乙肝-肝硬化应用恩替卡韦与复方鳖甲软肝片治疗的效果研究

目的观察乙肝-肝硬化联合应用恩替卡韦与复方鳖甲软肝片的疗效。方法利用随机单盲法,将我院近期接收的乙肝-肝硬化者84例分成试验组与对照组,每组42例。试验组联合应用恩替卡韦和复方鳖甲软肝片,对照组仅接受恩替卡韦治疗。观察两组疗效,比较肝功能以及肝纤维化指标的改善程度。结果两组用药后肝功能均得到改善,试验组的改善程度明显优于对照组,差异具有统计学意义(P<0.05);针对用药后的血清肝纤维化指标水平,试验组明显低于对照组,差异具有统计学意义(P<0.05)。结论将恩替卡韦、复方鳖甲软肝片联合用于乙肝-肝硬化中,有助于肝功能的恢复,具临床应用价值。

Liver stiffness in the hepatitis B virus carrier:A non-invasive marker of liver disease influenced by the pattern of transaminases

AIM： To investigate the usefulness of transient elastography by Fibroscan （FS）, a rapid non-invasive technique to evaluate liver fibrosis, in the management of chronic hepatitis B virus （HBV） carriers. METHODS： In 297 consecutive HBV carriers, we studied the correlation between liver stiffness （LS）, stage of liver disease and other factors potentially influencing FS measurements. In 87 chronic hepatitis B （CriB） patients, we monitored the FS variations according to the spontaneous or treatment-induced variations of biochemical activity during follow-up. RESULTS： FS values were 12.3 ± 3.3 kPa in acute hepatitis, 10.3 ± 8.8 kPa in chronic hepatitis, 4.3 ± 1.0 kPa in inactive carriers and 4.6 ± 1.2 kPa in blood donors. We identified the cut-offs of 7.5 and 11.8 kPa for the diagnosis of fibrosis ≥S3 and cirrhosis respectively, showing 93.9% and 86.5% sensitivity, 88.5% and 96.3% specificity, 76.7% and 86.7% positive predictive value （PPV）, 97.3% and 96.3% negative predictive value （NPV） and 90.1% and 94.2% diagnostic accuracy. At multivariate analysis in 171 untreated carriers, fibrosis stage （t = 13.187,P 〈 0.001）, active vs inactive HBV infection （t = 6.437, P 〈 0.001）, alanine aminotransferase （ALT） （t = 4.740, P 〈 0.001） and HBV-DNA levels （t = -2.046, P = 0.042） were independently associated with FS. Necroinflammation score （t = 2.158, 〉 10/18 vs ≤ 10/18, P = 0.035） and ALT levels （t = 3.566, P =0.001） were independently associated with LS in 83 untreated patients without cirrhosis and long-term biochemical remission （t = 4.662, P 〈 0.001） in 80 treated patients. During FS monitoring （mean followup 19.9 ± 7.1 mo） FS values paralleled those of ALT in patients with hepatitis exacerbation （with 1.2 to 4.4-fold increases in Crib patients） and showed a progressive decrease during antiviral therapy. CONCLUSION： FS is a non-invasive tool to monitor liver disease in chronic HBV carriers, provided that the pattern of biochemical activity is taken into account. In the inactive carrier, it identifies non-HBV-related causes of liver damage and transient reactivations. In CHB patients, it may warrant a more appropriate timing of control liver biopsies.

Clinicopathologic characteristics of intrahepatic cholangiocarcinoma in patients with positive serum a-fetoprotein

AIM:To explore clinicopathologic characteristics of intrahepatic cholangiocarcinoma (ICC) in patients with positive serum a-fetoprotein (AFP). METHODS:One hundred and thirty one patients who underwent surgical dissection for pathologically confirmed ICC were divided into a positive AFP (> 20 ng/mL) group (n = 32) and a negative AFP group (n = 99), whose clinicopathologic features were analyzed and compared. RESULTS:The positive rate of HBsAg and liver cirrhosis of the positive AFP group was higher than that of the negative AFP group, while the positive rate of CA19-9 (> 37 U/mL) and the lymph node metastasis rate was lower. CONCLUSION:ICC patients with positive AFP share many clinicopathologic similarities with hepatocellular carcinoma.

Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection

AIM: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known about the occurrence of bone disease in non-cirrhotic patients with chronic hepatitis B or C. Therefore, it was the aim of this study to evaluate this particular population for BMD and bone turnover markers. METHODS: Biochemical markers of bone turnover and BMD were measured in 43 consecutive patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. Mean age was 49 years (range 26-77 years). BMD was measured by dual X-ray absorptiometry in the femoral neck (FN) and the lumbar spine (LS) region. In addition, bone metabolism markers were measured. RESULTS: BMD was lowered in 25 (58%) of the patients with chronic hepatitis B or C (FN; 0.76 (0.53-0.99); LS: 0.96 (0.62-1.23) g/cm2). Eight (32%) osteopenic patients were diagnosed with osteoporosis. Bone-specific alkaline phosphatase (P= 0.005) and intact parathyroid hormone (iPTH) (P = 0.001) were significantly elevated in the more advanced stages of fibrosis. Mean T-score value was lower in patients with chronic hepatitis C as compared to patients suffering from chronic hepatitis B; however, the difference was not statistically significant (P= 0.09). CONCLUSION: There was a significantly reduced BMD in non-cirrhotic patients with chronic hepatitis B or C infection. Alterations of bone metabolism already occurred in advanced liver fibrosis without cirrhosis. According to our results, these secondary effects of chronic viral hepatitis should be further investigated.

Outcome of lamivudine-resistant hepatitis B virus is generally benign except in cirrhotics

AIM： We set to determine factors that determine clinical severity after the development of resistance.METHODS： Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups： 13/35 （37%） were non-cirrhotics with normal pre-treatment ALT （Group IA）, 12/35 （34%） were non-cirrhotics with elevated pre-treatment ALT （Group IB）, and 10/35 （29%） were cirrhotics （Group II）. Patients were followed for a median of 98 wk （range 26-220） after the emergence of genotypic resistance.RESULTS： Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients （75%） developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score （in the cirrhotic group） were predictive of clinical resistance and correlated with peak ALT levels and CPT score.CONCLUSION： The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death （30%） with the development of lamivudine resistance.

Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy

AIM:To evaluate the health-related quality of life (HRQOL) based on the Chinese version of SF-36 and Chronic Liver Disease Questionnaire (CLDQ) in subjects with chronic hepatitis B,liver cirrhosis,including patients with minimal hepatic encephalopathy (MHE). METHODS:The SF-36 and CLDQ were administered to 160 healthy volunteers,20 subjects with chronic hepatitis B and 106 patients with cirrhosis (33 cases exhibited MHE). HRQOL scores were compared among the different study groups. The SF-36 includes eight health concepts:physical functioning,role-physical,body pain,general health,vitality,social functioning,role-emotion,and mental health. Six domains of CLDQ were assessed:abdominal symptoms,fatigue,systemic symptoms,activity,emotional function and worry. RESULTS:Compared with healthy controls (96.9 ± 4.5,86.6 ± 18.4,90.1 ± 12.5,89.0 ± 5.7,87.5 ± 4.3,95.8 ± 7.1,88.5 ± 15.9,88.7 ± 5.2 in SF-36 and 6.7 ± 0.5,6.1 ± 0.6,6.3 ± 0.6,6.5 ± 0.5,6.3 ± 0.5,6.8 ± 0.4 in CLDQ),patients with chronic hepatitis B (86.3 ± 11.0,68.8 ± 21.3,78.9 ± 14.4,60.8 ± 10.5,70.8 ± 8.6,76.1 ± 12.6,50.0 ± 22.9,72.2 ± 10.6 and 5.5 ± 1.0,4.5 ± 1.0,5.2 ± 1.1,5.3 ± 0.9,4.8 ± 0.9,4.9 ± 1.0) and cirrhosis (52.8 ± 17.4,32.8 ± 27.9,61.6 ± 18.9,30.2 ± 18.3,47.9 ± 20.1,54.0 ± 19.2,28.9 ± 26.1,51.1 ± 17.8 and 4.7 ± 1.2,3.9 ± 1.2,4.7 ± 1.2,4.7 ± 1.3,4.7 ± 1.0,4.4 ± 1.1) had lower HRQOL on all scales of the SF-36 and CLDQ (P < 0.01 for all). Increasing severity of liver cirrhosis (based on the Child-Pugh score/presence or absence of MHE) was associated with a decrease in most components of SF-36 and CLDQ,especially SF-36.CONCLUSION:The Chinese version of SF-36 along with CLDQ is a valid and reliable method for testing MHE in patients with liver cirrhosis. Cirrhosis and MHE are associated with decreased HRQOL.

Globulin-platelet model predicts minimal fibrosis and cirrhosis in chronic hepatitis B virus infected patients

AIM： To establish a simple model consisting of the rou- tine laboratory variables to predict both minimal fibrosis and cirrhosis in chronic hepatitis B virus （HBV）-infected patients. METHODS： We retrospectively investigated 114 chron- ic HBV-infected patients who underwent liver biopsy in two different hospitals. Thirteen parameters were analyzed by step-wise regression analysis and correla- tion analysis. A new fibrosis index [globulin/platelet （GP） model] was developed, including globulin （GLOB） and platelet count （PLT）. GP model = GLOB （g/mL） x 100/PLT （x 109/L）. We evaluated the receiver operating characteristics analysis used to predict minimal fibrosis and compared six other available models. RESULTS： Thirteen clinical biochemical and hemato- logical variables [sex, age, PLT, alanine aminotransfer- ase, aspartate aminotransferase （AST）, albumin, GLOB, total bilirubin （T.bil）, direct bilirubin （D.bil）, glutamyl-transferase, alkaline phosphatase, HBV DNA and pro- thrombin time （PT）] were analyzed according to three stages of liver fibrosis （F0-F1, F2-F3 and F4）. Bivariate Spearman＇s rank correlation analysis showed that six variables, including age, PLT, T.bil, D.bil, GLOB and PT, were correlated with the three fibrosis stages （FS）. Cor- relation coefficients were 0.23, -0.412, 0.208, 0.220, 0.314 and 0.212; and P value was 0.014, 〈 0.001, 0.026, 0.018, 0.001 and 0.024, respectively. Univariate analysis revealed that only PLT and GLOB were signifi- cantly different in the three FS （PLT： F = 11.772, P 〈 0.001; GLOB： F = 6.612, P = 0.002）. Step-wise multiple regression analysis showed that PLT and GLOB were also independently correlated with FS （R2 = 0.237）. By Spearman＇s rank correlation analysis, GP model was significantly correlated with the three FS （r = 0.466, P 〈 0.001）. The median values in F0-F1, F2-F3 and F4 were 1.461, 1.720 and 2.634. Compared with the six available models （fibrosis index, AST-platelet ratio, FIB-4, fibrosis-cirrhosis index and age-AST model and age-PLT ratio）, GP model showed a highest correlation coefficient. The sensitivity and positive predictive value at a cutoff value 〈 1.68 for predicting minimal fibrosis F0-F1 were 72.4% and 71.2%, respectively. The speci- ficity and negative predictive value at a cutoff value 〈 2.53 for the prediction of cirrhosis were 84.5% and 96.7%. The area under the curve （AUC） of GP model for predicting minimal fibrosis and cirrhosis was 0.762 [95% confidence interval （CI）： 0.676-0.848] and 0.781 （95% CI： 0.638-0.924）. Although the differences were not statistically significant between GP model and the other models （P all 〉 0.05）, the AUC of GP model was the largest among the seven models. CONCLUSION： By establishing a simple model using available laboratory variables, chronic HBV-infected patients with minimal fibrosis and cirrhosis can be di- agnosed accurately, and the clinical application of this model may reduce the need for liver biopsy in HBV- infected patients.

Future prospectives for the management of chronic hepatitis B

Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately a million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load （HBV-DNA） plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory （interferons） and antiviral suppressants （nucleoside and nucleotide analogues） all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross-resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion： chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.

Hepatitis B virus genotypes in southwest Iran: Molecular, serological and clinical outcomes

AIM: To investigate the associations of hepatitis B virus (HBV) genotype with HBeAg and anti-HBe status, alanine aminotransferase (ALT) levels and HBV-DNA detection in different groups of HBV-infected patients in southwest Iran. METHODS: A total of 89 HBsAg-positive serum samples were collected from the same number of patients. All sera were then investigated to determine HBV DNA and serological markers. For all the polymerase chain reaction (PCR)-positive samples, biochemical, histopathological assays and genotyping were also performed. RESULTS: Genotype D was the only type of HBV foundin different clinical forms of acute and chronic infections. There was a high prevalence of HBeAg-negative HBV- infected patients with chronic hepatitis (52.7%). Out of 55 patients with chronic hepatitis, seven (12.7%) were diagnosed with cirrhosis. A significant association between the presence of anti-HBe antibody and an increase in ALT level, among either HBeAg-negative (P = 0.01) or HBeAg-positive (P = 0.026) patients, was demonstrated. No significant differences were observed between the clinical outcomes of HBeAg-positive and -negative individuals (P = 0.24). CONCLUSION: Genotype D has been recognized as the only type of HBV found in different clinical forms of HBV infections, including cirrhosis, among the residents of southwest Iran. Anti-HBe possibly plays a role in disease progression in some patients with chronic hepatitis, at least for a period of disease.

OBSERVATION ON THE EFFECT OF MOXIBUSTION ON HYPERBILIRUBINEMIA IN HEPATITIS B TYPE CIRRHOSIS PATIENTS

Objective: To study the effect of moxibustion on hyperbilirubinemia in hepatitis B cirrhosis patients. Methods: 56 cases of inpatients with hepatitis B cirrhosis were divided into treatment group (n=27) and control group (n=29) randomly. All the patients of these two groups were given with routine expectant treatment including administration of medicines (Bifendate, Eessentiale, Potenline, etc) for protecting liver functions, reducing the level of alanine aminotransferase (ALT), etc., and in the meantime, patients of the treatment group were also treated with moxibustion of Zusanli (足三里 ST 36), Taichong (太冲 LR 3) and Sanyinjiao (三阴交 SP 6), once daily, continuously for 4 weeks. Results: After 4 weeks of treatment, of the 27 and 29 cases of treatment and control group, 23 and 10 patients had improvement in clinical symptoms, 4 and 19 failed, with the total effective rates being 85.18% and 34.48% respectively. Serum total bilirubin (TBil) contents of treatment and control groups decreased significantly, and the level of TBil in the treatment group was significantly lower than that in the control group (P<0.01). Conclusion: Moxibustion is an effective remedy in relieving hyperbilirubinemia and improving clinical symptoms in the treatment of hepatitis B cirrhosis patients.

Brain metastases from hepatocellular carcinoma after hepatectomy

Hepatocellular carcinoma is a highly malignant neoplasm and frequently involves extrahepatic organs but decidedly rarely occurs in brain. We describe 3 cases of brain metastases in patients suffering from post-HBV hepatocarcinoma. The ＂stroke-like＂ presentation of the cerebral localization of the disease can be explained by both the important vascularization of the tumor and the frequent hemocoagulative alterations caused by the cirrhosis. The importance of diagnostic neuroradiology is briefly addressed, with reference to the fundamental role played by MRI. Surgery of these lesions does not present any particular technical problems as long as they are located in accessible areas and the patient＇s general and neurological conditions allow it. Postoperative radiotherapy seems to improve the quality and quantity of residual life, although the number of patients described in the literature was too small to draw any definite conclusion in this regard.

Lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis

A 69-year-old man was admitted to our hospital in October 2003,for further examination of two liver tumors.He was diagnosed with hepatocellular carcinoma(HCC) arising from decompensated hepatitis B virus(HBV)-related cirrhosis.Long-term lamivudine administration improved liver function dramatically despite repeated treatment for HCC.His Child-Pugh score was 9 points at start of lamivudine treatment,improving to 5 points after 1 year.His indocyanine green at 15 min after injection test score was 48%before lamivudine treat-ment,improving to 22%after 2 years and to 5%after 4 years.Radiofrequency ablation controlled the HCC foci and maintained his liver function.In April 2009,abdominal computed tomography revealed a tumor thrombus in the right portal vein.Since his indocyanine green test results had improved to less than 10%,we performed a right hepatectomy,which was successful.To our knowledge,there have been no documented reports of patients undergoing successful right hepatectomy for HCC arising from decompensated cirrhosis.The findings observed in our patient indicate the importance of nucleoside analogs for treating HBV-related HCC.

Lnc-TCL6 is a potential biomarker for early diagnosis and grade in liver-cirrhosis patients

Background:Long non-coding RNAs(lncRNAs)have been applied as biomarkers in many diseases.However,scarce biomarkers are available in single lncRNA differential expression associated with different clinical stages of liver cirrhosis(LC).The aim of the study is to identify some lncRNAs that can serve as non-invasive sensitive biomarkers for early diagnosis and grade of LC.Methods:Blood lncRNA expression was evaluated in three independent cohorts with 305 participants including healthy controls,hepatitis B virus(HBV)carriers,and patients with chronic hepatitis B(CHB)or LC.First,candidate lncRNAs were screened by CapitalBiotech microarray to diagnose cirrhosis.Quantitative reverse-transcriptase polymerase chain reaction was then used to investigate the expression of selected lncRNAs in the whole group of cirrhosis and different Child–Pugh classes.Ultimately,the diagnostic accuracy of the promising biomarker was examined and validated via Mann–Whitney test and receiver-operating characteristics analysis.Results:Lnc-TCL6 was identified as a sensitive biomarker for early diagnosis of LC(Child–Pugh A)compared with healthy controls(area under the ROC curve[AUC]=0.636),HBV carriers(AUC=0.671),and CHB patients(AUC=0.672).Furthermore,lnc-TCL6 showed a favourable capacity in discriminating among different Child–Pugh classes(AUC:0.711–0.837).Compared with healthy controls,HBV carriers,and CHB patients,the expression of lnc-TCL6 was obviously up-regulated in Child–Pugh A patients and,conversely,significantly down-regulated in Child–Pugh C patients.Conclusions:Lnc-TCL6 is a novel potential biomarker for early diagnosis of LC and is a possible predictor of disease progression.

Clinical study of warm needling moxibustion combined with entecavir in the treatment of compensated cirrhosis due to chronic hepatitis B

Objective:To investigate the efficacy and possible mechanism of action of warm needling moxibustion combined with entecavir in the treatment of compensated cirrhosis due to chronic hepatitis B(CHB).Methods:Ninety patients were randomly divided into a control group and an observation group,with 45 patients in each group.The control group was given oral entecavir,and the observation group was given additional warm needling moxibustion.The serum alanine transaminase(ALT),aspartate transaminase(AST),albumin(ALB)levels,portal vein internal diameter,splenic vein internal diameter,spleen thickness,and liver hardness were compared before and after treatment.The serum hyaluronic acid(HA),laminin(LN),procollagen typeⅢ(PCⅢ),typeⅣcollagen(Ⅳ-C),interleukin(IL)-21,and platelet-derived growth factor(PDGF)levels were also measured.Results:After treatment,the serum ALT and AST levels decreased(P<0.05),and the serum ALB levels increased(P<0.05)in both groups.The serum ALT and AST levels were lower in the observation group than in the control group(P<0.05),and the ALB level was higher in the observation group(P<0.05).The portal vein internal diameter,splenic vein internal diameter,spleen thickness,and liver hardness values were reduced in both groups after treatment(P<0.05),and were lower in the observation group than in the control group(P<0.05).The serum HA,LN,PCⅢ,andⅣ-C levels were reduced in both groups(P<0.05),and were lower in the observation group than in the control group(P<0.05).In the control group,the serum IL-21 level decreased(P<0.05),but the serum PDGF level did not change significantly(P>0.05);in the observation group,the serum IL-21 and PDGF levels decreased significantly(P<0.05)and were lower than those in the control group(P<0.05).Conclusion:Warm needling moxibustion combined with entecavir treatment can improve liver function,reduce the inner diameters of the portal vein and splenic vein,spleen thickness,and liver hardness,and improve liver fibrosis indicators in patients with CHB cirrhosis,which may be related to the reduction of serum IL-21 and PDGF levels.

Correlation between Traditional Chinese Medicine symptom patterns and serum concentration of zinc,iron,copper and magnesium in patients with hepatitis B and associated liver cirrhosis

OBJECTIVE:To investigate the correlation between the patterns of Traditional Chinese Medicine(TCM)syndromes and the serum concentration of zinc,iron,copper and magnesium of patients with chronic hepatitis B(CHB) and hepatitis B virus(HBV)-induced liver cirrhosis.METHODS:A total of 86 patients were included in the study between March 1,2009 and January 1,2010.All were diagnosed with CHB or HBV-induced liver cirrhosis according to the diagnosis standard of the Chinese Medical Association.Fasting serum concentrations of zinc,iron,copper and magnesium were measured.Patients were classified into different patterns of TCM symptoms according to TCM theory and clinical experience.RESULTS:In the HBV-induced liver cirrhosis group,the mean zinc concentration in patients with the TCM pattern of stagnation of fluid-Dampness was lower than that in patients with obstruction of collaterals by Blood stasis(P < 0.034).In the CHB group,the mean magnesium concentration in patients with toxic Heat flourishing was significantly lower than that in those with Damp-Heat in the Liver and Gallbladder,and those with Liver depression and Spleen deficiency(P < 0.021).The concentrations of iron and copper showed little difference among the different TCM symptom patterns.CONCLUSION:The serum zinc and magnesium concentrations correlated with certain TCM patterns of symptoms in patients with HBV-induced liver cirrhosis and CHB.It may be helpful to interpret the pathogenic change in the TCM symptom patterns in liver cirrhosis and CHB,and also to conduct clinical treatment of the diseases based on identified TCM patterns.