Prospect of Animal Models for Acute-on-chronic Liver Failure: A Mini-review.
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SUBMITTER: Hassan HM
PROVIDER: S-EPMC9547251 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Prospect of Animal Models for Acute-on-chronic Liver Failure: A Mini-review.
Hassan Hozeifa Mohamed HM Li Jun J
Journal of clinical and translational hepatology 20220428 5
Acute-on-chronic liver failure (ACLF) is a clinical syndrome that develops in patients with chronic liver diseases following a precipitating event and associated with a high mortality rate due to systemic multiorgan failure. Establishing a suitable and stable animal model to precisely elucidate the molecular basis of ACLF pathogenesis is essential for the development of effective early diagnostic and treatment strategies. In this context, this article provides a concise and inclusive review of b ...[more]
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Project description:Over the past 2 decades, the concept of acute-on-chronic liver failure (ACLF) has been proposed as an alternate path in the natural history of decompensated cirrhosis. ACLF thus is characterized by the presence of a precipitating event (identified or unidentified) in subjects with underlying chronic liver disease leading to rapid progression of liver injury and ending in multi-organ dysfunction characterized by high short-term mortality. Multiple organ failure and an increased risk for mortality are key to the diagnosis of ACLF. The prevalence of ACLF ranges from 24% to 40% in hospitalized patients. The pathophysiological basis of ACLF can be explained using the following 4-part model: predisposing event, injury caused by a precipitating event, response to injury, and organ failure. Although several mathematic scores have been proposed for identifying outcomes with ACLF, it is as yet unclear whether these organ failure scores are truly prognostic or only reflective of the dying process. Treatment paradigms continue to evolve but consist of early recognition, supportive intensive care, and consideration of liver transplantation before onset of irreversible multiple organ failure.
| S-EPMC4625547 | biostudies-literature
Project description:BackgroundAcute-on-chronic liver failure (ACLF) is featured with rapid deterioration of chronic liver disease and poor short-term prognosis. Liver transplantation (LT) is recognized as the curative option for ACLF. However, there is no standard in the prediction of the short-term survival among ACLF patients following LT.MethodPreoperative data of 132 ACLF patients receiving LT at our center were investigated retrospectively. Cox regression was performed to determine the risk factors for short-term survival among ACLF patients following LT. Five conventional score systems (the MELD score, ABIC, CLIF-C OFs, CLIF-SOFAs and CLIF-C ACLFs) in forecasting short-term survival were estimated through the receiver operating characteristic (ROC). Four machine-learning (ML) models, including support vector machine (SVM), logistic regression (LR), multi-layer perceptron (MLP) and random forest (RF), were also established for short-term survival prediction.ResultsCox regression analysis demonstrated that creatinine (Cr) and international normalized ratio (INR) were the two independent predictors for short-term survival among ACLF patients following LT. The ROC curves showed that the area under the curve (AUC) ML models was much larger than that of conventional models in predicting short-term survival. Among conventional models the model for end stage liver disease (MELD) score had the highest AUC (0.704), while among ML models the RF model yielded the largest AUC (0.940).ConclusionCompared with the traditional methods, the ML models showed good performance in the prediction of short-term prognosis among ACLF patients following LT and the RF model perform the best. It is promising to optimize organ allocation and promote transplant survival based on the prediction of ML models.
| S-EPMC8867783 | biostudies-literature
Project description:Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.
| S-EPMC9499845 | biostudies-literature
Project description:Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated chronic liver disease. It is characterised by high 28-day mortality, the presence of one or more organ failures (OFs) and a variable but severe grade of systemic inflammation. Despite the peculiarity of each one, every definition proposed for ACLF recognizes it as a proper clinical entity. In this paper, we provide an overview of the diagnostic criteria proposed by the different scientific societies and the clinical characteristics of the syndrome. Established and experimental treatments are also described. Among the former, the most relevant are directed to support organ failures, treat precipitating factors and carry out early assessment for liver transplantation (LT). Further studies are needed to better clarify pathophysiology of the syndrome and discover new therapies.
| S-EPMC8509281 | biostudies-literature
Project description:BackgroundIncreasing evidence reveals a close and reciprocal link between acute-on-chronic liver failure (ACLF) and immunodysfunction.MethodsA literature search in PubMed and abstract databases of relevant congresses was performed.ResultsImportant characteristics of liver cirrhosis like tissue hypoxia, cell death, or bacterial translocation maintain a state of chronic inflammation. Precipitating events of ACLF such as infections or alcoholic hepatitis are capable of strongly augmenting cirrhosis-associated systemic inflammation to grades sufficient to induce ACLF-defining organ failures. Chronic systemic inflammation, however, is causally linked to profound immunosuppression. As a consequence, patients with liver cirrhosis and in particular with ACLF are at high risk for severe infections. Promising strategies to ameliorate immunodysfunction, like albumin substitution, administration of recombinant interleukin-22 or granulocyte colony-stimulating factor, antibiotic prophylaxis, or anticoagulation, are under development and offer the chance to specifically prevent and treat ACLF.ConclusionA better understanding of the immunopathology of ACLF will likely translate into the implementation of specific therapeutic modalities to prevent and overcome ACLF.
| S-EPMC6189545 | biostudies-literature
Project description:Background and purposeThe diagnosis of acute on chronic liver failure (ACLF) carries a high short-term mortality, making early identification of at-risk patients crucial. To date, there are no models that predict which patients with compensated cirrhosis will develop ACLF, and limited models exist to predict ACLF mortality. We sought to create novel risk prediction models using a large North American cohort.MethodsWe performed a retrospective study of 75,922 patients with compensated cirrhosis from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) dataset. Using 70% derivation/30% validation sets, we identified ACLF patients using the Asian Pacific Association of Liver (APASL) definition. Multivariable logistic regression was used to derive prediction models (called VOCAL-Penn) for developing ACLF at 3, 6, and 12 months. We then created prediction models for ACLF mortality at 28 and 90 days.ResultsThe VOCAL-Penn models for ACLF development had very good discrimination [concordance (C) statistics of 0.93, 0.92, and 0.89 at 3, 6, and 12 months, respectively] and calibration. The mortality models also had good discrimination at 28 and 90 days (C statistics 0.89 and 0.88, respectively), outperforming the Model for End-stage Liver Disease (MELD), MELD-sodium, and the APASL ACLF Research Consortium ACLF scores.ConclusionWe have developed novel tools for predicting development of ACLF in compensated cirrhosis patients, as well as for ACLF mortality. These tools may be used to proactively guide patient follow-up, prognostication, escalation of care, and transplant evaluation. Receiver operating characteristic (ROC) curves for predicting development of APASL ACLF at 3 months (a), 6 months (b), and 1 year (c).
| S-EPMC7656856 | biostudies-literature
Project description:To validate prognostic scores for acute decompensation of cirrhosis and acute-on-chronic liver failure in Brazilian patients.This is a prospective cohort study designed to assess the prognostic performance of the chronic liver failure-consortium (CLIF-C) acute decompensation score (CLIF-C AD) and CLIF-C acute-on-chronic liver failure score (CLIF-C ACLF), regarding 28-d and 90-d mortality, as well as to compare them to other prognostic models, such as Model for End-Stage Liver Disease (MELD), MELD Sodium (MELD-Na), Child-Pugh (CP) score, and the CLIF-C Organ Failure score (CLIF-C OF). All participants were adults with acute decompensation of cirrhosis admitted to the Emergency Department of a tertiary hospital in southern Brazil. Prognostic performances were evaluated by means of the receiver operating characteristic (ROC) curves, area under the curves (AUC) and 95%CI.One hundred and thirteen cirrhotic patients were included. At admission, 18 patients had acute-on-chronic liver failure (ACLF) and 95 individuals had acute decompensation (AD) without ACLF, of which 24 eventually developed ACLF during the course of hospitalization (AD evolving to ACLF group). The AD group had significantly lower 28-d (9.0%) and 90-d (18.3%) mortality as compared to the AD evolving to ACLF group and to the ACLF group (both P < 0.001). On the other hand, 28-d and 90-d mortalities were not significantly different between AD evolving to ACLF group and ACLF group (P = 0.542 and P = 0.708, respectively). Among patients with ACLF, at 28 d from the diagnosis, CLIF-C ACLF was the only score able to predict mortality significantly better than the reference line, with an AUC (95%CI) of 0.71 (95%CI: 0.54-0.88, P = 0.021). Among patients with AD, all prognostic scores performed significantly better than the reference line regarding 28-d mortality, presenting with similar AUCs: CLIF-C AD score 0.75 (95%CI: 0.63-0.88), CP score 0.72 (95%CI: 0.59-0.85), MELD score 0.75 (95%CI: 0.61-0.90), MELD-Na score 0.76 (95%CI: 0.61-0.90), and CLIF-C OF score 0.74 (95%CI: 0.60-0.88). The same occurred concerning AUCs for 90-d mortality: CLIF-C AD score 0.70 (95%CI: 0.57-0.82), CP score 0.73 (95%CI: 0.62-0.84), MELD score 0.71 (95%CI: 0.59-0.83), MELD-Na score 0.73 (95%CI: 0.62-0.84), and CLIF-C OF score 0.65 (95%CI: 0.52-0.78).This study demonstrated that CLIF-C ACLF is the best available score for the prediction of 28-d mortality among patients with ACLF. CLIF-C AD score is also useful for the prediction of mortality among cirrhotic patients with AD not fulfilling diagnostic criteria for ACLF, but it was not superior to other well-established prognostic scores.
| S-EPMC5537190 | biostudies-other
Project description:Background and aims: We aimed to study the pathogenesis of AH in an animal model of acute-on-chronic alcoholic liver disease which combines chronic hepatic fibrosis with intragastric alcohol administration. Methods: Adult male C57BL6/J mice were treated with CCl4 (0.2 ml/kg, 2×weekly by intraperitoneal injections for 6 weeks) to induce chronic liver fibrosis. Then, ethyl alcohol (EtOH) (up to 25 g/kg/day, for 3 weeks) was administered continuously to mice via a gastric feeding tube, with or without one-half dose of CCl4. Liver and serum markers were evaluated to characterize acute-on-chronic-alcoholic liver disease in our model. Results: CCl4 or EtOH treatment alone induced liver fibrosis or steatohepatitis, respectively, findings that were consistent with expected pathology. Combined treatment with CCl4 and EtOH resulted in a marked exacerbation of liver injury, as evident by the development of hepatic inflammation, marked steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either treatment alone. Liver transcriptomic changes specific to combined treatment group demonstrated close concordance with pathways perturbed in human severe cases of AH. In addition to gene expression changes, E. coli and Candida species were also significantly more abundant in livers of mice co-treated with CCl4 and EtOH. Conclusions: Mice treated with CCl4 and EtOH displayed several key characteristics of human AH, including pericellular fibrosis, increased hepatic bacterial load, and dysregulation of the same molecular pathways. This model may be useful for developing therapeutics for AH.
2018-09-05 | GSE119470 | GEO
Project description:Background and aimsIt is critical but challenging to predict the prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This study systematically summarized and evaluated the quality and performance of available clinical prediction models (CPMs).MethodsA keyword search of articles on HBV-ACLF CPMs published in PubMed from January 1995 to April 2020 was performed. Both the quality and performance of the CPMs were assessed.ResultsFifty-two CPMs were identified, of which 31 were HBV-ACLF specific. The modeling data were mostly derived from retrospective (83.87%) and single-center (96.77%) cohorts, with sample sizes ranging from 46 to 1,202. Three-month mortality was the most common endpoint. The Asian Pacific Association for the Study of the Liver consensus (51.92%) and Chinese Medical Association liver failure guidelines (40.38%) were commonly used for HBV-ACLF diagnosis. Serum bilirubin (67.74%), the international normalized ratio (54.84%), and hepatic encephalopathy (51.61%) were the most frequent variables used in models. Model discrimination was commonly evaluated (88.46%), but model calibration was seldom performed. The model for end-stage liver disease score was the most widely used (84.62%); however, varying performance was reported among the studies.ConclusionsSubstantial limitations lie in the quality of HBV-ACLF-specific CPMs. Disease severity of study populations may impact model performance. The clinical utility of CPMs in predicting short-term prognosis of HBV-ACLF remains to be undefined.
| S-EPMC8666376 | biostudies-literature
Project description:IntroductionAcute liver failure is a rare disease with high mortality and liver transplantation is the only life saving therapy. Accurate prognosis of ALF is crucial for proper intervention.AimTo identify and characterize newly developed prognostic models of mortality for ALF patients, assess study quality, identify important variables and provide recommendations for the development of improved models in the future.MethodsThe online databases MEDLINE® (1950-2012) and EMBASE® (1980-2012) were searched for English-language articles that reported original data from clinical trials or observational studies on prognostic models in ALF patients. Studies were included if they developed a new model or modified existing prognostic models. The studies were evaluated based on an existing framework for scoring the methodological and reporting quality of prognostic models.ResultsTwenty studies were included, of which 18 reported on newly developed models, 1 on modification of the Kings College Criteria (KCC) and 1 on the Model for End-Stage Liver Disease (MELD). Ten studies compared the newly developed models to previously existing models (e.g. KCC); they all reported that the new models were superior. In the 12-point methodological quality score, only one study scored full points. On the 38-point reporting score, no study scored full points. There was a general lack of reporting on missing values. In addition, none of the studies used performance measures for calibration and accuracy (e.g. Hosmer-Lemeshow statistics, Brier score), and only 5 studies used the AUC as a measure of discrimination.ConclusionsThere are many studies on prognostic models for ALF but they show methodological and reporting limitations. Future studies could be improved by better reporting and handling of missing data, the inclusion of model calibration aspects, use of absolute risk measures, explicit considerations for variable selection, the use of a more extensive set of reference models and more thorough validation.
| S-EPMC3522683 | biostudies-literature