找准慢加急性肝衰竭研究的关键点和突破点

目前慢加急性肝衰竭（ACLF）有亚太肝病研究学会（APASL）（东方）和欧洲肝病学会一慢性肝衰竭（EASL—CLIF）合作组（西方）制定的两种诊断标准。APASL诊断标准针对肝功能衰竭且有肝外脏器累及者,而EASL—CLIF诊断标准则针对更晚期多脏器衰竭阶段的患者。两者诊断的ACLF均会混杂失代偿性肝硬化患者。ACLF的病理特征、完整定义以及肝损伤诱因与肝功能急性恶化的关联性是今后研究的关键和方向。     

1,5-Anhydroglucitol Predicts Mortality in Patients with HBV-Related Acute-on-chronic Liver Failure

Background and Aims1,5-Anhydroglucitol (1,5AG) activity has been reported in chronic liver disease. Hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF) patients have a high mortality. We aimed to discover the relationship between serum 1,5AG and the prognosis of HBV-ACLF.MethodsSerum 1,5AG levels were determined in 333 patients with HBV-ACLF, 300 without diabetes were allocated to derivation (n=206) and validation cohorts (n=94), and 33 were recruited to evaluate 1,5AG in those with diabetes. Forty patients with chronic hepatitis B, 40 with liver cirrhosis, and 40 healthy people were controls in the validation cohort.ResultsIn the derivation and validation cohorts, serum 1,5AG levels were significantly lower in nonsurvivors than in survivors. The AUC of 1,5AG for 28-day mortality was 0.811. In patients with diabetes, serum 1,5AG levels were also significantly lower in nonsurvivors than in survivors. In multivariate Cox regression analysis, serum 1,5AG levels were independently associated with 28-day mortality. A novel predictive model (ACTIG) based on 1,5AG, age, TB, cholesterol, and INR was derived to predict mortality. In ACTIG, the AUC for 28-day mortality was 0.914, which was superior to some prognostic score models. ACTIG was also comparable to those prognostic score models in predicting 6-month mortality. In mice with D-galactosamine/lipopolysaccharide-induced liver failure, 1,5AG levels were significantly reduced in serum and significantly increased in urine and liver tissue.ConclusionsSerum 1,5AG levels are a promising predictor of short-term mortality in HBV-ACLF patients. The 1,5AG distribution changed in mice with D-galactosamine/ lipopolysaccharide-induced liver failure.     

Prospect of Animal Models for Acute-on-chronic Liver Failure: A Mini-review

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 breakthroughs in ACLF animal model development.     

Acute-on-chronic Liver Failure in a Patient with Candida Endophthalmitis: A Case Report

Acute-on-chronic liver failure (ACLF) is a risk factor for fungal infection. Endogenous fungal endophthalmitis is a serious, sight-threatening disease. Common causes include immunocompromised state and intravenous drug use, permitting opportunistic pathogens to reach the eye through the blood stream. We report a case of Candida endophthalmitis in a 47 year-old woman who was admitted to our hospital with ACLF and poorly controlled diabetes. In addition, she was treated with glucocorticoids due to severe jaundice. After treatment for ACLF, the patient experienced fever with blurred vision in the left eye and was diagnosed with candidemia, endogenous Candida endophthalmitis in the left eye, and chorioretinitis in the right eye. Systemic and topical antifungal treatment was administered based on the positive Candida albicans test in intraocular fluid using second-generation sequencing. The patient underwent vitrectomy in the left eye and C. albicans was confirmed in vitreous cultures. Follow-up visit, at 6 weeks after the operation, showed only light perception in the left eye and stable visual acuity in the right eye. Physicians should be aware of endogenous fungal endophthalmitis in patients with ACLF, especially those with Candida infection, a history of glucocorticoid use, and diabetes. A dilated retinal examination should be performed by an ophthalmologist if ACLF patients develop fever and fungal infection.     

Clinical Prediction Models for Hepatitis B Virus-related Acute-on-chronic Liver Failure: A Technical Report

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.     

Development of a Widely Applicable and Simple Prognostic Score for Patients with Acute-on-chronic Liver Failure

Background and AimsAcute-on-chronic liver failure (ACLF) tends to progress rapidly with high short-term mortality. We aimed to create a widely applicable, simple prognostic (WASP) score for ACLF patients.MethodsA retrospective cohort of ACLF cases recruited from three centers in China were divided into training and validation sets to develop the new score. A prospective longitudinal cohort was recruited for further validation.ResultsA total of 541 cases were included in the training set, and seven independent ACLF prognostic factors were screened to construct a new quantitative WASP-ACLF table. In the validation set of 671 cases, WASP-ACLF showed better predictive ability for 28-day and 90-day mortality than the currently used prognostic scores at baseline, day 3, week 1, and week 2. The predictive efficacy and clinical validity of the model improved over time. Patients were assigned to low-, intermediate-, and high-risk groups by their WASP-ACLF scores. Compared with the other two groups, intermediate-risk patients had a more uncertain prognosis, with a 90-day mortality of 44.4–50.6%. Sequential assessments at weeks 1 and 2 found the 90-day mortality of intermediate-risk groups was <20% for patients with a ≥2 point decrease in WASP-ACLF and was up to 56% for patients with a ≥2 points increase. Similar results were observed in prospective data.ConclusionsThe new ACLF prognostic score was simple, widely applicable, and had good predictive efficacy. Continuous assessments and trend of change in WASP-ACLF need to be considered, especially for intermediate-risk patients.     

Clinical Course and Outcome Patterns of Acute-on-chronic Liver Failure: A Multicenter Retrospective Cohort Study

Background and AimsAcute-on-chronic liver failure (ACLF) is acute decompensation of liver function in the setting of chronic liver disease, and characterized by high short-term mortality. In this study, we sought to investigate the clinical course of patients at specific time points, and to propose dynamic prognostic criteria.MethodsWe assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study. The clinical course of patients was defined as disease recovery, improvement, worsening or steady patterns based on the variation tendency in prothrombin activity (PTA) and total bilirubin (TB) at different time points.ResultsResolution of PTA was observed in 231 patients (51%) at 12 weeks after the diagnosis of ACLF. Among the remaining patients, 66 (14.6%) showed improvement and 156 (34.4%) showed a steady or worsening course. In patients with resolved PTA, the clinical course of TB exhibited resolved pattern in 95.2%, improved in 3.9%, and steady or worse in 0.8%. Correspondingly, in patients with improved PTA, these values for TB were 28.8%, 27.3%, and 43.9%, respectively. In patients with steady or worsening PTA, these values for TB were 5.7%, 32.3%, and 65.6%, respectively. Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients.ConclusionsWe propose the following dynamic prognostic criteria: rapid progression, slow progression, rapid recovery, slow recovery, and slow persistence, which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.     

A Prognostic Nomogram with High Accuracy Based on 2D-SWE in Patients with Acute-on-chronic Liver Failure

Background and AimsAcute-on-chronic liver failure (ACLF) is associated with very high mortality. Accurate prediction of prognosis is critical in navigating optimal treatment decisions to improve patient survival. This study was aimed to develop a new nomogram integrating two-dimensional shear wave elastography (2D-SWE) values with other independent prognostic factors to improve the precision of predicting ACLF patient outcomes.MethodsA total of 449 consecutive patients with ACLF were recruited and randomly allocated to a training cohort (n=315) or a test cohort (n=134). 2D-SWE values, conventional ultrasound features, laboratory tests, and other clinical characteristics were included in univariate and multivariate analysis. Factors with prognostic value were then used to construct a novel prognostic nomogram. Receiver operating curves (ROCs) were generated to evaluate and compare the performance of the novel and published models including the Model for End-Stage Liver Disease (MELD), MELD combined with sodium (MELD-Na), and Jin’s model. The model was validated in a prospective cohort (n=102).ResultsA ACLF prognostic nomogram was developed with independent prognostic factors, including 2D-SWE, age, total bilirubin (TB), neutrophils (Neu), and the international normalized ratio (INR). The area under the ROC curve (AUC) was 0.849 for the new model in the training cohort and 0.861 in the prospective validation cohort, which were significantly greater than those for MELD (0.758), MELD-Na (0.750), and Jin’s model (0.777, all p <0.05). Calibration curve analysis revealed good agreement between the predicted and observed probabilities. The new nomogram had superior overall net benefit and clinical utility.ConclusionsWe established and validated a 2D-SWE-based noninvasive nomogram to predict the prognosis of ACLF patients that was more accurate than other prognostic models.     

Novel Prognostic Models for Predicting the 180-day Outcome for Patients with Hepatitis-B Virus-related Acute-on-chronic Liver Failure

Background and AimsIt remains difficult to forecast the 180-day prognosis of patients with hepatitis B virus-acute-on-chronic liver failure (HBV-ACLF) using existing prognostic models. The present study aimed to derive novel-innovative models to enhance the predictive effectiveness of the 180-day mortality in HBV-ACLF.MethodsThe present cohort study examined 171 HBV-ACLF patients (non-survivors, n=62; survivors, n=109). The 27 retrospectively collected parameters included the basic demographic characteristics, clinical comorbidities, and laboratory values. Backward stepwise logistic regression (LR) and the classification and regression tree (CART) analysis were used to derive two predictive models. Meanwhile, a nomogram was created based on the LR analysis. The accuracy of the LR and CART model was detected through the area under the receiver operating characteristic curve (AUROC), compared with model of end-stage liver disease (MELD) scores.ResultsAmong 171 HBV-ACLF patients, the mean age was 45.17 years-old, and 11.7% of the patients were female. The LR model was constructed with six independent factors, which included age, total bilirubin, prothrombin activity, lymphocytes, monocytes and hepatic encephalopathy. The following seven variables were the prognostic factors for HBV-ACLF in the CART model: age, total bilirubin, prothrombin time, lymphocytes, neutrophils, monocytes, and blood urea nitrogen. The AUROC for the CART model (0.878) was similar to that for the LR model (0.878, p=0.898), and this exceeded that for the MELD scores (0.728, p<0.0001).ConclusionsThe LR and CART model are both superior to the MELD scores in predicting the 180-day mortality of patients with HBV-ACLF. Both the LR and CART model can be used as medical decision-making tools by clinicians.     

PD-1 Involvement in Peripheral Blood CD8+ T Lymphocyte Dysfunction in Patients with Acute-on-chronic Liver Failure

Background and AimsProgrammed cell death-1 (PD-1) plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood. This study aimed to explore the role of PD-1 in CD8⁺ T lymphocyte dysfunction in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).MethodsThirty patients with HBV-ACLF and 30 healthy controls (HCs) were recruited. The differences in the numbers and functions of CD8⁺ T lymphocytes, PD-1 and glucose transporter-1 (Glut1) expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed. In vitro, the CD8⁺ T lymphocytes from HCs were cultured (HC group) and the CD8⁺ T lymphocytes from ACLF patients were cultured with PD-L1-IgG (ACLF+PD-1 group) or IgG (ACLF group). The numbers and functions of CD8⁺ T lymphocytes, PD-1 expression, glycogen uptake capacity, and Glut1, hexokinase-2 (HK2), and pyruvate kinase (PKM2) expression were analyzed among the HC group, ACLF group and ACLF+ PD-1group.ResultsThe absolute numbers of CD8⁺ T lymphocytes in the peripheral blood from patients with HBV-ACLF were lower than in the HCs (p<0.001). The expression of PD-1 in peripheral blood CD8⁺ T lymphocytes was lower in HCs than in patients with HBV-ACLF (p=0.021). Compared with HCs, PD-1 expression was increased (p=0.021) and Glut1 expression was decreased (p=0.016) in CD8⁺ T lymphocytes from the HBV-ACLF group. In vitro, glycogen uptake and functions of ACLF CD8⁺ T lymphocytes were significantly lower than that in HCs (p=0.017; all p<0.001). When PD-1/PD-L1 was activated, the glycogen uptake rate and expression levels of Glut1, HK2, and PKM2 showed a decreasing trend (ACLF+PD-1 group compared to ACLF group , all p<0.05). The functions of CD8⁺ T lymphocytes in the ACLF+PD-1 group [using biomarkers of Ki67, CD69, IL-2, interferon-gamma, and tumor necrosis factor-alpha- were lower than in the ACLF group (all p<0.05).ConclusionsCD8⁺ T lymphocyte dysfunction is observed in patients with HBV-ACLF. PD-1-induced T lymphocyte dysfunction might involve glycolysis inhibition.     

Serum from Acute-on-chronic Liver Failure Patients May Affect Mesenchymal Stem Cells Transplantation by Impairing the Immunosuppressive Function of Cells

Background and AimsThe safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of acute-on-chronic liver failure (ACLF) have been validated. However, the impact of the pathological ACLF microenvironment on MSCs is less well understood. This study was designed to explore the changes in the functional properties of MSCs exposed to ACLF serum.MethodsMSCs were cultured in the presence of 10%, 30% and 50% serum concentrations from ACLF patients and healthy volunteers. Then, the cell morphology, phenotype, apoptosis and proliferation of MSCs were evaluated, including the immunosuppressive effects. Subsequently, mRNA sequencing analysis was used to identify the molecules and pathways involved in MSC functional changes in the context of ACLF.ResultsIn the presence of ACLF serum, MSC morphology significantly changed but phenotype did not. Besides, MSC proliferation activity was weakened, while the apoptosis rate was lightly increased. Most importantly, the immunosuppressive function of MSCs was enhanced in a low-concentration serum environment but transformed into a proinflammatory response in a high-concentration serum environment. RNA sequencing indicated that 10% serum concentration from ACLF patients mediated the PI3K-Akt pathway to enhance the anti-inflammatory effect of MSCs, while the 50% serum concentration from ACLF patients promoted the conversion of MSCs into a proinflammatory function by affecting the cell cycle.ConclusionsThe 50% ACLF serum concentration is more similar to the environment in the human body, which means that direct peripheral blood intravenous infusion of MSCs may reduce the effect of transplantation. Combining treatments of plasma exchange to reduce harmful substances in serum may promote MSCs to exert a stronger anti-inflammatory effect.     

Development and Validation of a Nomogram for 90-day Outcome in Patients with Hepatitis B Virus-related Acute-on-chronic Liver Failure

Background and AimsIt is challenging to predict the 90-day outcomes of patients infected with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) via prevailing predictive models. This study aimed to develop an innovative model to enhance the analytical efficacy of 90-day mortality in HBV-ACLF.MethodsIn this study, 149 HBV-ACLF patients were evaluated by constructing a death risk prediction nomogram. Bootstrap resampling and an independent validation cohort comprising 31 patients from June 2019 to February 2020 were assessed for model confirmation.ResultsThe nomogram was constructed by entering and identifying five factors (age, total bilirubin, prothrombin activity (PTA), lymphocyte (L)%, and monocyte (M)%. Healthy refinement was achieved from the nomogram analysis, where the area under the receiver operating characteristic curve was 0.864 for the training cohort and 0.874 was achieved for the validation cohort. There was admirable concordance between the predicted and true results in the equilibrium curve. The decision curve assessment revealed the useful clinical application of the nomogram.ConclusionsWe constructed an innovative nomogram and validated it for the prediction of 90-day HBV-ACLF patient outcomes. This model might help develop optimized treatment protocol recommendations for HBV-ACLF patients.     

Acute Liver Failure

Acute liver failure is a rare but often catastrophic illness affecting the liver and multiple organ systems. Patients with acute liver failure require a multidisciplinary approach for adequate management. With improved critical care and the availability of liver transplantation, survival has significantly improved. Hepatic encephalopathy, cerebral edema and infections are the most common complications of acute liver failure. The evaluation requires a diligent search for a specific etiology of the liver failure, since certain causes may respond well to specific pharmacological therapies. Acetaminophen and non-acetaminophen drug-induced hepatotoxicity account for more than 50% of cases of acute liver failure. Assessment of prognosis frequently (at least on a daily basis) by using various prognostic tools, allows the treating team to decide whether or not to proceed with urgent liver transplantation. Artificial liver support devices are still in evaluation and not ready for use in clinical practice. While it is determined whether or not there is sufficient hepatic regeneration, the care of the patient with acute liver failure revolves around managing the dysfunction of multiple extra hepatic systems.     

Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation,Acute-on-chronic Liver Failure,and Death

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慢加急性肝衰竭

2007年4月4-7日,在河南省洛阳市举办的"第三届全国重型肝病及人工肝和血液净化学术年会"上,英国伦敦大学学院(University College London,UCL)肝病研究所肝衰竭组的Rajiv Jalan教授作了题为"acute-on-chronic livel failure(ACLF)"的报告.目前国内将ACLF译为"慢加急性肝衰竭".