Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

BACKGROUNDThe recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.AIMTo determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients.METHODSA prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.RESULTSOf the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.CONCLUSIONThe prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.     

Tenofovir Alafenamide Fumarate,Tenofovir Disoproxil Fumarate and Entecavir: Which is the Most Effective Drug for Chronic Hepatitis B? A Systematic Review and Meta-analysis

Background and AimsThe therapeutic effect of tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir (ETV) on chronic hepatitis B (CHB) patients remains inconsistent. The aim of this study was to explore the differences in virological responses to TAF, TDF and ETV in patients with CHB.MethodsLiterature searches were conducted of the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials and observational studies published up to July 21, 2020. Statistical comparisons of virological response between TDF, ETV, and TAF were carried out with pooled odds ratio (OR) values.ResultsThe virological response in TDF-treated CHB patients was notably superior to that of the ETV-treated CHB patients after 12-weeks [OR=1.12, 95% confidence interval (CI): 0.89–1.41], 24-weeks (OR=1.33, 95% CI: 1.11–1.61), 48-weeks (OR=1.62, 95% CI: 1.16–2.25), 72-weeks (OR=1.43, 95% CI: 0.78–2.62), and 96-weeks (OR=1.56, 95% CI: 0.87–2.81) treatment. No significant difference was observed for the virological responses in CHB patients after 48-weeks treatment with TAF or TDF. The virological response in TDF+ETV-treated CHB patients was superior to that of TDF-treated CHB patients after 24-weeks, 48-weeks (OR=1.54, 95% CI: 1.17–2.02), 96-weeks, and 144-weeks.ConclusionsThe virological response in TDF-treated CHB patients was superior to that in ETV-treated CHB patients, but there was no significant difference between TAF and TDF. In addition, the therapeutic effect of TDF+ETV was superior to TDF alone.     

Effectiveness of entecavir in preventing hepatocellular carcinoma development is genotype-dependent in hepatitis B virus-associated liver cirrhosis

BACKGROUND The oral nucleos(t)ide analogue,entecavir(ETV) was demonstrated to reduce the rate of hepatocellular carcinoma(HCC) in patients with hepatitis B virus(HBV)-associated liver cirrhosis.However,the reduction of HCC differs in various regions of the world.AIM To investigate the reduction of HCC development due to ETV therapy by metaanalysis.METHODS We surveyed the differences in HCC development following ETV treatment based on published articles using PubMed(2004-2019).RESULTS The regions with the most marked reduction in HCC development due to ETV therapy were Spain(1.0 %/year) and Canada(Southern part,1.3 %/year),and the most ineffective areas were South Korea(3.6 %-3.8 %/year),China(3.3 %/year),Taiwan(2.4 %-3.1 %/year),and Hong Kong(2.8 %/year).Following ETV administration,the incidence of HCC in genotype D regions(1.89 %±0.28 %/year,mean ± SE) was significantly lower than that in genotype C regions(2.91%±0.24%/year,P 0.01).With regard to the initial HBV-DNA level,in genotype C patients(average:5.61 Log_(10)IU/mL) this was almost the same as that in genotype D patients(average:5.46 Log_(10)IU/mL).Moreover,there was no association between the prevalence ratio of HBV and the incidence of HCC on ETV treatment.CONCLUSION The effectiveness of ETV in preventing HCC development in HBV-associated liver cirrhosis is genotype-dependent.     

Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures

AIM: To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients after multiple failures.METHODS: A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue (NA) treatments were included. Study subjects were treated with TDF alone (n = 13) or in combination with lamivudine (LAM, n = 12) or entecavir (ETV, n = 4) for ≥ 6 mo. Complete virologic response (CVR) was defined as an achievement of serum hepatitis B virus (HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment. Safety assessment was based on serum creatinine and phosphorus level. Eleven patients had histories of LAM and adefovir dipivoxil (ADV) treatment and 18 patients were exposed to LAM, ADV, and ETV. Twenty-seven patients (93.1%) were hepatitis B e antigen (HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL. The median treatment duration was 16 mo (range 7 to 29 mo).RESULTS: All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it. Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV. One patient had a resistance to both ADV and ETV. The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%, respectively. Although one patient failed to achieve CVR, serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL, achieving near CVR. No patients in this study showed viral breakthrough or primary non-response during the follow-up period. The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%, 12%, and 27% at 6, 12, and 18 mo of treatment, respectively. Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations. History of prior exposure to specific antiviral agents did not make a difference to treatment outcome. Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV. No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed. There were no other adverse events related to TDF therapy observed in the study subjects.CONCLUSION: TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.     

替诺福韦酯治疗多重耐药的乙型肝炎肝硬化患者疗效初步研究*

目的 探讨替诺福韦酯（TDF）治疗多重耐药的乙型肝炎肝硬化（LC）患者的治疗效果。方法 2014年10月~2016年6月我院诊治的乙型肝炎肝硬化患者80例,纳入患者在核苷（酸）类似物（NAs）治疗过程中出现多重耐药。采用随机数字表法将患者分为TDF治疗组40例和恩替卡韦（ETV）治疗组40例,均在接受TDF替换治疗12 w后,分别改为TDF或ETV继续治疗,观察48 w。结果 在治疗24 w, TDF治疗组血清ALT复常率和HBV DNA阴转率分别为70.0%和82.5%,显著高于ETV治疗组的50.0%和65.0%（P<0.05）;在48 w时,则分别为92.5%和95.0%,显著高于ETV组的70.0%和75.0% （P<0.05）;在48 w时,TDF组血清ALT、ALB、Child-Pugh评分和肝硬度值分别为（45.6±10.4） IU/L、（35.2±1.9） g/L、（6.3±1.1）和（14.5±2.5） kPa,显著优于ETV组【分别为（58.7±11.4） IU/L、（33.5±2.0） g/L、（7.9±1.2）和（17.5±2.8） kPa,P<0.05】;两组肾功能和血磷水平无显著变化,病毒学突破率分别为2.5%和5.0%（P>0.05）。结论 TDF可有效抑制HBV DNA复制,持续改善患者肝功能,病毒学突破率低,对肾功能无明显影响,安全可靠,可作为多重耐药的乙型肝炎肝硬化患者有效的挽救治疗药物。     

Serum zonulin levels in patients with liver cirrhosis: Prognostic implications

BACKGROUND Increased gut permeability and bacterial translocation play an important role in liver cirrhosis. Zonulin is a recently recognized protein involved in the disintegration of the intestinal barrier.AIM To investigate possible differences in serum zonulin levels among patients with different cirrhosis stages and their potential prognostic implications.METHODS Consecutive cirrhotic patients who attended our liver clinic were included in the study. Serum zonulin levels, clinical, radiological and biochemical data were collected at baseline. Patients who accepted participation in a regular surveillance program were followed-up for at least 12 mo.RESULTS We enrolled 116 cirrhotics [mean Child-Turcotte-Pugh(CTP) score: 6.2 ± 1.6;model for end-stage liver disease score: 11 ± 3.9]. The causes of cirrhosis were viral hepatitis(39%), alcohol(30%), non-alcoholic fatty liver disease(17%), and other(14%). At baseline, 53% had decompensated cirrhosis, 48% had ascites, and 32% had history of hepatic encephalopathy. Mean zonulin levels were significantly higher in patients with CTP-B class than CTP-A class(4.2 ± 2.4 ng/dL vs 3.5 ± 0.9 ng/dL, P = 0.038), with than without ascites(P = 0.006), and with than without history of encephalopathy(P = 0.011). Baseline serum zonulin levels were independently associated with the probability of decompensation at 1 year(P = 0.039), with an area under the receiving operating characteristic of 0.723 for predicting hepatic decompensation. Higher CTP score(P = 0.021) and portal vein diameter(P = 0.022) were independent predictors of mortality.CONCLUSION Serum zonulin levels are higher in patients with more advanced chronic liver disease and have significant prognostic value in identifying patients who will develop decompensation.     

Clinical outcome and predictors of survival after TIPS insertion in patients with liver cirrhosis

AIM:To determine the clinical outcome and predictors of survival after transjugular intrahepatic portosystemic stent shunt (TIPS) implantation in cirrhotic patients. METHODS:Eighty-one patients with liver cirrhosis and consequential portal hypertension had TIPS implantation (bare metal) for either refractory ascites (RA) (n= 27) or variceal bleeding (VB) (n = 54). Endpoints for the study were:technical success, stent occlusion and stent stenosis, rebleeding, RA and mortality. Clinical records of patients were collected and analysed. Baseline characteristics [e.g., age, sex, CHILD score and the model for end-stage liver disease score (MELD score), underlying disease] were retrieved. The Kaplan-Meier method was employed to calculate survival from the time of TIPS implantation and comparisons were made by log rank test. A multivariate analysis of factors influencing survival was carried out using the Cox proportional hazards regression model. Results were expressed as medians and ranges. Comparisons between groups were performed by using the Mann-Whitney Utest and the χ 2 test as appropriate. RESULTS:No difference could be seen in terms of age, sex, underlying disease or degree of portal pressure gradient (PPG) reduction between the ascites and the bleeding group. The PPG significantly decreased from 23.4 ± 5.3 mmHg (VB) vs 22.1 ± 5.5 mmHg (RA) before TIPS to 11.8 ± 4.0 vs 11.7 ± 4.2 after TIPS implantation (P = 0.001 within each group). There was a tendency towards more patients with stage CHILD A in the bleeding group compared to the ascites group (24 vs 6, P = 0.052). The median survival for the ascites group was 29 mo compared to 60 mo for the bleeding group (P = 0.009). The number of radiological controls for stent patency was 6.3 for bleeders and 3.8 for ascites patients (P = 0.029). Kaplan-Meier calculation indicated that stent occlusion at first control (P = 0.027), ascites prior to TIPS implantation (P = 0.009), CHILD stage (P = 0.013), MELD score (P = 0.001) and those patients not having undergone liver transplantation (P = 0.024) were significant predictors of survival. In the Cox regression model, stent occlusion (P = 0.022), RA (P = 0.043), CHILD stage (P = 0.015) and MELD score (P = 0.004) turned out to be independent prognostic factors of survival. The anticoagulation management (P = 0.097), the porto-systemic pressure gradient (P= 0.460) and rebleeding episodes (P = 0.765) had no significant effect on the overall survival. CONCLUSION:RA, stent occlusion, initial CHILD stage and MELD score are independent predictors of survival in patients with TIPS, speaking for a close follow-up in these circumstances.     

Histopathological evaluation of long-term tenofovir disoproxil fumarate treatment in patients with hepatitis be antigen-negative chronic hepatitis B

BACKGROUND Hepatitis B virus is a universal health problem.There are approximately 250 million people living with hepatitis B worldwide,and approximately 600000 of these people die every year due to the virus.AIM To compare the pretreatment and post-treatment histopathological results of patients with hepatitis be antigen(HBeAg)-negative chronic hepatitis B(CHB)who had been receiving tenofovir disoproxil fumarate(TDF)treatment at our clinic for at least 5 years.METHODS Patients with HBeAg-negative CHB who were being treated with TDF(245 mg/d)were included in the study.Liver biopsies of patients before TDF treatment and liver biopsies after 5 years of TDF treatment were retrospectively compared.RESULTS A total of 50 HBeAg-negative CHB patients were included in the study(mean age:47.9±10.4 years,men:27.54%).Histological improvement was observed in 78%(39)of the patients after 5 years of treatment.After the 5 years of treatment,the mean Ishak score of the patients was 1.3±1.3,and the mean histologic activity index score was 4.1±2.8.A 1.53 point reduction in Ishak fibrosis score was detected after long-term TDF treatment.CONCLUSION Liver biopsies after 5 years of TDF treatment revealed a significant histological response and a regression of the necroinflammatory score compared to pretreatment liver biopsies.To better understand the effects of antiviral treatments on the improvement of liver histology,long-term studies involving larger numbers of patients are needed.     

Effect of nucleos(t)ide analogues on blood lipid profiles in patients with chronic hepatitis B: A cross-sectional survey

This study aimed to explore the effects of the 3 nucleos(t)ide analogues (NAs) on lipid levels. We retrospectively included patients treated with NAs at 2 centers and collected their clinical data at their visiting points. Differences in blood lipid levels were analyzed by statistical methods, and factors related to hyperlipidemia were discussed. In these 2 centers, the prevalence rates of hypercholesterolemia were 12/181 (6.6%) for tenofovir alafenamide fumarate (TAF)-, 0/158 (0%) for tenofovir disoproxil fumarate (TDF)-, and 13/182 (7.1%) for entecavir (ETV)-treated individuals (P = .003). The prevalence rates of hypertriglyceridemia were 30/181 (16.6%) for TAF-, 11/158 (7.0%) for TDF-, and 26/182 (14.3%) for ETV-treated individuals (P = .025). In TAF (n = 181, 10 [6, 15] months), TDF (n = 158, 18 [7.5, 45] months), and ETV (n = 182, 24 [10, 60] months) groups, total cholesterol (TC) levels were 4.63 ± 0.91 mmol/L, 3.86 ± 0.61 mmol/L, and 4.53 ± 0.87 mmol/L, respectively; triglyceride (TG) levels were 1.27 ± 0.76 mmol/L, 0.87 ± 0.51 mmol/L, and 1.14 ± 0.67 mmol/L, respectively (P < .001). In multivariate regression analysis, factors associated with hypercholesterolemia were age (adjusted hazard risk [HR] = 1.055 [1.018–1.094]; P = .003) and body mass index (BMI) (adjusted HR = 0.817 [0.669–0.998]; P = .048). Factors associated with hypertriglyceridemia were TAF group (vs. TDF group) (adjusted HR = 0.405 [0.167–0.980]; P = .045), age (adjusted HR = 1.028 [1.002–1.055]; P = .038), and sex (adjusted HR = 0.190 [0.079–0.456]; P < .001). Among the patients treated with TAF (10 [6, 15] months), TDF (18 [7.5, 45] months), and ETV (24 [10, 60] months), the blood lipid levels in the TDF group were lower than those in the TAF group and ETV group, and the occurrence of hyperlipidemia was associated with age, sex, BMI, and different treatment.     

Nutritional status in relation to lifestyle in patients with compensated viral cirrhosis

AIM:To assess the nourishment status and lifestyle of non-hospitalized patients with compensated cirrhosis by using noninvasive methods.METHODS:The subjects for this study consisted of 27 healthy volunteers,59 patients with chronic viral hepatitis,and 74 patients with viral cirrhosis,from urban areas.We assessed the biochemical blood tests,anthropometric parameters,diet,lifestyle and physical activity of the patients.A homeostasis model assessment-insulin resistance(HOMA-IR) value of ≥ 2.5 was considered to indicate insulin resistance.We measured height,weight,waist circumference,arm circumference,triceps skin-fold thickness,and handgrip strength,and calculated body mass index,arm muscle circumference(AMC),and arm muscle area(AMA).We interviewed the subjects about their dietary habits and lifestyle using health assessment computer software.We surveyed daily physical activity using a pedometer.Univariate and multivariate logistic regression modeling were used to identify the relevant factors for insulin resistance.RESULTS:The rate of patients with HOMA-IR ≥ 2.5(which was considered to indicate insulin resistance) was 14(35.9%) in the chronic hepatitis and 17(37.8%) in the cirrhotic patients.AMC(%)(control vs chronic hepatitis,111.9% ± 10.5% vs 104.9% ± 10.7%,P = 0.021;control vs cirrhosis,111.9% ± 10.5% vs 102.7% ± 10.8%,P = 0.001) and AMA(%)(control vs chronic hepatitis,128.2% ± 25.1% vs 112.2% ± 22.9%,P = 0.013;control vs cirrhosis,128.2% ± 25.1% vs 107.5% ± 22.5%,P = 0.001) in patients with chronic hepatitis and liver cirrhosis were significantly lower than in the control subjects.Handgrip strength(%) in the cirrhosis group was significantly lower than in the controls(control vs cirrhosis,92.1% ± 16.2% vs 66.9% ± 17.6%,P 0.001).The results might reflect a decrease in muscle mass.The total nutrition intake and amounts of carbohydrates,protein and fat were not significantly different amongst the groups.Physical activity levels(kcal/d)(control vs cirrhosis,210 ± 113 kcal/d vs 125 ± 74 kcal/d,P = 0.001),number of steps(step/d)(control vs cirrhosis,8070 ±3027 step/d vs 5789 ± 3368 step/d,P = 0.011),and exercise(Ex)(Ex/wk)(control vs cirrhosis,12.4 ± 9.3 Ex/wk vs 7.0 ± 7.7 Ex/wk,P = 0.013) in the cirrhosis group was significantly lower than the control group.The results indicate that the physical activity level of the chronic hepatitis and cirrhosis groups were low.Univariate and multivariate logistic regression modeling suggested that Ex was associated with insulin resistance(odds ratio,6.809;95% CI,1.288-36.001;P = 0.024).The results seem to point towards decreased physical activity being a relevant factor for insulin resistance.CONCLUSION:Non-hospitalized cirrhotic patients may need to maintain an adequate dietary intake and receive lifestyle guidance to increase their physical activity levels.     

Clinical effects and complications of TIPS for portal hypertension due to cirrhosis:A single center

AIM:To determine the clinical effects and complications of transjugular intrahepatic portosystemic shunt(TIPS)for portal hypertension due to cirrhosis.METHODS:Two hundred and eighty patients with portal hypertension due to cirrhosis who underwent TIPS were retrospectively evaluated.Portal trunk pressure was measured before and after surgery.The changes in hemodynamics and the condition of the stent were assessed by ultrasound and the esophageal and fundic veins observed endoscopically.RESULTS:The success rate of TIPS was 99.3%.The portal trunk pressure was 26.8±3.6 cmH2O after surgery and 46.5±3.4 cmH2O before surgery(P<0.01).The velocity of blood flow in the portal vein increased.The internal diameters of the portal and splenic veins were reduced.The short-term hemostasis rate was100%.Esophageal varices disappeared completely in68%of patients and were obviously reduced in 32%.Varices of the stomach fundus disappeared completely in 80%and were obviously reduced in 20%of patients.Ascites disappeared in 62%,were markedly reduced in 24%,but were still apparent in 14%of patients.The total effective rate of ascites reduction was 86%.Hydrothorax completely disappeared in 100%of patients.The incidence of post-operative stent stenosis was 24%at 12 mo and 34%at 24 mo.The incidence of post-operative hepatic encephalopathy was 12%at3 mo,17%at 6 mo and 19%at 12 mo.The incidence of post-operative recurrent hemorrhage was 9%at 12mo,19%at 24 mo and 35%at 36 mo.The cumulative survival rate was 86%at 12 mo,81%at 24 mo,75%at 36 mo,57%at 48 mo and 45%at 60 mo.CONCLUSION:TIPS can effectively lower portal hypertension due to cirrhosis.It is significantly effective for hemorrhage of the digestive tract due to rupture of esophageal and fundic veins and for ascites and hydrothorax caused by portal hypertension.     

De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis

AIM:To compare efficacy of combined lamivudine(LAM)and adefovir dipivoxil(ADV)therapy with that of entecavir(ETV)monotherapy for hepatitis B virus(HBV)-related decompensated liver cirrhosis.METHODS:A total of 120 na ve patients with HBVrelated decompensated cirrhosis participated in this study.Sixty patients were treated with combined LAM and ADV therapy(LAM+ADV group),while the other60 were treated with ETV monotherapy(ETV group)for two years.Tests for liver and kidney function,alpha-fetoprotein,HBV serum markers,HBV DNA load,prothrombin time(PT),and ultrasonography or computed tomography scan of the liver were performed every1 to 3 mo.Repeated measure ANOVA and theχ2test were performed to compare the efficacy,side effects,and the cumulative survival rates at 48 and 96 wk.RESULTS:Forty-five patients in each group were observed for 96 wk.No significant differences in HBV DNA negative rates and alanine aminotransferase(ALT)normalization rates at weeks 48(χ2=2.12 and 2.88)and96(χ2=3.21 and 3.24)between the two groups were observed.Hepatitis B e antigen seroconversion rate in the LAM+ADV group at week 96 was significantly higher in the ETV group(43.5%vs 36.4%,χ2=4.09,P<0.05).Viral breakthrough occurred in 2 cases(4.4%)by week 48 and in 3 cases(6.7%)by week 96 in the LAM+ADV group,and no viral mutation was detected.In the ETV group,viral breakthrough occurred in 1 case(2.2%)at the end of week 96.An increase in albumin(F=18.9 and 17.3),decrease in total bilirubin and in ALT(F=16.5,17.1 and 23.7,24.8),reduced PT(F=22.7 and 24.5),and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores(F=18.5,17.8,and 24.2,23.8)were observed in both groups.The cumulative rates of mortality and liver transplantation were 16.7%(10/60)and 18.3%(11/60)in the LAM+ADV and ETV groups,respectively.CONCLUSION:Both LAM+ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication,improve liver function,and decrease mortality.     

Transjugular intrahepatic portosystemic shunt for severe jaundice in patients with acute Budd-Chiari syndrome

AIM:To evaluate the feasibility of transjugular intrahepatic portosystemic shunt(TIPS)for severe jaundice secondary to acute Budd-Chiari syndrome(BCS).METHODS:From February 2009 to March 2013,37patients with severe jaundice secondary to acute BCS were treated.Sixteen patients without hepatic venule,hepatic veins(HV)obstruction underwent percutaneous angioplasty of the inferior vena cava(IVC)and/or HVs.Twenty-one patients with HV occlusion underwent TIPS.Serum bilirubin,liver function,demographic data and operative data of the two groups of patients were analyzed.RESULTS:Twenty-one patients underwent TIPS and the technical success rate was 100%,with no technical complications.Sixteen patients underwent recanalization of the IVC and/or HVs and the technical success rate was 100%.The mean procedure time for TIPS was 84.0±12.11 min and angioplasty was44.11±5.12 min(P0.01).The mean portosystemic pressure in the TIPS group decreased significantly from 40.50±4.32 to 16.05±3.50 mm Hg(P0.01).The mean portosystemic pressure gradient decreased significantly from 33.60±2.62 to 7.30±2.21 mm Hg(P0.01).At 8 wk after the procedures,in the TIPS group,total bilirubin(TBIL)decreased significantly from 266.24±122.03 before surgery to 40.11±3.52μmol/L(P0.01)and direct bilirubin(DBIL)decreased significantly from 194.22±69.82μmol/L to 29.82±3.10μmol/L(P0.01).In the angioplasty group,bilirubin returned to the normal range,with TBIL decreased significantly from 258.22±72.71μmol/L to 13.33±3.54μmol/L(P0.01)and DBIL from175.08±39.27 to 4.03±1.74μmol/L(P0.01).Liver function improved faster than TBIL.After 2 wk,in the TIPS group,alanine aminotransferase(ALT)decreased significantly from 50.33±40.61 U/L to 28.67±7.02U/L(P0.01)and aspartate aminotransferase(AST)from 49.46±34.33 U/L to 26.89±8.68 U/L(P0.01).In the angioplasty group,ALT decreased significantly from 51.56±27.90 to 14.22±2.59μmol/L(P0.01)and AST from 60.66±39.89μmol/L to 8.18±1.89μmol/L(P0.01).After mean follow-up of 12.6 mo,there was no recurrence of jaundice in either group.CONCLUSION:Severe jaundice is not a contraindication for TIPS in patients with acute BCS and TIPS is appropriate for severe jaundice due to BCS.     

Ursodeoxycholic acid as a means of preventing atherosclerosis,steatosis and liver fibrosis in patients with nonalcoholic fatty liver disease

BACKGROUNDAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Weight loss is a key factor for successful NAFLD and CVD therapy. Ursodeoxycholic acid (UDCA), which is one of the first-line therapeutic agents for treatment of NAFLD, is reported to have a beneficial effect on dyslipidemia and ASCVD risk because of antioxidant properties.AIMTo evaluate the effects of 6 mo of UDCA treatment on hepatic function tests, lipid profile, hepatic steatosis and fibrosis, atherogenesis, and ASCVD risk in men and women with NAFLD, as well as to assess the impact of > 5% weight reduction on these parameters.METHODSAn open-label, multicenter, international noncomparative trial was carried out at primary health care settings and included 174 patients with ultrasound-diagnosed NAFLD who received 15 mg/kg/d UDCA for 6 mo and were prescribed lifestyle modification with diet and exercise. The efficacy criteria were liver enzymes, lipid profile, fatty liver index (FLI), noninvasive liver fibrosis tests (nonalcoholic fatty liver disease fibrosis score and liver fibrosis index), carotid intima-media thickness (CIMT), and ASCVD risk score. To test statistical hypotheses, the Wilcoxon test, paired t-test, Fisher’s exact test, and Pearson''s chi-squared test were used. RESULTSThe alanine aminotransferase (ALT) level changed by -14.1 U/L (-31.0; -5.3) from baseline to 3 mo and by -6.5 U/L (-14.0; 0.1) from 3 to 6 mo. The magnitude of ALT, aspartate transaminase, and glutamyltransferase decrease was greater during the first 3 mo of treatment compared to the subsequent 3 mo (P < 0.001, P < 0.01, P < 0.001, respectively). At 6 mo, in the total sample, we observed a statistically significant decrease in body weight and levels of FLI: 84.9 ± 10.4 vs 72.3 ± 17.6, P < 0.001, total cholesterol: 6.03 ± 1.36 vs 5.76 ± 1.21, Р < 0.001, low-density lipoprotein: 3.86 ± 1.01 vs 3.66 ± 0.91, Р < 0.001, and triglyceride: 3.18 (2.00; 4.29) vs 2.04 (1.40; 3.16), Р < 0.001. No effect on nonalcoholic fatty liver disease fibrosis score or liver fibrosis index was found. The CIMT decreased significantly in the total sample (0.985 ± 0.243 vs 0.968 ± 0.237, P = 0.013), whereas the high-density lipoprotein (Р = 0.036) and 10-year ASCVD risk (Р = 0.003) improved significantly only in women. Fifty-four patients (31%) achieved > 5% weight loss. At the end of the study, the FLI decreased significantly in patients with (88.3 ± 10.2 vs 71.4 ± 19.6, P < 0.001) and without > 5% weight loss (83.5 ± 10.3 vs 72.8 ± 16.7, P < 0.001). The changes in ALT, aspartate transaminase, glutamyltransferase, total cholesterol, and low-density lipoprotein levels were similar between the subgroups.CONCLUSIONUDCA normalizes liver enzymes greatly within the first 3 mo of treatment, improves lipid profile and hepatic steatosis independent of weight loss, and has a positive effect on CIMT in the total sample and 10-year ASCVD risk in women after 6 mo of treatment.     

Antiviral drug resistance increases hepatocellular carcinoma: A prospective decompensated cirrhosis cohort study

AIM:To study the clinical outcome of antiviral therapy in hepatitis B-related decompensated cirrhotic patients.METHODS:Three hundred and twelve patients with decompensated hepatitis B cirrhosis were evaluated in a prospective cohort.With two years of follow-up,198patients in the group receiving antiviral therapy with nucleos(t)ide analogues and 39 patients in the control group without antiviral treatment were analysed.RESULTS:Among the antiviral treatment patients,162had a complete virological response(CVR),and 36 were drug-resistant(DR).The two-year cumulative incidence of hepatocellular carcinoma(HCC)in the DR patients(30.6%)was significantly higher than that in both the CVR patients(4.3%)and the control group(10.3%)(P<0.001).Among the DR patients in particular,the incidence of HCC was 55.6%(5/9)in those who failed rescue therapy,which was extremely high.The rtA181T mutation was closely associated with rescue therapy failure(P=0.006).The Child-Pugh scores of the CVR group were significantly decreased compared with the baseline(8.9±2.3 vs 6.0±1.3,P=0.043).CONCLUSION:This study showed that antiviral drug resistance increased the risk of HCC in decompensated hepatitis B-related cirrhotic patients,especially in those who failed rescue therapy.     

恩替卡韦联合复方鳖甲软肝片治疗乙型肝炎肝硬化患者疗效及转归研究*

目的 研究应用恩替卡韦（ETV）联合复方鳖甲软肝片治疗乙型肝炎肝硬化患者的疗效及其对疾病转归的影响。方法 2014年1月~2016年12月我院收治的乙型肝炎肝硬化患者76例,采用随机数字表法将患者分为对照组36例和观察组40例,分别给予ETV或ETV联合复方鳖甲软肝片治疗,观察12 m月。采用 PCR法定量检测血清HBV DNA载量,采用放射免疫法检测血清透明质酸（HA）、Ⅲ型前胶原（PⅢP）、层粘连蛋白（LN）和Ⅳ型胶原（CⅣ）,常规行血生化和Fibroscan检查。结果 在治疗12 m末,观察组血清TBIL为（19.7±13.4） μmol/L,ALT水平为（28.3±9.4） U/L,均显著低于对照组的[（23.2±13.8） μmol/L和（53.6±10.2） U/L,P<0.05],观察组血清ALB水平为（37.2±5.6） g/L,PTA为（91.1±11.2） %,显著高于对照组[（34.7±6.1） g/L和（81.4±10.5） %,P<0.05];观察组CTP评分为（6.3±1.2）,显著低于对照组的[（8.1±1.4）,P<0.05],肝脏硬度检测（LSM）为（16.5±12.2） kPa,也显著低于对照组的[（22.7±14.4） kPa,P<0.05];观察组血清HA水平为（89.2±43.1） μg/L,PⅢP为（119.7±60.8） μg/L,LN为（98.7±30.2） μg/L,CⅣ为（102.6±29.7） μg/L,均低于对照组[分别为（184.3±58.2） μg/L、（254.5±74.7） μg/L、（140.8±39.7） μg/L、（165.7±41.2） μg/L,P<0.05];观察组血清HBV DNA阴转率为97.5%（39/40）,与对照组的94.4%（34/36）比,差异无统计学意义（P>0.05）,观察组血清HBV DNA载量为（3.2±0.3）log10 copies/ml,与对照组的（3.5±0.4）log10 copies/ml比,无显著性差异（P>0.05）;观察组腹水、肝性脑病、消化道出血和肝细胞癌发生率分别为17.5%、5.0%、10.0%和2.5%,显著低于对照组的52.7%、13.8%、16.7%和11.1% （P<0.05）;在观察的12 m内,观察组无死亡病例,而对照组死亡3例（8.3%）。结论 应用ETV联合复方鳖甲软肝片治疗能够明显改善乙型肝炎肝硬化患者肝功能指标,降低血清肝纤维化指标,改善预后。     

Outcomes of autologous bone marrow mononuclear cell transplantation in decompensated liver cirrhosis

AIM: To determine the long-term efficacy of autologous bone marrow mononuclear cells (BM-MNCs) transplantation in terms of improving liver function and reducing complications in patients with decompensated cirrhosis.METHODS: A total of 47 inpatients with decompensated liver cirrhosis were enrolled in this trial, including 32 patients undergoing a single BM-MNCs transplantation plus routine medical treatment, and 15 patients receiving medical treatment only as controls. Forty-three of 47 patients were infected with hepatitis B virus. Bone marrow of 80-100 mL was obtained from each patient and the BM-MNCs suspension was transfused into the liver via the hepatic artery. The efficacy of BM-MNCs transplantation was monitored during a 24-mo follow-up period.RESULTS: Liver function parameters in the two groups were observed at 1 mo after BM-MNCs transfusion. Prealbumin level was 118.3 ± 25.3 mg/L vs 101.4 ± 28.7 mg/L (P = 0.047); albumin level was 33.5 ± 3.6 g/L vs 30.3 ± 2.2 g/L (P = 0.002); total bilirubin 36.9 ± 9.7 mmol/L vs 45.6 ± 19.9 mmol/L (P = 0.048); prothrombin time 14.4 ± 2.3 s vs 15.9 ± 2.8 s (P = 0.046); prothrombin activity 84.3% ± 14.3% vs 74.4% ± 17.8% (P = 0.046); fibrinogen 2.28 ± 0.53 g/L vs 1.89 ± 0.44 g/L (P = 0.017); and platelet count 74.5 ± 15.7 × 10⁹/L vs 63.3 ± 15.7 × 10⁹/L (P = 0.027) in the treatment group and control group, respectively. Differences were statistically significant. The efficacy of BM-MNCs transplantation lasted 3-12 mo as compared with the control group. Serious complications such as hepatic encephalopathy and spontaneous bacterial peritonitis were also significantly reduced in BM-MNCs transfused patients compared with the controls. However, these improvements disappeared 24 mo after transplantation.CONCLUSION: BM-MNCs transplantation is safe and effective in patients with decompensated cirrhosis. It also decreases the incidence of serious complications.     

Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver

BACKGROUNDMany studies have investigated the progression of nonalcoholic fatty liver disease (NAFLD) and its predisposing risk factors, but the conclusions from these studies have been conflicting. More challenging is the fact that no effective treatment is currently available for NAFLD.AIMTo determine the effects of proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors on fatty infiltration of the liver.METHODSThis retrospective, chart review-based study was conducted on patients, 18-year-old and above, who were currently on PCSK9 inhibitor drug therapy. Patients were excluded from the study according to missing pre- or post-treatment imaging or laboratory values, presence of cirrhosis or rhabdomyolysis, or development of acute liver injury during the PCSK9 inhibitor treatment period; the latter being due to false elevation of liver function markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Radiographic improvement was assessed by a single radiologist, who read both the pre- and post-treatment images to minimize reading bias. Fatty infiltration of the liver was also assessed by changes in ALT and AST, with pre- and post-treatment levels compared by paired t-test (alpha criterion: 0.05).RESULTSOf the 29 patients included in the study, 8 were male (27.6%) and 21 were female (72.4%). Essential hypertension was present in 25 (86.2%) of the patients, diabetes mellitus in 18 (62.1%) and obesity in 15 (51.7%). In all, patients were on PCSK9 inhibitors for a mean duration of 23.69 ± 11.18 mo until the most recent ALT and AST measures were obtained. Of the 11 patients who received the radiologic diagnosis of hepatic steatosis, 8 (72.73%) achieved complete radiologic resolution upon use of PCSK9 inhibitors (mean duration of 17.6 mo). On average, the ALT level (IU/L) decreased from 21.83 ± 11.89 at pretreatment to 17.69 ± 8.00 at post-treatment (2-tailed P = 0.042) and AST level (IU/L) decreased from 22.48 ± 9.00 pretreatment to 20.59 ± 5.47 post-treatment (2-tailed P = 0.201).CONCLUSIONPCSK9 inhibitors can slow down or even completely resolve NAFLD.     

Differential Relapse Patterns After Discontinuation of Entecavir vs Tenofovir Disoproxil Fumarate in Chronic Hepatitis B

Background and AimsWhether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy.MethodsThis study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen–negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods.ResultsDuring a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups.ConclusionsTDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.     

Tenofovir vs. Entecavir on Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma after Radiofrequency Ablation

For patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) treated with curative radiofrequency ablation (RFA), the effect of entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF) on recurrence-free survival (RFS) and overall survival (OS) remains unclear. We aimed to compare the outcomes of patients receiving ETV or TDF after RFA. This study consecutively collected patients who were treated with ETV (n = 202) or TDF (n = 102) for chronic hepatitis B (CHB) after curative RFA of HCC from December 2015 to January 2021 at Sun Yat-sen University Cancer Center. There were 130 patients in the ETV group and 77 patients in the TDF group after we performed 1-to-n propensity score matching. Kaplan–Meier and Cox regression analyses were performed to validate possible risk factors for RFS and OS. In addition, we estimated the curative effect of ETV and TDF for HBV-related hepatitis by recording the change in serum HBV DNA and ALBI grade after RFA. During the study period (median 34.1 (interquartile range: 19.6–47.4 months) months), 123 (40.5%) patients suffered HCC recurrence, and 15 (4.9%) died. In the full cohort, the probability of HCC recurrence (41.6% vs. 37.3%, p = 0.49) and overall survival (95% vs. 95.1%, p = 0.39) at 5 years were similar between the ETV and TDF groups. In the matched cohort, HCC recurrence (40.8% vs. 40.3%, p = 0.35) and overall survival (96.9% vs. 93.5%, p = 0.12) at 5 years were similar between the ETV and TDF groups. Furthermore, the early RFS (<2 years) did not differ significantly between the two groups in the full and matched cohorts (p = 0.26, p = 0.13). Compared with the ALBI grade before RFA, the ALBI grade of 80 patients (41%) remained stable or improved in the ETV group and 64 patients (64%) in the TDF group (p < 0.001). The mean time of serum HBV DNA reduction to 0 was 9.13 (95% CI: 5.92–12.33) and 2.75 (95% CI: 2.01–3.49) months in the ETV and TDF groups, respectively (p = 0.015). The RFS and OS of patients after curative RFA for HCC were not significantly different between the ETV and TDF groups. TDF therapy was associated with a better effect of protecting liver function and reducing the load of HBV. Further validation studies are needed.