aid recovery of ALF. There is no difference between the efficiency of MARS and SPAD. Because of the limited data, there is a need for more randomized control trials. Evaluating cost and patient preference would aid in differentiating the systems.