Serum thymosin ��4 levels in patients with hepatitis B virus-related liver failure

AIM: To investigate whether serum thymosin β4 can provide diagnostic or prognostic information in liver failure patients caused by chronic hepatitis B virus (HBV) infection.METHODS: Serum thymosin β4 levels were measured in 30 patients with acute-on-chronic liver failure (ACLF), 31 patients with chronic liver failure (CLF), 30 patients with compensated liver cirrhosis (CR) and 32 patients with chronic hepatitis B and 30 healthy controls. Serum thymosin β4 levels were measured by enzyme-linked immunosorbent assay and Child-Pugh and model for end-stage liver disease (MELD) scores were calculated for each patient on admission.RESULTS: Compared with healthy controls, serum thymosin β4 levels in ACLF, CLF, CR and chronic hepatitis B patients were significantly lower, 6.5047 (4.7879-10.5314) μg/mL vs 0.4632 (0.2759-0.8768) μg/mL, 0.6981 (0.5209-1.2008) μg/mL, 1.8053 (0.8110-2.3397) μg/mL, 3.7803 (1.8570-6.4722) μg/mL, respectively (P < 0.001). The levels of thymosin β4 in liver failure (ACLF or CLF) patients were markedly lower than that in CR (P < 0.001), and a difference was also found between CLF and ACLF patients (P = 0.038). In patients with chronic liver disease, there was a positive relationship between thymosin β4 levels and albumin, choline esterase, and platelet (P < 0.001), and negative relationship with alanine aminotransferase (P = 0.020), aspartate aminotransferase, total bilirubin, international normalized ratio of prothrombin time, and Child-Pugh and MELD scores (P < 0.001). Of the 61 liver failure patients, the thymosin β4 levels of non-survivors were significantly lower than that of survivors (P = 0.007). Receiver operating characteristics analysis identified a thymosin β4 cutoff level of 0.5708 μg/mL for predicting poor prognosis in all liver failure patients. The serial thymosin β4 values were observed in 13 liver failure inpatients. Lower initial values were observed in the death. While greater improvement in thymosin β4 value was found in those who recovered from the disease.CONCLUSION: Serum thymosin β4 can be used as an important potential predictor for liver failure caused by chronic HBV infection.     

Plasma betatrophin levels in patients with liver cirrhosis

AIM: To investigate the plasma levels of betatrophin in patients with cirrhosis.METHODS: Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic,or histological criteria were included.The severity of cirrhosis was classified according to Pugh's modification of Child's classification and MELD score. Insulin resistance(IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects.Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay(DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were 4% and 10%,respectively. The normal values were between 2 and17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA(Aviscera Bioscience). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were 6% and 10%, respectively.RESULTS: Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects(P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B(P 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation(P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification(r = 0.53; P 0.01) or MELD score(r = 0.45; P 0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin(r= 0.39; P 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin(r =-0.41; P 0.01) or prothrombin time(r =-0.44;P 0.01). Moreover, insulin resistance was observed in82.5% of the cirrhotic patients. In this group of patients,betatrophin levels were significantly higher than those in the group of patients without IR(P 0.05).CONCLUSION: Plasma betatrophin is increased in patients with cirrhosis. This increase is related to the severity of cirrhosis, as well as with the emergence of insulin resistance.     

Outcomes of liver transplantation for end-stage biliary disease: A comparative study with end-stage liver disease

AIM: To evaluate the outcomes of patients with endstage biliary disease(ESBD) who underwent liver transplantation, to define the concept of ESBD, the criteria for patient selection and the optimal operation for decision-making.METHODS: Between June 2002 and June 2014, 43 patients with ESBD from two Chinese organ transplantation centres were evaluated for liver transplantation. The causes of liver disease were primary biliary cirrhosis(n = 8), cholelithiasis(n = 8), congenital biliary atresia(n = 2), graft-related cholangiopathy(n = 18), Caroli's disease(n = 2), iatrogenic bile duct injury(n = 2), primary sclerosing cholangitis(n = 1), intrahepatic bile duct paucity(n = 1) and Alagille's syndrome(n = 1). The patients with ESBD were compared with an end-stage liver disease(ESLD) case control group during the same period, and the potential prognostic values of multiple demographic and clinical variables were assessed. The examined variables included recipient age, sex, pre-transplant clinical status, pre-transplant laboratory values, operation condition and postoperative complications, as well as patient and allograft survival rates. Survival analysis was performed using Kaplan-Meier curves, and the rates were compared using log-rank tests. All variables identified by univariate analysis with P values 0.100 were subjected to multivariate analysis. A Cox proportional hazard regression model was used to determine the effect of the study variables on outcomes in the study group.RESULTS: Patients in the ESBD group had lower model for end-stage liver disease(MELD)/paediatric end-stage liver disease(PELD) scores and a higher frequency of previous abdominal surgery compared to patients in the ESLD group(19.2 ± 6.6 vs 22.0 ± 6.5, P = 0.023 and 1.8 ± 1.3 vs 0.1 ± 0.2, P = 0.000). Moreover, theoperation time and the time spent in intensive care were significantly higher in the ESBD group than in the ESLD group(527.4 ± 98.8 vs 443.0 ± 101.0, P = 0.000, and 12.74 ± 6.6 vs 10.0 ± 7.5, P = 0.000). The patient survival rate in the ESBD group was not significantly different from that of the ESBD group at 1, 3 and 5 years(ESBD: 90.7%, 88.4%, 79.4% vs ESLD: 84.9%, 80.92%, 79.0%, χ2 = 0.194, P = 0.660). The graftsurvival rates were also similar between the two groups at 1, 3 and 5 years(ESBD: 90.7%, 85.2%, 72.7% vs ESLD: 84.9%, 81.0%, 77.5%, χ2 = 0.003, P = 0.958). Univariate analysis identified MELD/PELD score(HR = 1.213, 95%CI: 1.081-1.362, P = 0.001) and bleeding volume(HR = 0.103, 95%CI: 0.020-0.538, P = 0.007) as significant factors affecting the outcomes of patients in the ESBD group. However, multivariate analysis revealed that MELD/PELD score(HR = 1.132, 95%CI: 1.005-1.275, P = 0.041) was the only negative factor that was associated with short survival time.CONCLUSION: MELD/PELD criteria do not adequately measure the clinical characteristics and staging of ESBD. The allocation system based on MELD/PELD criteria should be re-evaluated for patients with ESBD.     

Model for end stage of liver disease (MELD) is better than the Child-Pugh score for predicting in-hospital mortality related to esophageal variceal bleeding

Aim: The Child Pugh and MELD are good methods for predicting mortality in patients with chronic liver disease. We investigated their performance as risk factors for failure to control bleeding, in-hospital overall mortality and death related to esophageal variceal bleeding episodes. Methods: From a previous collected database, 212 cirrhotic patients with variceal bleeding admitted to our hospital were studied. The predictive capability of Child Pugh and MELD scores were compared using c statistics. Results: The Child-Pugh and MELD scores showed marginal capability for predicting failure to control bleeding (the area under receiver operating characteristics curve (AUROC) values were < 0.70 for both). The AUROC values for predicting inhospital overall mortality of Child-Pugh and MELD score were similar: 0.809 (CI 95%, 0.710 - 0.907) and 0.88 (CI 95% 0.77-0.99,) respectively. There was no significant difference between them (p > 0.05). The AU-ROC value of MELD for predicting mortality related to variceal bleeding was higher than the Child-Pugh score: 0.905 (CI 95% 0.801-1.00) vs 0.794 (CI 95% 0.676 - 0.913) respectively (p < 0.05). Conclusions: MELD and Child-Pugh were not efficacious scores for predicting failure to control bleeding. The Child-Pugh and MELD scores had similar capability for predicting in-hospital overall mortality. Nevertheless, MELD was significantly better than Child-Pugh score for predicting in-hospital mortality related to variceal bleeding.     

Adipokines levels are associated with the severity of liver disease in patients with alcoholic cirrhosis

AIM:To investigate the adipokine levels of leptin,adiponectin,resistin,visfatin,retinol-binding protein 4(RBP4),apelin in alcoholic liver cirrhosis(ALC).METHODS:Forty non-diabetic ALC patients[median age:59 years,males:35(87.5%),Child-Pugh(CP)score:median 7(5-12),CP A/B/C:18/10/12,Model for End-stage Liver Disease(MELD):median 10(6-25),follow-up:median 32.5 mo(10-43)]were prospectively included.The serum adipokine levels were estimated in duplicate by ELISA.Somatometric characteristics were assessed with tetrapolar bioelectrical impedance analysis.Pearson’s rank correlation coefficient was used to assess possible associations with adipokine levels.Univariate and multivariate Cox regression analysis was used to determine independent predictors for overallsurvival.RESULTS:Body mass index:median 25.9(range:20.1-39.3),fat:23.4%(7.6-42.1),fat mass:17.8(5.49-45.4),free fat mass:56.1(39.6-74.4),total body water(TBW):40.6(29.8-58.8).Leptin and visfatin levels were positively associated with fat mass(P0.001/P=0.027,respectively)and RBP4 with TBW(P=0.025).Median adiponectin levels were significantly higher in CPC compared to CPA(CPA:7.99±14.07,CPB:7.66±3.48,CPC:25.73±26.8,P=0.04),whereas median RBP4 and apelin levels decreased across the spectrum of disease severity(P=0.006/P=0.034,respectively).Following adjustment for fat mass,visfatin and adiponectin levels were significantly increased from CPA to CPC(both P0.001),whereas an inverse correlation was observed for both RBP4 and apelin(both P0.001).In the multivariate Cox regression analysis,only MELD had an independent association with overall survival(HR=1.53,95%CI:1.05-2.32;P=0.029).CONCLUSION:Adipokines are associated with deteriorating liver function in a complex manner in patients with alcoholic liver cirrhosis.     

Predictors of Minimal Hepatic Encephalopathy in Patients with Cirrhosis

Background/Aim:

Minimal hepatic encephalopathy (MHE) impairs patient’s daily functioning of life. Predictors of MHE in cirrhotic patients have not been evaluated.

Patients and Methods:

A total of 200 cirrhotic patients (Child A, 74 [37%]; Child B, 72 [36%]; Child C, 54 [27%]) were evaluated by psychometry, P300 auditory event-related potential (P300ERP) and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry (>2 S.D.) and P300ERP (>2.5 S.D.). Univariate and multivariate logistic regression analyses were performed to determine the predictors of MHE.

Results:

Eighty-two (41%) patients were diagnosed to have MHE – 26/74 (35%) in Child A, 26/72 (36%) in Child B and 30/54 (56%) in Child C. Ninety-seven (48.5%) patients had abnormal psychometric tests, and 96 (48%) had prolonged P300ERP (>358 ms). Sixteen (16.5%) patients with abnormal psychometry had P300ERP < 358 ms, and 15 (14.5%) patients with normal psychometry results had P300ERP > 358 ms. One hundred and three patients had CFF value < 39 Hz with specificity of 86.6% and sensitivity of 72.9% for MHE. Model for end-stage liver disease (MELD) (17.9 ± 5.7 vs. 13.4 ± 4.2, P = 0.005), Child-Turcotte-Pugh (CTP) score (8.4 ± 2.5 vs. 7.7 ± 2.2, P = 0.02), ammonia (104.8 ± 37.9 vs. 72.5 ± 45.2 µmol/L, P = 0.001) and CFF (37.0 ± 2.8 vs. 41.0 ± 3.4 Hz, P = 0.001) were significantly higher in MHE as compared to non-MHE patients. Ninety-one (45.5%) patients had MELD > 15.5, 115 (57.5%) had CTP score > 7.5, while 93 (46.5%) had venous ammonia > 84.5 µmol/L. On univariate analysis, MELD (8.52 [95% CI, 4.46-16.26; P = 0.001]), CFF (17.34 [95% CI, 8.16-36.85; P = 0.001]) and venous ammonia (7.80 [95% CI, 4.11-14.81; P = 0.003]) were associated with MHE; while CTP score (1.51 [95% CI, 0.85-2.69; P = 0.30]) was not significant. On multivariate analysis, MELD, CFF and venous ammonia were predictive of MHE.

Conclusion:

Prevalence of MHE in this study was 41%; and MELD > 15.5, CFF < 39 Hz and venous ammonia > 84.5 µmol/L were predictive of MHE.     

Polysomnographic sleep aspects in liver cirrhosis: A case control study

AIM: To study sleep aspects and parameters in cirrhotic patients and assess the role of liver dysfunction severity in polysomnographic results. METHODS: This was a case-control study. Patients with a diagnosis of liver cirrhosis were consecutively enrolled in the study. Clinical examinations and laboratory liver tests were performed in all patients, and disease severity was assessed using the Child-Pugh score. The control group consisted of ageand gender-matched healthy volunteers. All individuals answered a questionnaire about habits, behaviors, and complaints related to sleep and were submitted to polysomnography. Sleep parameters were compared between the two groups, and separate analyses were performed among classesof Child-Pugh classification in the cirrhotic group. RESULTS: Forty-two cirrhotic patients and forty-two controls were enrolled. Compared to the control group, the cirrhotic group exhibited lower sleep efficiency (mean ± SD: 73.89% ± 14.99% vs 84.43% ± 8.55%, P < 0.01), increased latency (151.27 ± 93.24 min vs 90.62 ± 54.74 min, P < 0.01) and a lower percentage of rapid eye movement (REM) sleep (14.04% ± 5.64% vs 20.71% ± 6.77%, P < 0.05) as well as a higher frequency of periodic limb movements (10.56 ± 2.85/h vs 2.79 ± 0.61/h, P < 0.01). The comparison of sleep parameters among Child A, B and C cirrhotic patients revealed a significant reduction of REM sleep stage occurrence in individuals with severe liver disease (Child C patients) compared to Child A/B patients (polysomnography percentage of REM sleep stage of patients Child A: 16.1% ± 1.2%; Child B: 14.9% ± 1.2%; Child C: 8.6% ± 1.6%, P < 0.05). CONCLUSION: Cirrhosis was associated with shorter sleep time, reduced sleep efficiency, increased sleep latency, increased REM latency and reduced REM sleep. Additionally, disease severity influences sleep parameters.     

Role of cystatin C and renal resistive index in assessment of renal function in patients with liver cirrhosis

AIM:To evaluate the clinical significance of cystatin C and renal resistive index for the determination of renal function in patients with liver cirrhosis.METHODS:We conducted a study of 63 patients with liver cirrhosis.A control group comprised of 30 age and gender-matched healthy persons.Serum cystatin C was determined in all study subjects and renal Doppler ultrasonography was made.Estimated glomerular filtration rate from serum creatinine(GFRCr)and cystatin C(GFRCys)was calculated.RESULTS:We confirmed significant differences in val-ues of cystatin C between patients with different stages of liver cirrhosis according to Child-Pugh(P=0.01),and a significant correlation with model of end stage liver disease(MELD)score(rs=0.527,P<0.001).More patients with decreased glomerular filtration rate were identified based on GFRCys than on GFRCr(P<0.001).Significantly higher renal resistive index was noted in Child-Pugh C than in A(P<0.001)and B stage(P=0.001).Also,a significant correlation between renal resistive index and MELD score was observed(rs=0.607,P<0.001).Renal resistive index correlated significantly with cystatin C(rs=0.283,P=0.028)and showed a negative correlation with GFRCys(rs=-0.31,P=0.016).CONCLUSION:Cystatin C may be a more reliable marker for assessment of liver insufficiency.Additionally,cystatin C and renal resistive index represent sensitive indicators of renal dysfunction in patients with liver cirrhosis.     

Prealbumin is predictive for postoperative liver insufficiency in patients undergoing liver resection

AIM: To investigate the risk factors for postoperative liver insufficiency in patients with Child-Pugh class A liver function undergoing liver resection.METHODS: A total of 427 consecutive patients undergoing partial hepatectomy from October 2007 to April 2011 at a single center (Department of Hepatic SurgeryI, Eastern Hepatobiliary Surgery Hospital, Shanghai, China) were included in the study. All the patients had preoperative liver function of Child-Pugh class A and were diagnosed as having primary liver cancer by postoperative histopathology. Surgery was performed by the same team and hepatic resection was carried out by a clamp crushing method. A clamp/unclamp time of 15 min/5 min was adopted for hepatic inflow occlusion. Patients’ records of demographic variables, intraoperative parameters, pathological findings and laboratory test results were reviewed. Postoperative liver insufficiency and failure were defined as prolonged hyperbilirubinemia unrelated to biliary obstruction or leak, clinically apparent ascites, prolonged coagulopathy requiring frozen fresh plasma, and/or hepatic encephalopathy. The incidence of postoperative liver insufficiency or liver failure was observed and the attributing risk factors were analyzed. A multivariate analysis was conducted to determine the independent predictive factors.RESULTS: Among the 427 patients, there were 362 males and 65 females, with a mean age of 51.1 ± 10.4 years. Most patients (86.4%) had a background of viral hepatitis and 234 (54.8%) patients had liver cirrhosis. Indications for partial hepatectomy included hepatocellular carcinoma (391 patients), intrahepatic cholangiocarcinoma (31 patients) and a combination of both (5 patients). Hepatic resections of ≤ 3 and ≥ 4 liver segments were performed in 358 (83.8%) and 69 (16.2%) patients, respectively. Seventeen (4.0%) patients developed liver insufficiency after hepatectomy, of whom 10 patients manifested as prolonged hyperbilirubinemia unrelated to biliary obstruction or leak, 6 patients had clinically apparent ascites and prolonged coagulopathy, 1 patient had hepatic encephalopathy and died on day 21 after surgery. On univariate analysis, age ≥ 60 years and prealbumin < 170 mg/dL were found to be significantly correlated with postoperative liver insufficiency (P = 0.045 and P = 0.009, respectively). There was no statistical difference in postoperative liver insufficiency between patients with or without hepatitis, liver cirrhosis and esophagogastric varices. Intraoperative parameters (type of resection, inflow blood occlusion time, blood loss and blood transfusion) and laboratory test results were not associated with postoperative liver insufficiency either. Age ≥ 60 years and prealbumin < 170 mg/dL were selected on multivariate analysis, and only prealbumin < 170 mg/dL remained predictive (hazard ratio, 3.192; 95%CI: 1.185-8.601, P = 0.022).CONCLUSION: Prealbumin serum level is a predictive factor for postoperative liver insufficiency in patients with liver function of Child-Pugh class A undergoing hepatectomy. Since prealbumin is a good marker of nutritional status, the improved nutritional status may decrease the incidence of liver insufficiency.     

Nutritional care in hospitalized patients with chronic liver disease

AIM: To evaluate the practice of nutritional assessment and management of hospitalised patients with cirrhosis and the impact of malnutrition on their clinical outcome.METHODS: This was a retrospective cohort study on patients with liver cirrhosis consecutively admitted to the Department of Gastroenterology and Hepatology at the Royal Adelaide Hospital over 24 mo. Details were gathered related to the patients’ demographics, disease severity, nutritional status and assessment, biochemistry and clinical outcomes. Nutritional status was assessed by a dietician and determined by subjective global assessment. Estimated energy and protein requirements were calculated by Simple Ratio Method. Intake was estimated from dietary history and/or food charts, and represented as a percentage of estimated daily requirements. Median duration of follow up was 14.9 (0-41.4) mo.RESULTS: Of the 231 cirrhotic patients (167 male, age: 56.3 ± 0.9 years, 9% Child-Pugh A, 42% Child-Pugh B and 49% Child-Pugh C), 131 (57%) had formal nutritional assessment during their admission and 74 (56%) were judged to have malnutrition. In-hospital caloric (15.6 ± 1.2 kcal/kg vs 23.7 ± 2.3 kcal/kg, P = 0.0003) and protein intake (0.65 ± 0.06 g/kg vs 1.01 ± 0.07 g/kg, P = 0.0003) was significantly reduced in patients with malnutrition. Of the malnourished cohort, 12 (16%) received enteral nutrition during hospitalisation and only 6 (8%) received ongoing dietetic review and assessment following discharge from hospital. The overall mortality was 51%, and was higher in patients with malnutrition compared to those without (HR = 5.29, 95%CI: 2.31-12.1; P < 0.001).CONCLUSION: Malnutrition is common in hospitalised patients with cirrhosis and is associated with higher mortality. Formal nutritional assessment, however, is inadequate. This highlights the need for meticulous nutritional evaluation and management in these patients.     

I_κB kinase-beta inhibitor attenuates hepatic fibrosis in mice

AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice rec...     

乙型肝炎肝硬化患者血清B7-H3和IL-18水平变化及其临床意义探讨

目的 通过检测乙型肝炎肝硬化患者血清B7-H3和白细胞介素-18（IL-18）水平,探讨它们水平变化与疾病进展的相关性。方法 2015年4月~2017年3月纳入113例乙型肝炎肝硬化患者,其中代偿期肝硬化患者33例,失代偿期肝硬化患者80例,和健康志愿者20名。采用ELISA法检测血清B7-H3和IL-18水平,采用直线相关分析肝硬化患者血清B7-H3与IL-18水平间的相关性。结果 80例失代偿期肝硬化患者血清B7-H3水平为（62.29±22.17） ng/ml,显著高于33例代偿期肝硬化患者的（32.27±10.29） ng/ml（P<0.05）或20例健康人的（11.35±4.48） ng/ml（P<0.05）,代偿期肝硬化患者血清B7-H3水平也显著高于健康人（P<0.05）;失代偿期肝硬化患者血清IL-18水平为（585.63±121.28） pg/ml,显著高于代偿期肝硬化患者的（396.29±86.91） pg/ml（P<0.05）或健康人的（155.31±76.93） pg/ml（P<0.05）,代偿期肝硬化患者血清IL-18水平也显著高于健康人（P<0.05）;肝硬化患者血清B7-H3水平与IL-18水平间呈显著正相关（r=0.4111,P<0.01）;26例Child-Pugh C级患者血清B7-H3水平为（76.53±22.76） ng/ml,显著高于33例Child-Pugh A级患者的（23.27±9.84） ng/ml或54例Child-Pugh B级患者的（52.21±13.94） ng/ml（P<0.05）,Child-Pugh C患者IL-18水平为（594.13±112.21） pg/ml,显著高于Child-Pugh B级患者的（408.06±92.41） pg/ml或Child-Pugh A级患者的（243.82±57.03） pg/ml（P<0.05）,Child-Pugh B级患者血清IL-18水平也显著高于Child-Pugh A级（P<0.05）。结论 乙型肝炎肝硬化患者血清B7-H3和IL-18水平升高,两者呈正相关,提示B7-H3可能是乙型肝炎肝硬化患者一个预后不良因子,通过与IL-18的协同作用,引起体内免疫功能紊乱,加重了肝细胞损伤,从而促进了疾病的发生和发展。     

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.     

Model for end-stage liver disease-based allocation system for liver transplantation in Argentina: does it work outside the United States?

Background

In July 2005, Argentina was the first country after the United States to adopt the MELD system. The purpose of the present study was to analyse the impact of this new system on the adult liver waiting list (WL).

Methods

Between 2005 and 2009, 1773 adult patients were listed for liver transplantation: 150 emergencies and 1623 electives. Elective patients were categorized using the MELD system. A prospective database was used to analyse mortality and probability to be transplanted (PTBT) on the WL.

Results

The waiting time increased inversely with the MELD score and PTBT positively correlated with MELD score. With scores ≥ 18 the PTBT remained over 50%. However, the largest MELD subgroup with <10 points (n =433) had the lower PTBT (3%). In contrast, patients with T₂ hepatocellular carcinoma benefited excessively with the highest PTBT (84.2%) and the lowest mortality rate (5.4%). The WL mortality increased after MELD adoption (10% vs. 14.8% vs. P < 0.01). Patients with <10 MELD points had >fourfold probability of dying on the WL than PTBT (14.3% vs. 3%; P < 0.0001).

Conclusions

After MELD implementation, WL mortality increased and most patients who died had a low MELD score. A comprehensive revision of the MELD system must be performed to include cultural and socio-economical variables that could affect each country individually.     

Inhibition of sphingosine kinase 1 ameliorates acute liver failure by reducing high-mobility group box 1 cytoplasmic translocation in liver cells

AIM: To determine the therapeutic potential of sphingosine kinase 1(Sphk1) inhibition and its underlying mechanism in a well-characterized mouse model of D-galactosamine(D-Gal N)/lipopolysaccharide(LPS)-induced acute liver failure(ALF).METHODS: Balb/c mice were randomly assigned to different groups,with ALF induced by intraperitoneal injection of D-Ga IN(600 mg/kg) and LPS(10 μg/kg). The Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels at different time points within one week were determined using a multi-parametric analyzer. Serum high-mobility group box 1(HMGB1),tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,IL-6,IL-10,and sphingosine-1-phosphate were detected by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after acute liver injury induction were assessed by hematoxylin and eosin staining. HMGB1 expression in hepatocytes and cytoplasmic translocation were detected by immunohistochemistry. Expression of Sphk1 in liver tissue and peripheral blood mononuclear cells(PBMCs) was analyzed by Western blot.RESULTS: The expression of Sphk1 in liver tissue and PBMCs was upregulated in Gal N/LPS-induced ALF. Upregulated Sphk1 expression in liver tissue was mainly caused by Kupffer cells,the resident macrophages of the liver. The survival rates of mice in the N,Ndimethylsphingosine(DMS,a specific inhibitor of Sph K1) treatment group were significantly higher than that of the control group(P 0.001). DMS treatment significantly decreased the levels of serum ALT and AST at 6,12,and 24 h compared with that of the control group(P 0.01 for all). Serum HMGB1 levels at 6,12,and 24 h,as well as serum TNF-α,IL-6,and IL-1β levels at 12 h,were significantly lower in the DMS treatment group than in the control group(P 0.01 for all). Furthermore,hepatic inflammation,necrosis,and HMGB1 cytoplasm translocation in liver cells were significantly decreased in the DMS treatment group compared to the control group(43.72% ± 5.51% vs 3.57% ± 0.83%,χ2 = 12.81,P 0.01).CONCLUSION: Inhibition of Sph K1 ameliorates ALF by reducing HMGB1 cytoplasmic translocation in liver cells,and so might be a potential therapeutic strategy for this disease.     

Effect of non-alcoholic beer,diet and exercise on endothelial function,nutrition and quality of life in patients with cirrhosis

BACKGROUNDThe implementation of nutritional strategies targeting several variables at once could benefit patients with cirrhosis. Non-alcoholic beer has different compounds that exert antioxidant, anti-inflammatory and nutritional properties.AIMTo evaluate the effect of diet + exercise and non-alcoholic beer on nutritional status, endothelial function and quality of life in patients with cirrhosis. METHODSIn this randomized open clinical trial, patients with cirrhosis were randomized into two groups: The intervention (non-alcoholic beer + diet + exercise) and control (water + diet + exercise) group. Treatment consisted of 330 mL non-alcoholic beer/day or the same amount of water, plus an individualized dietary plan and an exercise program with a pedometer-based bracelet to reach at least 5000 steps/d and > 2500 above the baseline during 8 wk. Endothelial function (flow-mediated dilation, plethysmography), biochemical and nutritional variables and quality of life (CLDQ) were evaluated.RESULTSForty-three patients were included in the study, 21 in the control group and 22 in the intervention group. The mean age was 53.5 ± 7.8 years, 60% were women, the median MELD score was 8 (7-10) and most patients were Child-Pugh A (88%). Adherence to the interventions was > 90% in both groups, there were no adverse events and all biochemical parameters remained stable in both groups. Endothelial function improved in both groups. All measured nutritional parameters improved in the intervention group, compared to only 2 in the control group and quality of life improved in both groups; however, more domains improved in the intervention group.CONCLUSIONThe intervention consisting of non-alcoholic beer, diet and exercise seems to be safe and well tolerated in patients with cirrhosis, and shows improvement in nutritional status, endothelial function, and quality of life. These results need to be further confirmed.     

Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma

AIM: To examine the significance of branched-chain amino acid (BCAA) treatment before transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).METHODS: This study included 99 patients who underwent TACE therapy for HCC at our hospital and were followed up without treatment for at least 6 mo between January 2004 and January 2010. They were divided into 2 groups: those receiving BCAA granules (n = 40) or regular diet (n = 59, control). Data obtained were retrospectively analyzed (prior to TACE, and 1 wk, 1, 3, and 6 mo after TACE) in terms of nutritional condition and clinical laboratory parameters (serum albumin level and Child-Pugh score), both of which are determinants of hepatic functional reserve.RESULTS: The BCAA group comprised 27 males and 13 females with a mean age of 69.9 ± 8.8 years. The patients of the BCAA group were classified as follows: Child-Pugh A/B/C in 22/15/3 patients, and Stage II/III/IVA HCC in 12/23/5 patients, respectively. The control group comprised 32 males and 27 females with a mean age of 73.2 ± 10.1 years. In the control group, 9 patients had chronic hepatitis, Child-Pugh A/B/C in 39/10/1 patients, and StageI/II/III/IVA HCC in 1/11/35/12 patients, respectively. Overall, both serum albumin level and Child-Pugh score improved significantly in the BCAA group as compared with the control 3 and 6 mo after TACE (P < 0.05). Further analysis was performed by the following categorization: (1) child-Pugh classification; (2) liver cirrhosis subgroup with a serum albumin level > 3.5 g/dL; and (3) epirubicin dose. A similar trend indicating a significant improvement of all variables in the BCAA group was noted (P < 0.05).CONCLUSION: Treatment with BCAA granules in patients who have undergone TACE for HCC is considered useful to maintain their hepatic functional reserve.     

Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4-/- mouse model

AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4~(-/-)(Abcb4~(-/-)) mouse model.METHODS: Female and male Abcb4~(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4~(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4~(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4~(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4~(-/-) mice.     

Vigorous, but differential mononuclear cell response of cirrhotic patients to bacterial ligands

AIM: To study the role of gram-positive and gram-negative bacteria in the pathogenesis of liver injury, specifically the activation of inflammatory mediators. METHODS: Peripheral blood mononuclear cells of 20 out-patients were studied, 10 of them with cirrhosis.Peripheral blood mononuclear cells were isolated and exposed to lipopolysaccharide or lipoteichoic acid. CD14, Toll-like receptor 2 and 4 expression was determined by flow cytometry, and tumor necrosis factor (TNF) α, interleukin (IL)-1β, IL-6, IL-12...