The course and survival of patients with liver cirrhosis and acute liver failure on the background of chronic

Aims. We comparative investigated the frequency, precipitating factors, lifetimes and predictive factors of survival in patients with liver cirrhosis (LC) and acute-on-chronic liver failure (ACLF). Material and methods. We collected data from 310 hospitalized patients with LC. Patients divided into groups: 1 — patients with compensation of LC; 2 — patients with decompensation of LC, but without organ failure (OF) and 3 — patients with ACLF. Diagnostic criteria for ACLF based on consensus recommendations of EASL. Survival was assessed according to the Kaplan-Meier method. Results. 48 patients with LC reported clinical signs of ACLF. 28-day mortality was in 4,8% of patients without ACLF and in 42,0% of patients with ACLF. 90-day mortality of patients with ACLF was 50% versus 11.6% in patients without ACLF. 6-month survival rate of patients with the development of acute decompensation with organ failure was only 33,3%. The lifetimes of patients with ACLF was only 136,65 ± 18,96 days. The predictive factors of survival of patients with LC and ACLF are: the number of organ failure, indicators of CLIF-SOFA and MELD, Child-Pugh score, degree of hepatic encephalopathy, leukocytosis, hyperbilirubinemia, hypercreatininemia and increased INR. Conclusion. The prevalence of ACLF in patients with LC is 15,5% and develops against a background of stable compensated or decompensated CP. The frequent trigger of ACLF is infection, which causes acute decompensation with the development of multiple organ failure and a high incidence of short-term mortality. The 28-day mortality rate in patients with ACLF was 8.7 times greater than the mortality rate in patients with decompensated LC without ACLF.

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Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure

Cells ◽

10.3390/cells9122632 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2632

Author(s):

Mireia Casulleras ◽

Ingrid W. Zhang ◽

Cristina López-Vicario ◽

Joan Clària

Keyword(s):

Liver Failure ◽

Organ Failure ◽

Chronic Liver ◽

Decompensated Cirrhosis ◽

Chronic Liver Failure ◽

Drug Induced ◽

Interleukin 22 ◽

Secondary Infections ◽

Short Term Mortality ◽

Acute Decompensation

Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure(s) and high short-term mortality. ACLF frequently occurs in close temporal relationship to a precipitating event, such as acute alcoholic, drug-induced or viral hepatitis or bacterial infection and, in cases without precipitating events, probably related to intestinal translocation of bacterial products. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. This hyperinflammatory state ultimately impairs the host defensive mechanisms of immune cells, rendering ACLF patients immunocompromised and more vulnerable to secondary infections, and therefore to higher organ dysfunction and mortality. In this review, we describe the prevailing characteristics of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on cells of the innate immune system (i.e., monocytes and neutrophils), their triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]), their effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) and the consequences on tissue immunopathology. In addition, this review includes a chapter discussing new emerging therapies based on the modulation of leukocyte function by the administration of pleiotropic proteins such as albumin, Toll-like receptor 4 antagonists, interleukin-22 or stem cell therapy. Finally, the importance of finding an appropriate intervention that reduces inflammation without inducing immunosuppression is highlighted as one of the main therapeutic challenges in cirrhosis.

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Systemic Inflammation and Acute-on-Chronic Liver Failure: Too Much, Not Enough

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2018/1027152 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Wim Laleman ◽

Joan Claria ◽

Schalk Van der Merwe ◽

Richard Moreau ◽

Jonel Trebicka

Keyword(s):

Inflammatory Response ◽

Liver Failure ◽

Organ Failure ◽

Plasma Exchange ◽

Chronic Liver Failure ◽

Albumin Dialysis ◽

Short Term ◽

Gut Dysbiosis ◽

Short Term Mortality ◽

Acute Decompensation

ACLF is a specific, but complex and multifactorial form of acute decompensation of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure, and high short-term mortality. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. Later in its course, immuno-exhaustion/immunoparalysis prevails predisposing the patient to secondary infectious events and reescalation in end-organ dysfunction and mortality. The management of patients with ACLF is still poorly defined. However, as its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant further study such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating usefulness of TLR4 antagonists, modulators of gut dysbiosis (pre- or probiotics), and FXR-agonists.

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APACHE II Score and Multiple Organ Failure Score as Predictors of Mortality Rate of Critically Ill Patients

Korean Journal of Anesthesiology ◽

10.4097/kjae.1997.32.5.754 ◽

1997 ◽

Vol 32 (5) ◽

pp. 754

Author(s):

Eun Chi Bang ◽

Shin Ok Koh ◽

Jai Won Jung

Keyword(s):

Mortality Rate ◽

Multiple Organ Failure ◽

Organ Failure ◽

Critically Ill ◽

Critically Ill Patients ◽

Multiple Organ ◽

Apache Ii ◽

Apache Ii Score ◽

Predictors Of Mortality ◽

Organ Failure Score

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Acute-on-chronic liver failure: to admit to intensive care or not?

British Journal of Hospital Medicine ◽

10.12968/hmed.2020.0310 ◽

2020 ◽

Vol 81 (9) ◽

pp. 1-6

Author(s):

Asif Arshad ◽

Lylah Irshad ◽

Theodore Nabavi ◽

Tony Whitehouse

Keyword(s):

Liver Failure ◽

Organ Failure ◽

Gastrointestinal Haemorrhage ◽

Chronic Liver ◽

Organ Support ◽

Chronic Liver Failure ◽

Short Term Mortality ◽

Organ Failures ◽

Clinical Scoring ◽

Excessive Alcohol

Acute-on-chronic liver failure is used to describe an acute decline in liver function in a patient with existing liver disease combined with other organ failure. Acute-on-chronic liver failure is associated with high short-term mortality, and the greater the number and severity of organ failures, the higher the mortality. The most commonly identified precipitants of acute-on-chronic liver failure include bacterial infection, gastrointestinal haemorrhage, viral hepatitis and recent excessive alcohol intake. Since some of these aetiologies are treatable, organ failure may return to pre-decompensation levels in up to 55% of patients. As a result, a trial of critical care treatment may be appropriate for many of these patients. Clinical scoring tools may help clinicians recognise futility, allowing timely withdrawal of organ support and shifting the focus of care toward palliation.

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Acute-on-chronic liver failure: definition, prognosis and management

Frontline Gastroenterology ◽

10.1136/flgastro-2018-101103 ◽

2019 ◽

Vol 11 (6) ◽

pp. 458-467

Author(s):

Ahmed Amin ◽

Rajeshwar P Mookerjee

Keyword(s):

Liver Transplantation ◽

Liver Failure ◽

Organ Failure ◽

Limited Resource ◽

Chronic Liver ◽

Rapid Progression ◽

Organ Shortage ◽

Chronic Liver Failure ◽

Hepatic Decompensation ◽

Short Term Mortality

Acute-on-chronic liver failure (ACLF) is a recently described entity in chronic liver disease defined by acute hepatic decompensation, organ failure and a high risk of short-term mortality (usually less than 4 weeks). This condition is distinct from acute liver failure and stable progression of cirrhosis in numerous ways, including triggering precipitant factors, systemic inflammation, rapid progression and a potential for recovery. While a clear definition of ACLF has been forwarded from a large European Consortium study, some heterogeneity remains in how patients present and the types of organ failure, depending on whether they are described in Asian or European studies. Active alcoholism, acute alcoholic hepatitis and infections are the most frequent precipitants for ACLF. Underpinning the pathophysiology of ACLF is a state of persistent inflammation and immune dysfunction, collectively driving a systematic inflammatory response syndrome and an increased propensity to sepsis. Prevention and early treatment of organ failure are key in influencing survival. Given increasing organ shortage and more marginal grafts, liver transplantation is a limited resource and emphasises the need for new therapies to improve ACLF outcomes. Recent data indicate that liver transplantation has encouraging outcomes even in patients with advanced ACLF if patients are carefully selected during the permissive window of clinical presentation. ACLF remains a significant challenge in the field of hepatology, with considerable research and resource being channelled to improve upon the definition, prognostication, treatment and unravelling of mechanistic drivers. This Review discusses updates in ACLF definition, prognosis and management.

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Serum cholinesterase, an underestimated marker in the prediction of acute-on-chronic liver failure, organ failure and LTx-free survival in patients with liver cirrhosis?

Journal of Hepatology ◽

10.1016/s0168-8278(20)31485-9 ◽

2020 ◽

Vol 73 ◽

pp. S504

Author(s):

Tammo Lambert Tergast ◽

Abdul-Rahman Kabbani ◽

Marie Schultalbers ◽

Michael P. Manns ◽

Markus Cornberg ◽

...

Keyword(s):

Liver Cirrhosis ◽

Liver Failure ◽

Organ Failure ◽

Chronic Liver ◽

Serum Cholinesterase ◽

Chronic Liver Failure ◽

Free Survival

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HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure

Mediators of Inflammation ◽

10.1155/2017/5928078 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 23

Author(s):

Runkuan Yang ◽

Xiaoping Zou ◽

Jyrki Tenhunen ◽

Tor Inge Tønnessen

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Multiple Organ Failure ◽

Organ Failure ◽

Systemic Inflammation ◽

Cell Injury ◽

Inflammatory Responses ◽

Multiple Organ ◽

Hepatocyte Regeneration ◽

Extracellular Histones

Acute liver failure (ALF) is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF) and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT). BT triggers/induces systemic inflammatory responses syndrome (SIRS), which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

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NEUTROPHIL-LYMPHOCYTE RATIO PREDICTS SHORT-TERM MORTALITY IN PATIENTS HOSPITALIZED FOR ACUTE DECOMPENSATION OF CIRRHOSIS

Arquivos de Gastroenterologia ◽

10.1590/s0004-2803.202100000-23 ◽

2021 ◽

Author(s):

Claudia MACCALI ◽

Fernanda Cristina de AUGUSTINHO ◽

Tamara Liana ZOCCHE ◽

Telma Erotides SILVA ◽

Janaína Luz NARCISO-SCHIAVON ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Survival Probability ◽

Hospitalized Patients ◽

Short Term ◽

Neutrophil Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Kaplan Meier ◽

Short Term Mortality ◽

Acute Decompensation

ABSTRACT BACKGROUND: Individuals with cirrhosis have a chronic systemic inflammation associated with an immune dysfunction, affecting the progression of the liver disease. The neutrophil-lymphocyte ratio (NLR) was proposed as a marker of systemic inflammatory response and survival in patients with cirrhosis. OBJECTIVE: Evaluate the prognostic role of NLR in cirrhotic patients and its relation with inflammatory cytokines(IL-6, IL-10 and IL-17). METHODS: In this prospective study two groups were evaluated: 1) Stable cirrhotic in outpatient follow-up (n=193); 2) Hospitalized cirrhotic for acute decompensation for at least 48 hours (n=334) with admission and 48 hours tests evaluation. Circulating inflammatory cytokines were available for 130 hospitalized patients. RESULTS: In outpatients with stable cirrhosis, NLR correlated with MELD score and other variables associated with severity of disease. However, after a median of 32 months of follow up NLR was not associated with mortality (HR 1.058, 95%CI 0.900-1.243; P=0.495). In hospitalized patients, NLR at 48-hour after admission was independently associated with 90-day survival (HR 1.061, 95%CI 1.020-1.103; P=0.003) in multivariate Cox-regression analysis. The 90-day Kaplan-Meier survival probability was 87% for patients with a 48-hour NLR <3.6 and 62% for NLR ≥3.6 (P<0.001). Elevation of NLR in the first 48 hours was also independently associated with mortality (HR 2.038, 95%CI 1295-3207; P=0.002). The 90-day Kaplan-Meier survival probability was 83% when NLR did not increase and 62% when NLR increased (P<0.001). IL-6, IL-10 and IL-17 at admission were positively correlated with both admission and 48-hour NLR. Lower levels of baseline IL-10 were associated with NLR increase during first 48-hour. CONCLUSION: NLR evaluated at 48 hours of hospitalization and its early increase after admission were independently associated with short-term mortality in patients hospitalized for acute decompensation of cirrhosis.

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Dysregulated Adaptive Immunity Is an Early Event in Liver Cirrhosis Preceding Acute-on-Chronic Liver Failure

Frontiers in Immunology ◽

10.3389/fimmu.2020.534731 ◽

2021 ◽

Vol 11 ◽

Author(s):

Sabrina Rueschenbaum ◽

Sandra Ciesek ◽

Alexander Queck ◽

Marek Widera ◽

Katharina Schwarzkopf ◽

...

Keyword(s):

T Cells ◽

Liver Cirrhosis ◽

Liver Failure ◽

Cd8 T Cells ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Decompensated Liver Cirrhosis ◽

Tt Virus ◽

Adaptive Immune ◽

Acute Decompensation

IntroductionAcute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of Torque teno (TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF.ConclusionImpaired innate and—in particular—adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.

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