Risk factors for progression to acute-on-chronic liver failure during severe acute exacerbation of chronic hepatitis B virus infection

BACKGROUND Acute exacerbation in patients with chronic hepatitis B virus(HBV) infection results in different severities of liver injury. The risk factors related to progression to hepatic decompensation(HD) and acute-on-chronic liver failure(ACLF) in patients with severe acute exacerbation(SAE) of chronic HBV infection remain unknown.AIM To identify risk factors related to progression to HD and ACLF in compensated patients with SAE of chronic HBV infection.METHODS The baseline characteristics of 164 patients with SAE of chronic HBV infection were retrospectively reviewed. Independent risk factors associated with progression to HD and ACLF were identified. The predictive values of our previously established prediction model in patients with acute exacerbation(AE model) and the model for end-stage liver disease(MELD) score in predicting the development of ACLF were evaluated.RESULTS Among 164 patients with SAE, 83(50.6%) had compensated liver cirrhosis(LC),43 had progression to HD without ACLF, and 29 had progression to ACLF within 28 d after admission. Independent risk factors associated with progression to HD were LC and low alanine aminotransferase. Independent risk factors for progression to ACLF were LC, high MELD score, high aspartate aminotransferase(AST) levels, and low prothrombin activity(PTA). The area under the receiver operating characteristic of the AE model [0.844, 95%confidence interval(CI): 0.779-0.896] was significantly higher than that of MELD score(0.690, 95%CI: 0.613-0.760, P < 0.05) in predicting the development of ACLF.CONCLUSION In patients with SAE of chronic HBV infection, LC is an independent risk factor for progression to both HD and ACLF. High MELD score, high AST, and low PTA are associated with progression to ACLF. The AE model is a better predictor of ACLF development in patients with SAE than MELD score.     

Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation

Acute on chronic liver failure(ACLF)is a disease entity with a high mortality rate.The acute event arises from drugs and toxins,viral infections,bacterial sepsis,interventions(both surgical and non-surgical)and vascular events on top of a known or occult chronic liver disease.ACLF secondary to reactivation of chronic hepatitis B virus is a distinct condition;the high mortality of which can be managed in the wake of new potent antiviral therapy.For example,lamivudine and entecavir use has shown definite short-term survival benefits,even though drug resistance is a concern in the former.The renoprotective effects of telbivudine have been shown in a few studies to be useful in the presence of renal dysfunction.Monotherapy with newer agents such as tenofovir and a combination of nucleos(t)ides is promising for improving survival in this special group of liver disease patients.This review describes the current status of potent antiviral therapy in patient with acute on chronic liver failure due to reactivation of chronic hepatitis B,thereby providing an algorithm in management of such patients.     

Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure

Spontaneous reactivation of chronic hepatitis B (CHB) is an important cause of acute-on-chronic liver failure (ACLF). Antiviral drugs may help reduce the high morbidity and mortality in such patients, especially in places where liver transplant is not available. The aim was to evaluate the efficacy of tenofovir and to determine the predictors of mortality in patients with spontaneous reactivation of CHB with ACLF. Consecutive patients of ACLF due to spontaneous reactivation of CHB were randomized to receive either tenofovir or placebo. The primary endpoint was survival at 3 months. Of the 90 patients with ACLF of different etiologies, 27 (26%) were due to reactivation of CHB and were enrolled. The median baseline hepatitis B virus (HBV) DNA level was 9 × 10(5) IU/mL. Fourteen patients received tenofovir and 13 placebo. At 3 months the probability of survival was higher in the tenofovir than the placebo group (8/14 [57%] versus 2/13 [15%], respectively; P = 0.03). The cause of death in the 15 patients was progressive liver failure leading to multiorgan failure. Liver transplantation could not be offered due to its nonavailability. In the surviving patients, there was a significant improvement in the Child-Turcotte Pugh (CTP) and model for endstage liver disease (MELD) scores and significant decline in the HBV DNA levels in the tenofovir group, whereas these parameters did not change significantly in the placebo group. More than 2 log reduction in HBV DNA levels at 2 weeks was found to be an independent predictor of survival. CONCLUSION: Tenofovir significantly reduces HBV-DNA levels, improves CTP and MELD scores, and reduces mortality in patients with severe spontaneous reactivation of CHB presenting as ACLF. Reduction in HBV-DNA levels at 2 weeks should be a desirable goal and is a good predictor of survival.     

HBV相关慢加急性肝衰竭免疫病理发病机制研究进展

慢加急性肝衰竭(ACLF)是在慢性肝病基础上发生的急性肝功能失代偿。在我国,引起ACLF的首要病因是乙型肝炎病毒感染,其中病毒诱发的淋巴毒性T细胞活化和细胞因子大量分泌为代表的免疫病理损伤是肝衰竭发病的中心环节。本文将从抗原递呈、效应细胞的直接杀伤、宿主遗传背景、免疫相关细胞因子和免疫过激状态的抑制性调节等方面介绍HBV相关ACLF免疫病理发病机制的研究进展。     

Score model for predicting acute-on-chronic liver failure risk in chronic hepatitis B

AIM: To establish a clinical scoring model to predict risk of acute-on-chronic liver failure(ACLF) in chronic hepatitis B(CHB) patients.METHODS: This was a retrospective study of 1457 patients hospitalized for CHB between October 2008 and October 2013 at the Beijing Ditan Hospital, Capital Medical University, China. The patients were divided into two groups: severe acute exacerbation(SAE) group(n = 382) and non-SAE group(n = 1075). The SAE group was classified as the high-risk group based on the higher incidence of ACLF in this group than in the non-SAE group(13.6% vs 0.4%). Two-thirds of SAE patients were randomly assigned to risk-model derivation and the other one-third to model validation. Univariate risk factors associated with the outcome were entered into a multivariate logistic regression model for screening independent risk factors. Each variable was assigned an integer value based on the regression coefficients, and the final score was the sum of these values in the derivation set. Model discrimination and calibration were assessed using area under the receiver operating characteristic curve and the Hosmer-Lemeshow test. RESULTS: The risk prediction scoring model includedthe following four factors: age ≥ 40 years, total bilirubin ≥ 171 μmol/L, prothrombin activity 40%-60%, and hepatitis B virus DNA 107 copies/m L. The sum risk score ranged from 0 to 7; 0-3 identified patients with lower risk of ACLF, whereas 4-7 identified patients with higher risk. The Kaplan-Meier analysis showed the cumulative risk for ACLF and ACLF-related death in the two risk groups(0-3 and 4-7 scores) of the primary cohort over 56 d, and log-rank test revealed a significant difference(2.0% vs 33.8% and 0.8% vs 9.4%, respectively; both P 0.0001). In the derivation and validation data sets, the model had good discrimination(C index = 0.857, 95% confidence interval: 0.800-0.913 and C index = 0.889, 95% confidence interval: 0.820-0.957, respectively) and calibration demonstrated by the Hosmer-Lemeshow test(χ2 = 4.516, P = 0.808 and χ2 = 1.959, P = 0.923, respectively).CONCLUSION: Using the scoring model, clinicians can easily identify patients(total score ≥ 4) at high risk of ACLF and ACLF-related death early during SAE.     

乙型肝炎相关慢加急性肝衰竭患者的预后因素分析

目的 探讨影响乙型肝炎相关慢加急性肝衰竭患者预后的危险因素.方法 记录263例乙型肝炎相关慢加急性肝衰竭患者治疗基线时血清胆碱酯酶、白蛋白及胆固醇等反应肝脏储备功能的临床指标及重要并发症的发生情况,并计算其MELD评分.所有患者随访满1年.通过Cox比例风险回归模型筛选出影响预后的独立危险因素.结果 在1年的随访时间内,67例死亡,病死率为25.5％.死亡组血清胆碱酯酶、白蛋白、胆固醇水平均较存活组低.血清胆固醇水平随着MELD值的升高而下降.Cox比例风险回归模型分析得出,肝性脑病、肝肾综合征、上消化道出血、胆固醇≤2.5 mmol/L、MELD评分≥30是影响乙型肝炎相关慢加急性肝衰竭患者预后的独立危险因素,RR分别为6.286、2.983、2.272、2.168及1.853.结论 胆固醇≤2.5 mmol/L、肝性脑病、肝肾综合征、上消化道出血及MELD评分≥30是决定乙型肝炎相关慢加急性肝衰竭患者预后的主要危险因素.     

Modified model for end-stage liver disease improves shortterm prognosis of hepatitis B virus-related acute-on-chronic liver failure

AIM To investigate whether the short-term prognosis of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF) could be improved by using a modified model for end-stage liver disease(MELD) including serum lactate.METHODS This clinical study was conducted at the First Affiliated Hospital, Fujian Medicine University, China. From 2009 to 2015, 236 patients diagnosed with HBV-related ACLF at our center were recruited for this 3-month followup study. Demographic data and serum lactate levels were collected from the patients. The MELD scores with or without serum lactate levels from survival and nonsurvival groups were recorded and compared.RESULTS Two hundred and thirty-six patients with HBV-ACLF were divided into two groups: survival group(S) andnon-survival group(NS). Compared with the NS group, the patients in survival the S group had a significantly lower level of serum lactate(3.11 ± 1.98 vs 4.67 ± 2.43, t = 5.43, P 0.001) and MELD score(23.33 ± 5.42 vs 30.37 ± 6.58, t = 9.01, P = 0.023). Furthermore, serum lactate level was positively correlated with MELD score(r = 0.315, P 0.001). Therefore, a modified MELD including serum lactate was developed by logistic regression analysis(0.314 × lactate + 0.172 × MELD-5.923). In predicting 3-month mortality using the MELD-LAC model, the patients from the S group had significantly lower baseline scores(-0.930 ± 1.34) when compared with those from the NS group(0.771 ± 1.32, t = 9.735, P 0.001). The area under the receiver operating characteristic curve(AUROC) was 0.859 calculated by using the MELD-LAC model, which was significantly higher than that calculated by using the lactate level(0.790) or MELD alone(0.818). When the cutoff value was set at-0.4741, the sensitivity, specificity, positive predictive value and negative predictive value for predicting short-term mortality were 91.5%, 80.10%, 94.34% and 74.62%, respectively. When the MELD-LAC scores at baseline level were set at-0.5561 and 0.6879, the corresponding mortality rates within three months were 75% and 90%, respectively.CONCLUSION The short-term prognosis of HBV-related ACLF was improved by using a modified MELD including serum lactate from the present 6-year clinical study.     

Predictors of the outcomes of acute-on-chronic hepatitis B liver failure

AIM:To identify the risk factors in predicting the outcome of acute-on-chronic hepatitis B liver failure patients.METHODS:We retrospectively divided 113 patients with acute-on-chronic liver failure-hepatitis B virus(ACLF-HBV) and without concurrent hepatitis C or D virus infection and hepatocellular carcinoma into two groups according to their outcomes after anti-HBV therapy.Their demographic,clinical,and biochemical data on the day of diagnosis and after the first week of treatment were analyzed using the Mann-Whitney U test,Fisher's exact test,and a multiple logistic regression analysis.RESULTS:The study included 113 patients(87 men and 26 women) with a mean age of 49.84 years.Fiftytwo patients survived,and 61 patients died.Liver failure(85.2%),sepsis(34.4%),and multiple organ failure(39.3%) were the main causes of death.Multivariate analyses showed that Acute Physiology and Chronic Health Evaluation(APACHE) Ⅱ scores ≥ 12 [odds ratio(OR) = 7.160,95% CI:2.834-18.092,P 0.001] and positive blood culture(OR = 13.520,95% CI:2.740-66.721,P = 0.001) on the day of diagnosis and model for end-stage liver disease(MELD) scores ≥ 28(OR = 8.182,95% CI:1.884-35.527,P = 0.005) after the first week of treatment were independent predictors of mortality.CONCLUSION:APACHE Ⅱ scores on the day of diagnosis and MELD scores after the first week of anti-HBV therapy are feasible predictors of outcome in ACLFHBV patients.     

拉米夫定治疗慢性乙型肝炎慢加急性肝衰竭患者的疗效观察

目的 观察拉米夫定治疗慢性乙型肝炎慢加急性肝衰竭(HBV-ACLF)早、中期患者48周的临床疗效及和病毒学应答的关系.方法 回顾性分析了73例使用拉米夫定治疗的HBV-ACLF早、中期患者,观察0、4、8、24、48周的凝血酶原时间活动度、ALT、AST、总胆红素、白蛋白、血尿素氮、肌酐、HBV DNA定量、病毒学应答及生存率.使用SPSS17.0软件分析,组间两均数比较用成组t检验,两率间比较用x2检验.结果 (1)在4、8、24、48周时完全病毒学应答率分别为57.5％ (42/73)、71.0％ (44/62)、83.1％ (49/59)、86.5％ (45/52);部分病毒学应答率分别为30.1％ (22/73)、25.8％ (16/62)、16.9％ (10/59)、13.5％ (7/52).(2) 48周时总的生存率为71.2％(52/73);完全病毒学应答患者、部分病毒学应答患者生存率分别为61.6％ (45/73)、9.6％ (7/73);完全病毒学应答患者的预后优于部分病毒学应答患者,两组比较,x2=6.829,P＜0.01,差异有统计学意义.(3)肝功能、MELD评分,HBV DNA定量在第8、24、48周较基线水平有明显改善.结论 拉米夫定治疗HBV-ACLF早、中期患者具有良好的临床疗效,预后与病毒学应答有关.     

Role of nutritional status and nutritional support in outcome of hepatitis B virus-associated acute-on-chronic liver failure

BACKGROUND Hepatitis B virus-associated acute-on-chronic liver failure(HBV-ACLF) is an important type of liver failure in Asia. There is a direct relationship between HBVACLF and gastrointestinal barrier function. However, the nutritional status of HBV-ACLF patients has been poorly studied.AIM To investigate the nutritional risk and nutritional status of HBV-ACLF patients and evaluated the impact of nutritional support on the gastrointestinal barrier and 28-d mortality.METHODS Nutritional risk screening assessment and gastrointestinal barrier biomarkers of patients with HBV-ACLF(n = 234) and patients in the compensatory period of liver cirrhosis(the control group)(n = 234) were compared during the period between 2016 and 2018. Changes were analyzed after nutritional support in HBVACLF patients. Valuable biomarkers have been explored to predict 28-d death. The 28-d survival between HBV-ACLF patients with nutritional support(n = 234) or no nutritional support(2014-2016)(n = 207) was compared.RESULTS The nutritional risk of the HBV-ACLF patients was significantly higher than that of the control group. The nutritional intake of the patients with HBV-ACLF was lower than that of the control group. The decrease in skeletal muscle and fat content and the deficiency of fat intake were more obvious(P 0.001). The coccus-bacillus ratio, secretory immunoglobulin A, and serum D-lactate were significantly increased in HBV-ACLF patients. The survival group had a lower nutritional risk, lower D-lactate, and cytokine levels(endotoxin, tumor necrosis factor alpha, interleukin-10, and interleukin-1). Interleukin-10 may be a potential predictor of death in HBV-ACLF patients. The 28-d survival of the nutritional support group was better than that of the non-nutritional support group(P = 0.016).CONCLUSION Patients with HBV-ACLF have insufficient nutritional intake and high nutritional risk, and their intestinal barrier function is impaired. Individualized and dynamic nutritional support is associated with a better prognosis of 28-d mortality in HBVACLF patients.     

Entecavir vs lamivudine therapy for na?ve patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure

AIM:To investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure(ACLF).METHODS:This was a single center,prospective cohort study.Eligible,consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100mg/d.All patients were given standard comprehensive internal medicine.The primary endpoint was survival rate at day 60,and secondary endpoints were reduction in hepatitis B virus(HBV)DNA and alanine aminotransferase(ALT)levels,and improvement in Child-Turcotte-Pugh(CTP)and model for end-stage liver disease(MELD)scores at day 60 and survival rate at week 52.RESULTS:One hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B:65 were included in the entecavir group and 54 in the lamivudine group(full analysis set).No significant differences were found in patient baseline clinical parameters.At day 60,entecavir did not improve the probability of survival(P=0.066),despite resulting in faster virological suppression(P<0.001),higher rates of virological response(P<0.05)and greater reductions in the CTP and MELD scores(all P<0.05)than lamivudine.Intriguingly,at week 52,the probability of survival was higher in the entecavir group than in the lamivudine group[42/65(64.6%)vs 26/54(48.1%),respectively;P=0.038].The pretreatment MELD score(B,1.357;95%Cl:2.138-7.062;P=0.000)and virological response at day30(B,1.556;95%Cl:1.811-12.411;P=0.002),were found to be good predictors for 52-wk survival.CONCLUSION:Entecavir significantly reduced HBV DNA levels,decreased the CTP and MELD scores,and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF.     

Entecavir treatment prevents disease progression in hepatitis B virus-related acute-on-chronic liver failure: establishment of a novel logistical regression model

Background

Hepatitis B-related acute-on-chronic liver failure (ACLF) has a poor prognosis with very high mortality. Unfortunately, most prognostic predictive models of liver failure are complicated and offer suboptimal sensitivity. Experience in entecavir (ETV)-treated patients with hepatitis B virus (HBV)-ACLF is limited.

Aims

This study was designed to evaluate the efficacy and safety of ETV in patients with HBV-ACLF and to develop a novel model (Tongji prognostic predictor model, TPPM) for prognostic prediction of HBV-ACLF patients.

Method

In this retrospective study, 248 patients with HBV-ACLF were enrolled. There were no significant differences in baseline clinical and virologic characteristics between patients treated with and without ETV.

Results

The 1- and 3-month survival rates of patients in the ETV-treated group (n?=?124) were 72.58 and 61.29%, respectively, significantly higher than that in NA-free group (n?=?124), which were 53.23 and 45.97%, respectively. By Hosmor and Lemeshow test, TPPM for HBV-ACLF had a very good degree of fit with disease prognosis. Based on this unique group of patients, the TPPM scoring offered a better prediction value in both specificity and sensitivity for 3-month mortality of patients with HBV-ACLF compared with MELD scoring system with statistically significant difference. In the patients with HBV-ACLF, using a cutoff of 0.22 for 3-month predicted mortality by TPPM, the positive predictive value was 93.6% and negative predictive value 91.3%.

Conclusion

ETV treatment prevented disease progression and increased the survival of patients with HBV-ACLF. The established TPPM scoring system offers superior predictor value in both specificity and sensitivity for HBV-ACLF patients when compared with MELD.     

Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure

AIM: To determine the prognostic value of circulating indicators of cell death in acute-on-chronic liver failure (ACLF) patients with chronic hepatitis B virus (HBV) infection as the single etiology.METHODS: Full length and caspase cleaved cytokeratin 18 (detected as M65 and M30 antigens) represent circulating indicators of necrosis and apoptosis. M65 and M30 were identified by enzyme-linked immunosorbent assay in 169 subjects including healthy controls (n = 33), patients with chronic hepatitis B (CHB, n = 55) and patients with ACLF (n = 81). According to the 3-mo survival period, ACLF patients were defined as having spontaneous recovery (n = 33) and non-spontaneous recovery which included deceased patients and those who required liver transplantation (n = 48).RESULTS: Both biomarker levels significantly increased gradually as liver disease progressed (for M65: P < 0.001 for all; for M30: control vs CHB, P = 0.072; others: P < 0.001 for all). In contrast, the M30/M65 ratio was significantly higher in controls compared with CHB patients (P = 0.010) or ACLF patients (P < 0.001). In addition, the area under receiver operating characteristic curve (AUC) analysis demonstrated that both biomarkers had diagnostic value (AUC ≥ 0.80) in identifying ACLF from CHB patients. Interestingly, it is worth noting that the M30/M65 ratio was significantly different between spontaneous and non-spontaneous recovery in ACLF patients (P = 0.032). The prognostic value of the M30/M65 ratio was compared with the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores at the 3-mo survival period, the AUC of the M30/M65 ratio was 0.66 with a sensitivity of 52.9% and the highest specificity of 92.6% (MELD:AUC = 0.71; sensitivity, 79.4%; specificity, 63.0%; Child-Pugh: AUC = 0.77; sensitivity, 61.8%; specificity, 88.9%).CONCLUSION: M65 and M30 are strongly associated with liver disease severity. The M30/M65 ratio may be a potential prognostic marker for spontaneous recovery in patients with HBV-related ACLF.     

Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure

AIM:To investigate the survival rates and prognostic factors in patients with hepatitis B virus-related acuteon-chronic liver failure(HBV-ACLF).METHODS:Clinical data in hospitalized patients with HBV-ACLF admitted from 2006 to 2009 were retrospectively analyzed.Their general conditions and survival were analyzed by survival analysis and Cox regression analysis.RESULTS:A total of 190 patients were included in this study.The overall 1-year survival rate was 57.6%.Patients not treated with antiviral drugs had ...     

慢加急性乙型肝炎肝衰竭患者发生感染和急性肾损伤危险因素分析

目的 探讨慢加急性乙型肝炎肝衰竭(HBV-ACLF)患者发生感染和急性肾损伤(AKI)的危险因素.方法 2017年9月～2019年9月我科收治的HBV-ACLF患者102例,发生感染48例,发生AKI 32例,应用Logistics回归分析影响患者并发感染和AKI的相关影响因素.结果 感染组住院天数≥15 d、存在侵入...     

miR-708与慢性乙型肝炎相关慢加急性肝衰竭患者预后的关系

目的 探究miR-708与慢性乙型肝炎（CHB）相关慢加急性肝衰竭（ACLF）患者预后的关系。方法 前瞻性选取2018年3月至2020年6月在海南医学院第二附属医院就诊的128例CHB-ACLF患者（设为CHB-ACLF组）和100例CHB患者（设为CHB组）作为研究对象。根据CHB-ACLF患者的预后生存情况将其分为生存组（n=66）和死亡组（n=62）。采用实时荧光定量PCR法检测各组血清miR-708的表达水平,并分析其与CHB-ACLF患者预后90 d生存情况的关系。结果CHB-ACLF组的血清miR-708相对表达量低于CHB组（0.43±0.16比0.75±0.14）,两组差异有统计学意义（P<0.05）。生存组的血清miR-708相对表达量高于死亡组（0.52±0.14比0.33±0.11）,两组差异有统计学意义（P<0.05）。多因素logistic回归分析结果显示,国际标准化比值（INR）、肌酐和终末期肝病模型（MELD）评分是CHB-ACLF患者预后生存的独立危险因素（P<0.05）,miR-708是CHB-ACLF患者预后生存的独立保护因素（P&...     

慢加急性肝衰竭与慢性肝衰竭的临床分析

目的探讨慢加急性肝衰竭与慢性肝衰竭的临床差异。方法选取肝组织病理诊断为慢性重型肝炎97例,按肝衰竭诊疗指南分为慢加急性肝衰竭29例和慢性肝衰竭68例,比较2组临床及检验指标特点。结果慢加急性肝衰竭在慢性重型肝炎中占29.9%。慢性肝衰竭与慢加急性肝衰竭的区别在于前者有肝硬化,患者年龄较大,ALB、PLT、HB更低,更易出现腹水,而ALT较低。结论慢性肝衰竭是在肝硬化基础上发生的慢性重型肝炎,临床上与慢加急性肝衰竭的主要区别是,除有肝衰竭的表现外还存在脾功能亢进和门脉高压的表现。