Association Between Serum Level of Hepatitis B Surface Antigen at End of Entecavir Therapy and Risk of Relapse in E Antigen-Negative Patients.

BACKGROUND & AIMS: This study investigated whether serum level of hepatitis B surface antigen (HBsAg) at the end of entecavir treatment was associated with risk of relapse. METHODS: We performed a prospective multicenter study of 161 consecutive patients with chronic hepatitis B in whom the hepatitis B virus was no longer detected after 3 years or more of entecavir therapy. Treatment ended between July 1, 2011 and July 1, 2015. Patients were monitored for clinical relapse (hepatitis B virus DNA >2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) and virologic relapse (hepatitis B virus DNA >2000 IU/mL). Outcomes were calculated using the Kaplan-Meier method and risk factors were identified by Cox proportional hazards modeling. RESULTS: Two years after therapy ended, 49.2% of patients in the entire cohort had a clinical relapse (95% confidence interval [CI], 40.9%-58.1%) and 81.7% had a virologic relapse (95% CI, 74.3%-88.0%). Among patients who were hepatitis B e antigen-negative at the end of therapy, 39.2% had a clinical relapse (95% CI, 30.3%-49.6%) and 77.4% had a virologic relapse (95% CI, 68.6%-85.2%). Serum level of HBsAg was associated with relapse in the hepatitis B e antigen-negative patients (Ptrend = .006 for clinical relapse; Ptrend = .0001 for virologic relapse). In multivariate Cox regression analysis, the hazard ratio (per log IU/mL increment) for clinical relapse was 2.47 (95% CI, 1.45-4.23) and for virologic relapse was 1.80 (95% CI, 1.33-2.45). The 11 (9%) patients with levels of HBsAg <10 IU/mL did not relapse. CONCLUSIONS: Serum level of HBsAg is associated with risk of relapse in patients who are hepatitis B e antigen-negative after treatment with entecavir. A low titer of HBsAg might be used to identify patients at low risk for relapse after treatment.

Mosapride as an adjunct to lansoprazole for symptom relief of reflux oesophagitis.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Reflux oesophagitis is a common clinical disorder associated with significant morbidity. Proton pump inhibitors are the current pharmacotherapy of choice, but not all treated patients achieve symptom relief. Little is known about the efficacy of mosapride, a prokinetic agent which decreases episodes of gastro-oesophageal reflux, as an adjunct to proton pump inhibitors in improving the symptoms of reflux oesophagitis. WHAT THIS STUDY ADDS Mosapride was generally not more effective than placebo as an adjunct therapy to a standard dose of lansoprazole in decreasing the symptom burden of patients with reflux oesophagitis. However, in a subgroup with more severe symptoms, combination therapy with lansoprazole and mosapride was possibly superior to monotherapy with lansoprazole. AIMS To investigate if mosapride, a prokinetic agent, was an effective adjunct to acid suppression in improving the symptoms of reflux oesophagitis. METHODS Patients (n= 96) with reflux oesophagitis were randomly assigned to either mosapride (5 mg three times daily) or placebo for 4 weeks. Symptom severity was assessed by a validated questionnaire at enrolment, 4 and 8 weeks after medication. The primary outcome for the first 4 weeks was decrease in symptom scores. After a 3 day washout period, patients initially allocated to mosapride crossed over to placebo and vice versa for the next 4 weeks. The outcome of the second phase was maintenance of symptom control. All patients received lansoprazole (30 mg once daily) throughout study. RESULTS The decreased symptom score after 4 weeks of treatment with lansoprazole and mosapride (n= 50) was 13.42 +/- 1.16 (mean +/- SEM), similar to that of lansoprazole plus placebo (10.85 +/- 1.03, n= 46), with an insignificant difference of 2.57 (95% CI -0.53, 5.67, P= 0.103). However, a sub-group analysis for patients with pre-treatment scores of >18 points (n= 48) revealed that lansoprazole plus mosapride achieved a greater reduction of symptom score than lansoprazole plus placebo (18.22 +/- 1.91 vs. 12.88 +/- 1.65; mean difference of 5.34, 95% CI 0.28, 10.40, P= 0.039). In the second phase, there was no difference between lansoprazole with mosapride or placebo in maintaining symptom control (39/44 or 86.64% vs. 41/50 or 82%, P= 0.401). Subgroup analysis for those with substantial residual symptoms revealed similar results. CONCLUSION Compared with placebo, mosapride generally does not provide additional benefit to a standard dose of lansoprazole in patients with reflux oesophagitis, except possibly in the subgroup of severely symptomatic patients.

A randomized controlled trial comparing two different dosages of infusional pantoprazole in peptic ulcer bleeding.

AIM: The optimal dosage of proton pump inhibitor in bleeding peptic ulcers remains controversial. The aim was to compare the clinical effectiveness of two doses of infusional pantoprazole in peptic ulcer bleeding. METHODS: Peptic ulcer patients (n= 120) with bleeding stigmata were enrolled after successful endoscopic therapy. After an initial bolus injection of 80 mg pantoprazole, patients were randomized to receive continuously infused pantoprazole at either 192 mg day(-1) or 40 mg every 6 h (i.e. 160 mg day(-1)) for 3 days. Clinical outcomes between the two groups within 14 days were compared, with 14-day recurrent bleeding regarded as the primary end-point. RESULTS: Both groups (n= 60 each) were well matched in demographic and clinical factors upon entry. Bleeding totally recurred in 11 (9.2%) patients, with six (10%) in the 192 mg day(-1) group and five (8.3%) in the 160 mg day(-1) group (relative risk of bleeding recurrence between two treatments 1.2; 95% CI 0.39, 3.72). All secondary outcomes between the two groups were similar, including the amount of blood transfusion (mean 1179 ml vs. 1203 ml, P > 0.1), hospital stay (mean 9.5 days vs. 9.9 days, P > 0.1), need for surgery (n= 1 vs. n= 0, P > 0.1), and mortality (n= 1 vs. n= 0, P > 0.1). CONCLUSIONS: Following endoscopic haemostasis, infusional pantoprazole at either 192 mg day(-1) or 40 mg every 6 h appear similar.

Prevalence of HFE mutations and relation to serum iron status in patients with chronic hepatitis C and patients with nonalcoholic fatty liver disease in Taiwan.

AIM: To assess the prevalence of the two mutations, C282Y and H63D of HFE gene, in healthy subjects, patients with chronic hepatitis C (CHC), and patients with nonalcoholic fatty liver disease (NAFLD) in Taiwan and to explore the contribution of the HFE mutation on serum iron stores in CHC and NAFLD groups. METHODS: We examined C282Y and H63D mutations of HFE gene in 125 healthy subjects, 29 patients with CHC, and 33 patients with NAFLD. The serum iron markers, including ferritin, iron, and total iron binding capacity (TIBC), were assessed in all patients. RESULTS: All of the healthy subjects and patients were free from C282Y mutation. The prevalence of H63D heter-ozygosity was 4/125 (3.20%) in healthy subjects, 2/29 (6.90%) in CHC group, and 1/33 (3.03%) in NAFLD group. The healthy subjects showed no significant difference in the prevalence of H63D mutation as compared with the CHC or NAFLD group. Increased serum iron store was found in 34.48% of CHC patients and 36.36% of NAFLD patients. In three patients of H63D heterozygosity, only one CHC patient had increased serum iron store. There was no significant difference in the prevalence of HFE mutations between patients with increased serum iron store and those without in CHC or NAFLD group. CONCLUSION: The HFE mutations may not contribute to iron accumulation in the CHC or NAFLD group even when serum iron overload is observed in more than one-third of these patients in Taiwan.

Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma.

AIM: Des-gamma-carboxy prothrombin (DCP) has been reported to be more sensitive and specific in diagnosing hepatocellular carcinoma (HCC) when compared with alpha-fetoprotein (AFP). However, its ability to identify small HCC still remains unclear. Thus, we conducted a cross-sectional case control study to evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. METHODS: Serum DCP and AFP levels were determined in 127 patients. Among these patients, 32 were with non-cirrhotic chronic hepatitis, 34 were with compensated cirrhosis, and 61 were with HCC. The cut-off value for the DCP and AFP were set as 40 mAU/mL and 20 ng/mL, respectively. To compare the diagnostic value of DCP and AFP in distinguishing HCC from nonmalignant chronic liver disease, receiver operating characteristic (ROC) curves were constructed for each assay. RESULTS: The accuracy, sensitivity and specificity of DCP were higher than AFP in detecting HCC (81.9%, 77% and 86.4% vs 68.5%, 59% and 77.3%, respectively). The area under the ROC (AUROC) curves revealed that DCP had a better accuracy than AFP in diagnosis of HCC (0.85 [95%CI, 0.78-0.91] vs 0.73 [95%CI, 0.65-0.81], P = 0.013). In 39 patients with solitary HCC, the positive rates of DCP were 100% in patients with tumor size larger than 3 cm, 66.7% in patients with tumor size 2-3 cm and 50% in patients with tumor size less than 2 cm. The positive rates of AFP in patients with tumor size larger than 3 cm, 2-3 cm and less than 2 cm were 55.6%, 50%, and 33.3%, respectively. The median level of DCP in HCC patients with tumor size larger than 3 cm was significantly higher than those with tumor size 2-3 cm and those with the size of less than 2 cm. CONCLUSION: Our study indicates that DCP has a better diagnostic value than AFP in differentiating HCC from nonmalignant chronic liver disease. DCP has not only a stronger correlation with HCC than AFP in tumor size but also more effectiveness than AFP in detecting small size of HCC.

Spontaneous regression of hepatocellular carcinoma: a case report and literature review.

A case of spontaneous regression of hepatocellular carcinoma is reported and compared with the reports published in the English literature. Spontaneous regression of a histologically proven hepatocellular carcinoma was observed in a 42-year-old male patient with chronic hepatitis B. The patient refused to receive any medical therapy. The tumor subsequently regressed without specific treatment, as demonstrated radiologically by computed tomography 22 months and ultrasonography 24 months after initial diagnosis. We review 27 case reports of apparently spontaneous regression of hepatocellular carcinoma that have been published in the English literature from 1982 to 2002. In this report, we present our unusual case and discuss possible causes of spontaneous total necrosis or regression of hepatocellular carcinoma.

Long-term survival of Taiwanese patients with hepatocellular carcinoma after combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection.

BACKGROUND AND PURPOSE: Several studies have shown a superior effect of combination therapy with transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) compared with either monotherapy for the treatment of advanced hepatocellular carcinoma (HCC), but there have been no reports on combination treatment from Taiwan. This study investigated the long-term survival and prognostic factors of HCC patients treated with TACE/PEI combination therapy. METHODS: A total of 153 consecutive HCC patients, with tumor sizes between 2 and 3 cm in 47 patients, between 3 and 5 cm in 66 patients, and between 5 and 13 cm in 40 patients, who received TACE/PEI combination therapy were included in this retrospective study. The mean follow-up duration was 23 +/- 17 months (range, 1 to 78 months). RESULTS: The 1-, 2-, 3-, 4-, 5-, and 6-year cumulative survival rates for the patients were 78%, 54%, 40%, 22%, 12%, and 5%, respectively. Multivariate analysis using Cox's proportional hazards model showed that the stage of cirrhosis (Child's class B or C vs class A) was the only factor that significantly affected the survival rate (p = 0.02) [relative risk, 2.10; 95% confidence interval, 1.12 to 3.96]. Univariate analysis showed that survival was poorer in patients with tumors greater than 5 cm than in patients with tumors 2 to 5 cm in largest dimension; this difference was not significant in the multivariate analysis. No serious complications were observed during or after treatment. CONCLUSIONS: TACE combined with PEI is an alternative treatment for patients with larger HCC who are not suitable for surgical resection. A superior outcome can be expected in patients with Child's class A cirrhosis.

MR cholangiopancreatography: prospective comparison of 3-dimensional turbo spin echo and single-shot turbo spin echo with ERCP.

BACKGROUND AND PURPOSE: Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive technique for examination of the biliopancreatic tract. Respiratory-triggered 3-dimensional turbo spin echo (3DTSE RT) and breath-hold thick slab single-shot turbo spin echo (ssTSE BH) are both useful MRCP techniques. The purpose of this study was to compare these 2 sequences with endoscopic retrograde cholangiopancreatography (ERCP) in patients with biliary tract disease. METHODS: Forty four patients with suspected biliary obstruction were recruited to receive MRCP within 3 days before ERCP. MRCP was performed using both 3DTSE RT with maximum intensity projection images and ssTSE BH. ERCP was performed and assessed by 2 endoscopists. RESULTS: MRCP was successfully performed in all patients, whereas ERCP failed in 6 patients (13.6%). MRCP was effective in detecting the presence of choledocholithiasis in 13 of 14 patients, ERCP in 12 of 12, and 2 failed ERCP. MRCP was effective in detecting benign biliary obstruction in 18 of 19 patients, and ERCP in 15 of 15, but 4 patients failed ERCP and choledocholithiasis was misdiagnosed by MRCP in 1 patient. Both MRCP and ERCP correctly diagnosed malignant bile duct obstruction in 10 of 11 patients, and both misdiagnosed that condition as benign obstruction in 1 patient. There was no significant difference between MRCP and successful ERCP in detecting lesions. MRCP was significantly better than ERCP when both successful and failed ERCP were encountered (p = 0.0498). Both 3DTSE RT and ssTSE BH produced the same results in depicting the biliary ducts and lesions in 37 patients (84.1%). Four patients (9.1%) showed better images on 3DTSE RT, whereas 3 patients (6.8%) showed better images on ssTSE BH. CONCLUSIONS: 3DTSE RT and the ssTSE BH were complementary to each other in MRCP studies. Using these 2 techniques, MRCP has a high successful rate and diagnostic accuracy when compared with ERCP in detecting bile duct disease.

Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND/AIMS: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan. METHODS: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease. RESULTS: HBV carriers with older age (> 50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22-25, P < 0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.41-12.03, P = 0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.30-14.52, P = 0.02). CONCLUSIONS: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.

Carbon dioxide-enhanced sonographically guided percutaneous ethanol injection: treatment of patients with viable and recurrent hepatocellular carcinoma.

OBJECTIVE: Viable portions of tumors can persist and recurrent tumors sometimes appear in patients with hepatocellular carcinoma who have undergone transcatheter arterial chemoembolization, percutaneous ethanol injection, or a combination of the two. Some of these tumors are difficult to treat or do not respond to additional treatment using the same protocol. In this article, we examine the use of carbon dioxide (CO(2))-enhanced sonographically guided percutaneous ethanol injection to treat patients with such tumors. SUBJECTS AND METHODS. Our study population was 44 patients with 53 viable portions of tumors or recurrent hepatocellular carcinomas that had developed after the initial treatment of the primary tumor. The tumors were treated with CO(2)-enhanced sonographically guided percutaneous ethanol injection via the catheter that had been placed in the hepatic artery for angiography. Thirty-seven (84.1%) of the 44 patients had cirrhosis. Of these 37 patients, 23 had Child-Pugh class A cirrhosis, and 14 had Child-Pugh class B. RESULTS: Overall, thirty-four (64.2%) of the 53 tumors showed complete necrosis after treatment, eight (15.1%) of the 53 showed partial necrosis, and 11 (20.8%) of the 53 showed no response. The cumulative survival rates of patients who underwent CO(2)-enhanced sonographically guided percutaneous ethanol injection were 81%, 71%, and 44% for 1, 2, and 3 years, respectively. The small tumors were more responsive to the treatment. The tumor recurrence rate was 56.8%. In 9.1% of these cases, carcinoma had metastasized to other organs. CONCLUSION: CO(2)-enhanced sonographically guided percutaneous ethanol injection is effective for patients with viable portions of a treated tumor or new tumors who have undergone transcatheter arterial chemoembolization, percutaneous ethanol injection, or a combination of the two treatments. This finding is especially true of patients who are not good candidates for repeated treatments.

Evolution of hepatitis B virus precore/basal core promoter gene in HBeAg-positive chronic hepatitis B patients receiving lamivudine therapy.

AIM: Lamivudine is effective in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, but the relapse rate after cessation of treatment is high. The evolution of viral genome may contribute to the viral replication under antiviral pressure of lamivudine. We therefore determined the evolution of hepatitis B virus (HBV) precore/basal core promoter and polymerase genes in HBeAg-positive chronic hepatitis B patient during lamivudine therapy. METHOD: Thirteen patients with HBeAg-positive chronic hepatitis who had received short-term lamivudine therapy (mean, 30 weeks) during 1999-2001 were enrolled. The precore/basal core promoter region and polymerase gene were amplified and directly sequenced before, during and post lamivudine treatment. RESULT: HBeAg loss or seroconversion occurred in 11, but eight relapsed after stopping therapy and five had reversion of HBeAg. Before treatment, basal core promoter mutation was found in 1. In the first 3 months of therapy, a rapid decline of serum HBV DNA level accompanied with basal core promoter mutation appeared in 11 of 13 patients (vs. before therapy; P=0.003). However, this mutant was replaced by wild-type virus in four of eight patients who relapsed after treatment. There was no significant change of precore sequences before and during therapy. CONCLUSIONS: Lamivudine therapy may result in the rapid development of basal core promoter mutation of HBV, but this mutation may revert to wild type gradually after cessation of therapy.

Assessment of vascularity in hepatic tumors: comparison of power Doppler sonography and intraarterial CO(2)-enhanced sonography.

OBJECTIVE: The purpose of the study was to compare power Doppler sonography with intraarterial CO(2)-enhanced sonography for revealing vascularity in treated and untreated hepatic tumors. SUBJECTS AND METHODS: Fifty-five patients with 93 liver tumors were prospectively examined with power Doppler sonography and CO(2)-enhanced sonography. These tumors included 29 hepatocellular carcinomas in patients with no previous treatment, 26 treated hepatocellular carcinomas, and 38 hemangiomas. The vascular depiction of power Doppler sonography was compared with that obtained in the early phase of CO(2)-enhanced sonography. The results of angiography were also recorded for comparison. RESULTS: In the hepatocellular carcinomas, power Doppler sonography was the same as CO(2)-enhanced sonography in 18 (62%) of 29 tumors, was inferior to CO(2)-enhanced sonography in nine (31%) of 29 tumors, and was superior to CO(2)-enhanced sonography in two (7%) of 29 tumors. In the treated hepatocellular carcinomas, power Doppler sonography was the same as CO(2)-enhanced sonography in 15 (58%) of 26 tumors and was inferior in 11 (42%) of 26 tumors. In hemangiomas, the same vascularity was found in both studies in 15 (39%) of 38 tumors, CO(2)-enhanced sonography was superior in 22 (58%) of 38 tumors, and power Doppler sonography was superior in one (3%) of 38 tumors. As a whole, 45% of the 93 tumors showed better vascular depiction on CO(2)-enhanced sonography. However, 19.4% of tumors were hypovascular using power Doppler sonography but hypervascular using CO(2)-enhanced sonography. CONCLUSION: Power Doppler sonography is a useful technique for screening hepatic tumor vascularity. CO(2)-enhanced sonography is superior to power Doppler sonography in depicting tumor vascularity in treated hepatocellular carcinomas and in hemangiomas, especially small hemangiomas.