Hepatitis: Changchien CS

Lee CM, Hung CH, Lu SN, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosong Township, Kaohsiung, Taiwan, ROC. · Chang Gung Med J. · Pubmed #18419050 links to  free full text

Abstract: The incidence of hepatitis C virus (HCV) -related hepatocellular carcinoma (HCC) has been increasing in several countries including Taiwan. There are six main genotypes, each of which contains closely related subtypes. Molecular epidemiological studies have shown marked differences in the genotype distribution by geographical region and between patient groups. HCV genotype 1 may play a role in the development of HCC, although some studies have argued against this. A sustained virological response secondary to interferon monotherapy or interferon/ribavirin combination therapy may reduce the risk of HCC and improve survival in chronic hepatitis C patients. The HCV genotypes are associated with therapeutic response. Rapid virological response is also a predictor of therapeutic response. Although viral characteristics have consistently been shown to be important predictors of treatment response, identification of additional host immune and genetic factors involved in determining the outcome of antiviral therapy is necessary. Newly developed bio-techniques (microarray, proteomes, bioinformatics), drugs, and treatment strategies may elucidate the pathogenesis and improve the therapeutic response in HCV infection.

Lee CM, Hung CH, Lu SN, Wang JH, Tung HD, Huang WS, Chen CL, Chen WJ, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan (ROC). · Intervirology. · Pubmed #16166793 No free full text.

Abstract: Etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas of the world. Hepatitis B virus infection is associated with HCC. However, hepatitis C virus (HCV) infection plays an increasingly more important role in the development of HCC and is associated with more than 30% of HCC in Taiwan. The prevalence of HCV infection and HCV genotypes vary in different geographic areas. The prevalence of HCV genotype 1b (HCV-1b) was around 50-70% in Taiwan and even varied in different townships. In addition to host factors, HCV genotypes may be associated with the development of HCC. In our study, the prevalence of HCV-1b in patients with HCC was significantly higher than in those with liver cirrhosis and chronic hepatitis; multivariate analysis revealed that the disease severity was significantly correlated with age and HCV-1b. Furthermore, HCV-1b was associated with a lower response rate to interferon (IFN) therapy than HCV-2. Our study has demonstrated that mutations in the IFN sensitivity-determining region, spanning nucleotides 2,209-2,248 in the NS5A region, correlate with the sustained virological response to combination therapy with IFN and ribavirin in patients with chronic HCV-1b infection in Taiwan. A third-generation enzyme immunoassay for antibody to HCV can be used to predict viremia and monitor the virological response.

Kee KM, Wang JH, Lee CM, Changchien CS, Eng HL. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung. · Chang Gung Med J. · Pubmed #15796260 links to  free full text

Abstract: Dermatomyositis is a rare and idiopathic inflammatory myopathy with characteristic cutaneous manifestations. In recent years, some researchers have showed the cause of dermatomyositis might be due to an autoimmune response induced by viral infections. However, chronic hepatitis C virus (HCV) infection associated with dermatomyositis is very rare. In this report, we present a patient with dematomyositis with abnormal liver function test results and elevated alfa-fetoprotein level. After excluding multiple viral infections known to cause myositis, the case was proven to be chronic hepatitis C by positive HCV-RNA in the serum. Abdominal computed tomography showed a liver tumor on the right lobe and needle biopsy proved it to be hepatocellular carcinoma. Chronic hepatitis C or hepatocellular carcinoma might cause dermatomyositis by inducing the formation of autoantibodies. Chronic hepatitis C or hepatocellular carcinoma should be considered in patients of dermatomyositis if no other cause is found.

Yen YH, Lu SN, Chen CH, Wang JH, Wu CM, Hung CH, Tseng PL, Hu TH, Changchien CS, Lee CM. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. · Liver Int. · Pubmed #18036099 No free full text.

Abstract: BACKGROUND: To elucidate the associations between the changing patterns of hepatitis B e antigen (HBeAg) levels and the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants in HBeAg non-seroconverted patients undergoing lamivudine therapy. METHODS: This study analysed 76 HBeAg-positive naïve chronic hepatitis B patients treated with lamivudine. The median duration of therapy was 52 weeks. The YMDD mutants were detected in 35 patients. The changing patterns of HBeAg levels were categorized into three groups: Descending, Descending-Ascending and Fluctuation. HBeAg breakthrough was defined as progressive HBeAg decreasing to <10% of pretreatment levels, followed by increases exceeding 50 S/Co [the ratio of the sample (S) to the cut-off (Co)] above nadir levels. RESULTS: Of 76 patients, the sensitivity and specificity for predicting YMDD mutants by the Descending-Ascending pattern were 66 and 100% respectively. Of 17 patients with YMDD mutants in the Descending-Ascending group, hepatitis B virus (HBV) DNA first increased, followed by increased HBeAg levels and finally by biochemical breakthrough. The median intervals between virological breakthrough and HBeAg breakthrough, between HBeAg breakthrough and biochemical breakthrough and between virological breakthrough and biochemical breakthrough were 4, 24 and 33 weeks respectively. CONCLUSIONS: Serial HBeAg levels are useful in predicting YMDD mutant emergence in HBeAg non-seroconverted patients during lamivudine therapy.

Chen CH, Wang JH, Lee CM, Hung CH, Hu TH, Wang JC, Lu SN, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung Univeristy College of Medicine, Kaohsiung, Taiwan. · Antivir Ther. · Pubmed #17310821 No free full text.

Abstract: BACKGROUND AND AIMS: The incidence of adefovir dipivoxil (ADV) resistance in patients with lamivudine (3TC)-resistant mutants who received ADV therapy remains unclear. The aims of this study were to determine the virological response to ADV, the incidence and the risk factors of ADV resistance, and the associated factors of initial virological response (IVR) in lamivudine-resistant patients. PATIENTS AND METHODS: Forty-six consecutive lamivudine-resistant chronic hepatitis B patients treated with ADV for more than 12 months with or without 3TC overlapping were prospectively examined for virological response and adefovir resistance. RESULTS: IVR was documented in 24 (52.2%) of patients. Of the 46 patients, 11 had ADV resistance (5 rtN236T, 5 rtA181T, 1 rtA181T and rtN236T). The cumulative incidence of ADV resistance at month 6, 12, 18 and 24 was 0%, 6.5%, 24.6% and 38.3% respectively. Compared with those without ADV resistance, patients with ADV resistance had a significantly higher rate of liver cirrhosis. Based on Cox regression analysis, the significant risk factor of ADV resistance was younger age (OR=0.92, 95% CI=0.86-0.99, P=0.023) and liver cirrhosis (OR=5.3, 95% CI=1.12-25.09, P=0.036). In addition, patients with ADV resistance were associated with higher HBV DNA levels and lower HBV DNA reduction in first 6 months of ADV treatment than those without ADV resistance. CONCLUSION: Only half of our patients achieved IVR on ADV treatment. The incidence of ADV resistance was high in 3TC-resistant patients treated with ADV.

Hung CH, Lee CM, Lu SN, Wang JH, Hu TH, Tung HD, Chen CH, Chen WJ, Changchien CS. · Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Viral Hepat. · Pubmed #16842444 No free full text.

Abstract: We assessed the efficacy of interferon (IFN) alpha-2b plus ribavirin therapy in patients with hepatitis C virus (HCV)-related cirrhosis, and elucidated the risk factors for the development of hepatocellular carcinoma (HCC) to determine whether these therapies might reduce the incidence of HCC. One hundred and thirty-two HCV-cirrhotic patients receiving IFN alpha-2b (3 or 5 MU thrice weekly) and oral ribavirin (1,000-1,200 mg/day) for 24 or 48 weeks were analysed. Cumulative incidence of HCC was estimated by the Kaplan-Meier method. The prognostic relevance of clinical variables and HCC occurrence was evaluated by univariate analysis with the log-rank test and by multivariate Cox's regression analysis. A total of 116 patients completed the treatment and 73 (55%) achieved a sustained virological response (SVR). Stepwise logistic regression analysis showed that nongenotype 1b (P < 0.001) and low viral load (P = 0.018) were independent variables of SVR. During a median follow-up period of 37 (12-63) months, HCC developed in 11 patients with non-SVR and five with SVR (P = 0.0178), whereas there was no difference between those with transient biochemical response and nonresponse (P = 0.5970). The Kaplan-Meier method also showed that old age (>or=60 years) (P = 0.0034) and genotype 1b (P = 0.0104) were associated with HCC occurrence. Using Cox's regression analysis, non-SVR (odds ratio = 3.521, P = 0.036), male (odds ratio = 6.269, P = 0.011) and old age (odds ratio = 3.076, P = 0.049) were independent significant risk factors contributing to HCC development. Our results suggest that achieving SVR by IFN alpha-2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV-related cirrhosis.

Tseng PL, Lu SN, Tung HD, Wang JH, Changchien CS, Lee CM. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Viral Hepat. · Pubmed #15985009 No free full text.

Abstract: Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.

Hung CH, Lee CM, Lu SN, Wang JH, Tung HD, Chen CH, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Gastroenterol Hepatol. · Pubmed #15853986 No free full text.

Abstract: BACKGROUND: Patients with dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection have responded poorly to interferon (IFN) monotherapy. The purpose of the present paper was to assess the effect of combined IFN-alpha and ribavirin therapy in patients infected with both hepatitis B and C. METHODS: Thirty-six patients received 3 or 5 MU IFN-alpha-2b thrice weekly and oral ribavirin (800-1200 mg/day) for 24 weeks. All patients had positive hepatitis B surface antigen, antibody to HCV, and HCV-RNA. Before treatment, one patient had positive hepatitis B e antigen. Eighteen patients had positive HBV-DNA tested by Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ, USA), with a mean HBV-DNA level of 3.1 +/- 0.9 log copies/mL. Another 72 patients with HCV infection alone served as controls. RESULTS: Adverse events led to withdrawal in three patients receiving 5 MU IFN. Based on an intent-to-treat analysis, the biochemical response and serum HCV clearance rate at the end of 48 weeks follow up was similar in patients with dual infection and HCV infection alone (56% vs 72%; and 69% vs 71%, respectively). There was no significant difference in sustained HCV clearance rate between the 3-MU group (n = 13) and the 5-MU group (n = 23; 85% vs 61%). At the end of 48 weeks follow up, two (11%) of 18 pretreatment viremic patients had negative serum HBV-DNA (<200 copies/mL), while eight of those without pretreatment viremia had re-occurrence of HBV-DNA. CONCLUSIONS: Combination therapy with IFN-alpha and ribavirin was effective in achieving sustained HCV clearance in patients with dual HBV and HCV infection, comparable to those with hepatitis C infection alone. Combination therapy using 3 MU IFN-alpha seemed as effective as 5 MU, and was well tolerated in the study population. However, large-scale control trials are necessary to clarify these findings.

Chen CH, Lee CM, Lu SN, Wang JH, Tung HD, Hung CH, Chen WJ, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan. · J Hepatol. · Pubmed #15336449 No free full text.

Abstract: BACKGROUND/AIMS: The aim of this study was to compare the clinical outcome between patients continuing and discontinuing lamivudine therapy after the biochemical breakthrough of hepatitis B virus tyrosine-methionine-aspartate-aspartate (YMDD) mutant. METHODS: YMDD mutants were detected in 51 chronic hepatitis B patients who experienced a flare-up of alanine aminotransferase (ALT) during lamivudine treatment. Twenty-seven of them discontinued lamivudine therapy (group A), and 24 continued therapy (group B) after biochemical breakthrough. The follow-up period was 12 months in both the groups. RESULTS: There was no significant difference between groups A and B in the incidence and severity of ALT peaks and hepatic decompensation within the first 3 months after biochemical breakthrough. After the fourth month of biochemical breakthrough, however, group A experienced acute exacerbation more frequently [20/26 (77%) vs. 7/23 (30%); P=0.002] and higher ALT peaks than group B. The same result was found when the patients were divided into naïve and retreated or cirrhotic and non-cirrhotic groups. Hepatic decompensation at the onset of biochemical breakthrough was associated with higher mortality (OR=70, 95% CI=6.06-807.75). CONCLUSIONS: Patients who discontinued lamivudine therapy increased the frequency of flare-ups and higher ALT peaks than those who continued therapy after 4 months post-breakthrough.

Lee CM, Ong GY, Lu SN, Wang JH, Liao CA, Tung HD, Chen TM, Changchien CS. · Liver Unit, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Hepatol. · Pubmed #12399235 No free full text.

Abstract: BACKGROUND/AIMS: Lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B was reported to be durable by several studies but controversy still exists. The aim of this study was to evaluate the durability of the responses of lamivudine treatment. METHODS: Among 53 chronic hepatitis B patients who had acute exacerbation and had finished lamivudine therapy after at least 6 months of treatment, 31 patients achieved full HBeAg seroconversion twice at least 1 month apart, and subsequently stopped lamivudine therapy. Post-treatment monitoring was continued for up to 87 weeks. Alanine transaminase (ALT), HBeAg and hepatitis B virus (HBV) DNA were used as indicators for relapse. RESULTS: The cumulative relapse rates at 48 and 72 weeks post-treatment were 45.4% and 56.3%, respectively. During follow up, normal ALT levels precluded relapse while ALT levels over two times the upper limit of normal indicated relapse, which correlated well with HBeAg or HBV DNA reappearance. Patients older than 25 years were more likely to experience post-treatment relapse. CONCLUSIONS: Lamivudine-induced full HBeAg seroconversion was not durable in the Taiwanese population. ALT levels were useful for relapse detection. Age was the only independent predictive factor for relapse.

Chen CH, Changchien CS, Lee CM, Tung WC, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. · Department of Internal Medicine, Division of Hepatogastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. · Int J Cancer. · Pubmed #19431214 No free full text.

Abstract: This study was to investigate the clinical significance and virologic factors of occult hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) patients without hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (non-B, non-C) in Taiwan. Serum HBV DNA (occult HBV) was detected in 90 of 222 non-B, non-C HCC patients and 24 of 300 non-B, non-C controls without HCC. Of 90 occult HBV-infected HCC patients, the sequences of HBV pre-S/surface, X and enhancer II/core promoter/precore genes were analyzed from 40 patients. Direct sequencing of such genes was also performed in 24 non-B, non-C controls without HCC and 40 HBsAg-positive HCC controls. Compared with non-B, non-C controls without HCC, non-B, non-C subjects with HCC had significantly higher prevalence of occult HBV (p < 0.0001). Moreover, M1I and Q2K in pre-S2 gene and G1721A were more common in occult HBV-infected patients with HCC than in those without HCC. Compared with the HBsAg-positive HCC controls, occult HBV-infected HCC patients had higher frequencies of M1I and Q2K in pre-S2 gene, G185R and S210N in surface gene, A36T and A44L in X gene, and G1721A in enhancer II gene, and had lower rates of pre-S deletions and A1762T/G1764A, A1846T, G1896A and G1899A in core promoter/precore genes. Multivariate analysis showed Q2K in pre-S2 gene, G1721A and A1846T were independent factors for occult HBV-infected HCC. Our study suggested that the virological factors of HBV related to HCC were different between occult HBV-infected and HBsAg-positive patients. The G1721A, M1I and Q2K in pre-S2 gene may be useful viral markers for HCC in occult HBV carriers.

Wang JH, Changchien CS, Hung CH, Eng HL, Tung WC, Kee KM, Chen CH, Hu TH, Lee CM, Lu SN. · Department of Internal Medicine, Division of Hepato-Gastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Niao Sung, Kaohsiung, Taiwan. · J Gastroenterol. · Pubmed #19308312 No free full text.

Abstract: BACKGROUND: The aim of this study was to assess the diagnostic performances of liver stiffness measurement (LSM), ultrasonography (US) and their combined use in predicting the extent of hepatic fibrosis. METHODS: Consecutive patients with chronic hepatitis B (HBV) or hepatitis C virus (HCV) infections, with indications for liver biopsy, were prospectively enrolled. LSM was performed on the same day as biopsy. US scores, including assessment of liver surface, liver parenchyma, intrahepatic vessels and spleen index, were used to assess the degree of hepatic fibrosis. The pathological findings were used as a reference standard and diagnostic accuracy was assessed and compared. RESULTS: Three-hundred and twenty patients, including 199 men and 121 women, with a mean age of 50.8 years, were analyzed. There were 214 (66.9%) HCV patients, 88 (27.5%) HBV patients and 18 (5.6%) patients with both HCV and HBV. LSM correlated significantly with the hepatic fibrosis (F) scores, necro-inflammatory activity and US scores in multivariate analysis. The diagnostic accuracy of LSM is significantly superior to US, and equal to combined LSM with US, in the prediction of all HCV-related fibrosis scores. The cut-off value of LSM is 6 kPa for diagnosing F > =1, with a positive predictive value of 91%. Also, the cut-off value is 12 kPa for the prediction of cirrhosis, with a negative predictive value of 94%. CONCLUSIONS: LSM is useful for predicting hepatic fibrosis and excluding cirrhosis. A combination of LSM and US does not improve the accuracy in assessing hepatic fibrosis.

Tai WC, Hu TH, Wang JH, Hung CH, Lu SN, Changchien CS, Lee CM. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · J Formos Med Assoc. · Pubmed #19293036 links to  free full text

Abstract: BACKGROUND/PURPOSE: Chronic hepatitis C (CHC) shows a significant association with cirrhosis and hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is important in the diagnosis of HCC, but elevated AFP levels have also been observed in CHC without HCC. We evaluated the clinical correlation between elevated AFP levels and CHC. METHODS: From April 1999 to November 2004, 654 CHC patients with no evidence of HCC from imaging studies were collected by chart review. RESULTS: The prevalence of elevated AFP levels (>or= 15 ng/mL) was 23.9%. Univariate analysis revealed that age, histological activity index (HAI) fibrosis score of 3/4, HAI inflammation score >or= 7, aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, AST/ALT ratio, and total bilirubin level were associated with elevated AFP levels. Multivariate analysis revealed that age (>or= 55 vs. < 55 years), HAI inflammation score (>or= 7 vs. < 7), ALT (> 150 vs. <or= 150 U/L), and platelet count (<or= 150 x 109 vs. > 150 x 109 cells/L) were associated with elevated AFP levels. Multivariate analysis also revealed that hepatitis C virus (HCV) genotype 1b, platelet count <or= 150 x 109 cells/L, AST > 80 U/L and AFP >or= 6 ng/mL were associated with advanced fibrosis. Using a cut-off AFP level of >or= 6.0 ng/mL, the sensitivity and specificity of diagnosing fibrosis score 3/4 was 74.3% and 68.4%, respectively. Using a cut-off AFP level of >or= 15.0 ng/mL, the sensitivity and specificity of diagnosing fibrosis score 3/4 was 35.7% and 91.1%, respectively. Conclusion: Elevated AFP levels were observed in 23.9% of patients with CHC. Elevated AFP levels correlated positively with age, HAI inflammation score, ALT elevation, and thrombocytopenia. In addition, HCV genotype 1b, thrombocytopenia, AST elevation, and AFP level >or= 6 ng/mL were associated with advanced fibrosis.

Tsai MC, Chen CH, Lee CM, Chen YT, Chien YS, Hung CH, Wang JH, Lu SN, Yen YH, Changchien CS, Hu TH. · Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 833, Taiwan. · J Hepatol. · Pubmed #19070392 No free full text.

Abstract: BACKGROUND/AIMS: In renal transplant recipients (RTRs), chronic hepatitis B virus (HBV) infection may lead to poor outcomes. This study aimed to investigate the role of the HBV genotype, core promoter and precore mutations in advanced liver disease in RTRs. METHODS: We retrospectively reviewed 51 RTRs positive for hepatitis B surface antigen (HBsAg). HBV genotype determination and direct sequencing of core promoter and precore regions were performed using the baseline and end-of-follow-up sera post-renal transplantation. RESULTS: Alanine Transaminase (ALT) and HBV DNA levels were elevated after transplantation (66%). HBV genotypes B and C were found in 45 (88%) and 6 (12%) patients, respectively. There was no significant association of cirrhosis development with ALT, and hepatitis B-e antigen (HBeAg) levels, type of immunosuppressant, HBV genotype, T1762/A1764 and A1896 mutations, and duration of follow-up, except endpoint HBV DNA levels (> or =10(5)copies/ml). High T1762/A1764 mutation rates were associated with high HBV DNA levels (P=0.036) at the endpoint. CONCLUSIONS: HBV DNA replication was enhanced in RTRs with T1762/A1764 mutation. Increased serum HBV DNA levels were associated with cirrhosis development. T1762/A1764 mutation and cirrhosis development did not show significant correlation because of small sample size and/or interventional anti-viral therapies during follow-up.

Chen CH, Changchien CS, Lee CM, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan. · J Infect Dis. · Pubmed #18939932 No free full text.

Abstract: BACKGROUND: We sought to investigate the role of sequence variations in pre-S/surface and basal core promoter (BCP)/precore regions of the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC). METHODS: The direct sequencing in pre-S/surface and BCP/precore regions of HBV was determined for 80 patients with HCC and 160 control patients with HBV infection. RESULTS: Compared with control patients, patients with HCC had higher frequencies of pre-S deletions and amino acid substitutions at codon 4, 7, and 81 in pre-S1 genes; at the start codon in pre-S2 genes; and at codon 68 in surface genes. Patients also had a lower frequency of amino acid substitution at codon 2 in pre-S2 genes, compared with control patients. In BCP/precore regions, patients with HCC had higher frequencies of C or G1753, A1762/T1764, T1846, and A1899. Multivariate analysis showed that pre-S deletions, I68T surface gene, T1762/A1764, and A1899 were independent factors associated with the development of HCC. The HBV strain with a complex mutation pattern rather than a single mutation was associated with HCC, and the HCC risks increased for patients having these factors in combination. CONCLUSIONS: Pre-S deletions, I68T in surface gene, T1762/A1764, and A1899 were independent risk factors for HCC. Combination of these viral mutations appeared to increase the risk of HCC.

Tseng PL, Tai MH, Huang CC, Wang CC, Lin JW, Hung CH, Chen CH, Wang JH, Lu SN, Lee CM, Changchien CS, Hu TH. · Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · J Surg Oncol. · Pubmed #18646041 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: To elucidate the clinicopathological correlations among vascular endothelial growth factor (VEGF), microvessel density (MVD) and tumor suppressor gene p53 in hepatocellular carcinomas (HCCs), we adopted a new definition of "VEGF overexpression." METHODS: The expressions of VEGF, MVD, and p53 in 113 HCC specimens were analyzed by immunohistochemistry. RESULTS: VEGF expression in surrounding liver tended to be stronger (VEGF overexpression, 31%) than, or similar to (57%) that in HCCs (P = 0.001). P53 positivity was noted in 42 cases (37.1%). MVD ranged from 22 to 201 microvessels/field determined for 5 high-power fields. VEGF expression in HCCs was positively correlated with MVD (P = 0.001). VEGF overexpression is positively correlated with young age (P = 0.008), male gender (P = 0.01), hepatitis B viremia (P = 0.013), high alpha-fetoprotein levels (P < 0.001), p53 (+) (P = 0.036), advanced-stage HCC (P = 0.015), and HCC dedifferentiation (P = 0.004). Survival analyses indicated that VEGF overexpression, high MVD, and advanced-stage HCC were independent poor prognostic factors for disease-free and overall survival. CONCLUSION: This study provides evidence of a positive association between parameters reflective of angiogenesis, and p53 expression in HCCs. VEGF overexpression exhibited a significant correlation with viremia and survival.

Hung CH, Lu SN, Wang JH, Hung SF, Chen CH, Hu TH, Lee CM, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung 833, Kaohsiung, Taiwan. · J Infect. · Pubmed #18346790 No free full text.

Abstract: OBJECTIVE: Diagnosis of acute hepatitis C (AHC) relies on documented positive-seroconversion of antibody to hepatitis C virus (anti-HCV) that is infrequently encountered. To clarify the epidemiology and clinical course of AHC, we tried to find more AHC patients from a computerized laboratory database by using a supplemental criterion of rising anti-HCV titer. METHODS: All the computerized laboratory databases of anti-HCV and alanine aminotransferase (ALT) were reviewed. Candidates for AHC were identified by either anti-HCV positive seroconversion, rise of anti-HCV titer (signal to cut-off ratio (S/CO) ratio < 40 to > or = 40), or spontaneous HCV RNA clearance. AHC cases and their matched chronic hepatitis C controls were interviewed by a case-control study concerning risk factors. RESULTS: AHC was identified in 123 patients (68 men and 55 women; median age: 48.4+/-13.9 years), who had higher rates of recent surgery (p=0.037) and frequent injection therapy (p=0.036) compared to controls. Self-limited AHC was observed in 18 (19.1%, 95% confidence interval: 12.3-25.9%) of 94 AHC patients who had been followed for 6 months, with a higher bilirubin level (> or = 2 vs. < 2, p=0.007) compared to those evolved to chronic infection. CONCLUSIONS: Screening of a laboratory database for anti-HCV and ALT might uncover more AHC candidates to disclose the epidemiology and clinical course of AHC.

Wang JH, Changchien CS, Hu TH, Lee CM, Kee KM, Lin CY, Chen CL, Chen TY, Huang YJ, Lu SN. · Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. · Eur J Cancer. · Pubmed #18337087 No free full text.

Abstract: The Barcelona Clinic Liver Cancer (BCLC) staging offers prognostic stratification and treatment allocation for hepatocellular carcinoma (HCC). We conducted this retrospective study to assess the efficacy of different treatment options for patients with initial HCC diagnosis. Survival rate and median survival times associated with different treatment options in each stage of BCLC classification were compared using the Kaplan-Meier method and log-rank test. A total of 3892 patients were enrolled. Overall survival rates were 46.2% at 1 year and 16.6% at 5 years. The median survival times decreased from 57.7 months in very early stage to 1.6 months in terminal stage. Surgical resection offered the best survival benefit for patients in very early, early and even intermediate stages. Transarterial embolisation and conformal radiotherapy offered survival benefits for selected patients in advanced and terminal stages. In conclusion, following the treatment schedules allocated by BCLC staging had survival benefits for HCC patients.

Changchien CS, Chen CL, Yen YH, Wang JH, Hu TH, Lee CM, Wang CC, Cheng YF, Huang YJ, Lin CY, Lu SN. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University of Medicine, 123 Tapei Rd., Niaosung, 833, Kaohsiung, Taiwan. · J Gastroenterol. · Pubmed #18306990 No free full text.

Abstract: BACKGROUND: This hospital-based analysis was conducted to identify prognostic factors of hepatocellular carcinoma (HCC) in a hepatitis B virus endemic area. METHODS: A total of 6381 HCC cases, diagnosed from 1986 to 2002, were enrolled, and 2890 (42.3%) of them were not treated. Survival rates were analyzed by correlation with the national mortality databank. Missing data and correlations among prognostic factors were considered in the analysis. RESULTS: The overall 1-year, 3-year, 5-year, and 7-year survival rates were 44.3%, 24.9%, 17.1%, and 13%, respectively. Multivariate analysis revealed that the independent factors influencing survival were the initial treatment modality, degree of liver function impairment, hepatitis B surface antigen positivity, tumor status, and alpha-fetoprotein. Besides these well-known prognostic factors, high alanine aminotransferase (ALT) levels and a high aspartate aminotransferase (AST)/ALT ratio were identified as independent poor prognostic factors. CONCLUSIONS: This study, which considered untreated cases, missing data, and correlations between variables and official survival data sets, provides a large-scale comprehensive survival analysis. According to our results, high ALT and high AST/ALT were independent poor prognostic factors. Therefore, viral activity should be controlled in HCC patients, and patients with elevated AST/ALT ratios should be carefully monitored.

Hung CH, Lee CM, Kuo FY, Jiang SR, Hu TH, Chen CH, Wang JH, Lu SN, Eng HL, Changchien CS. · Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Liver Int. · Pubmed #18290776 No free full text.

Abstract: BACKGROUND: Steatosis is recognized as a predictor of the severity as well as the progression of fibrosis in chronic hepatitis C. The mechanisms that cause increased hepatocellular injury associated with steatosis remain largely unknown. METHODS: We studied the correlation of hepatic expression of death receptors: Fas and tumour necrosis factor-alpha receptor 1 (TNF-R1), and downstream caspase (caspase-3) with hepatic steatosis by immunohistochemical study in chronic hepatitis C and determined the role of nuclear factor-kappaB (NF-kappaB). RESULTS: Ninety patients (49 males and 41 females, mean age of 50.5 +/- 10.4 years, genotype 1 or 2) with chronic hepatitis C virus infection were recruited. The factors associated with steatosis grade were body mass index (P=0.004) and fibrosis stage (P=0.034). Moderate/severe steatosis was an independent variable associated with advanced fibrosis stage by stepwise logistic regression analysis. The expression of immunoreactivity for Fas, TNF-R1 and active caspases-3 in liver tissues was significantly correlated with the steatosis grade (P<0.001, P<0.001 and P<0.001 respectively). The extent of active caspases-3 correlated significantly with the expression of Fas (r=0.659, P<0.001) and TNF-R1 (r=0.617, P<0.001). NF-kappaB p65 expression correlated significantly with the extent of Fas (r=0.405, P<0.001), TNF-R1 (r=0.448, P=0.002) and active caspase-3 (r=0.313, P=0.003), and correlated with steatosis grade (P<0.001) but not with inflammatory and fibrosis scores. CONCLUSION: Our observations suggest a mechanism whereby steatosis contributes to the progression of liver injury in chronic hepatitis C through upregulation of death receptors and activation of NF-kappaB.

Chen CH, Wang MH, Wang JH, Hung CH, Hu TH, Lee SC, Tung HD, Lee CM, Changchien CS, Chen PF, Hsu MC, Lu SN. · Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan. · Am J Trop Med Hyg. · Pubmed #17978082 links to  free full text

Abstract: This community-based study evaluated the role of aflatoxin exposure in advanced liver disease in hepatitis C virus (HCV)-endemic townships. Preventive health examination was performed on 314 adults > or = 40 years of age recruited from HCV-endemic townships in Tainan, Taiwan. Aflatoxin-albumin in serum was quantified by a new enzyme-linked immunosorbent assay method. After adjusting serum albumin levels and platelet counts, aflatoxin-Bi albumin adducts was still an independent risk factor for advanced liver disease among all 314 residents (> 8 versus < or = 8 (AFBi)-albumin/albumin; OR = 2.29, 95% CI = 1.23-4.27, P = 0.009) and particularly in anti-HCV-positive subjects (OR = 2.09, 95% CI = 1.09-4.0, P = 0.026). Levels of AFB1-albumin/albumin were significantly related to ultrasonographic parenchyma scores (P < 0.001, one-way ANOVA) in all and anti-HCV-positive subjects. The findings indicated aflatoxin exposure may be associated with advanced liver disease in chronic hepatitis C patients in HCV-endemic regions in Taiwan.

Chen CH, Hung CH, Lee CM, Hu TH, Wang JH, Wang JC, Lu SN, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan. · Gastroenterology. · Pubmed #17915220 No free full text.

Abstract: BACKGROUND & AIMS: This longitudinal study investigated the interactions and roles of hepatitis B virus (HBV) genotypes, pre-S deletions, and core promoter and precore mutations on the progression of liver disease in hepatitis B e antigen (HBeAg)-negative patients. METHODS: A total of 141 HBeAg-negative patients without liver cirrhosis or hepatocellular carcinoma at study entry were recruited for this study, including 45 inactive HBV carriers and 96 patients with HBeAg-negative chronic hepatitis B. The HBV genotypes and the sequences of pre-S, core promoter, and precore regions were determined. RESULTS: Compared with patients without developing liver cirrhosis, patients with the development of liver cirrhosis had higher rates of genotype C; pre-S deletions; C or G1753, T1762/A1764, T1766, and/or A1768 mutants; and G1799 variant. Cox regression analysis showed that older age, higher total bilirubin and HBV DNA levels, pre-S deletions, and T1766 and/or A1768 mutants were significantly associated with the development of liver cirrhosis. HBV with a complex mutation pattern (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutants) rather than a single mutation was associated with the development of liver cirrhosis, and the patterns of mutation combinations differed between HBV genotype B and C. Moreover, pre-S deletion was a significant risk factor for hepatocellular carcinoma. CONCLUSIONS: This study indicated that pre-S deletion and combined mutations of HBV are useful molecular markers for predicting the clinical outcomes of HBeAg-negative patients.

Chen CH, Lee CM, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN, Changchien CS. · Division of Hepatogastroenterology, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Liver Int. · Pubmed #17617124 No free full text.

Abstract: BACKGROUND/AIMS: The aims of this longitudinal study were to investigate whether the clinical outcome and evolution of core promoter and precore mutations were different during hepatitis B e antigen (HBeAg) seroconversion between hepatitis B virus (HBV) genotypes B and C in HBeAg-positive patients with chronic hepatitis B. PATIENTS AND METHODS: The core promoter and precore sequences were determined from serial sera of 156 HBeAg-positive patients with chronic HBV infection. RESULTS: In HBV genotype C, the T1762/A1764 mutant was detected earlier than the A1896 mutant, and the frequency was significantly higher than in HBV genotype Ba over the entire follow-up period. In HBV genotype Ba, A1896 was found earlier than the T1762/A1764 mutant, and the frequency was significantly higher than in genotype C only before HBeAg seroconversion, and the A1896 mutant played an important role in HBeAg seroconversion in HBV genotype Ba. In addition, the T1846 variant was an independent factor associated with HBeAg seroconversion. Furthermore, HBV genotype C was associated with the development of G or C1753 and T1766/A1768 mutations, and the reactivation of hepatitis after HBeAg seroconversion. Based on Cox's regression analysis, the significant risk factors of liver cirrhosis were older age at entry [hazard ratio (HR)=1.085, 95% confidence interval (CI)=1.036-1.136, P=0.001], alanine transaminase (ALT) >80 U/l (HR=3.48, 95% CI=1.37-8.86, P=0.009), and the T1762/A1764 mutant (HR=5.54, 95% CI=2.18-14.08, P<0.001). CONCLUSIONS: Our study showed that different HBV genotypes were associated with various mutations in the core promoter and precore regions during HBeAg seroconversion. T1762/A1764 mutation could be useful in predicting clinical outcomes in HBeAg-positive patients with HBV infection.

Hung CH, Lee CM, Lu SN, Wang JH, Chen CH, Hu TH, Kee KM, Chang KC, Tseng PL, Yen YH, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Liver Int. · Pubmed #17032408 No free full text.

Abstract: BACKGROUND: One major side effect of combination antiviral therapy is the development of anemia, which is more severe among the Asian population. We conducted this large-scaled study to explore the incidence, risk factors, and impact on treatment response of anemia in chronic hepatitis C patients receiving combination antiviral therapy. METHODS: Four hundred and sixty-six chronic hepatitis C patients were treated with interferon-alpha-2b (IFN-alpha-2b) three or five million units thrice weekly, or pegylated-IFN-alpha-2b 1-1.5 microg/kg weekly plus ribavirin (1000-1200 mg/day) for 24 weeks. Severe anemia was defined as hemoglobin concentration <10 g/dl. RESULTS: The mean decrease of hemoglobin was 3.9+/-1.3 g/dl. Thirty-nine percent of patients had developed severe anemia during therapy. Stepwise logistic regression analysis revealed that old age (> or =50 years) (odds ratio [OR]=1.935, P=0.001) and baseline hemoglobin level (> or =14 g/dl) (OR=2.975, P<0.001) were significantly correlated with maximal decreases in hemoglobin. Using Cox's regression analysis, pretreatment platelet counts (<150 000/mm(3)) (OR=1.821, P<0.001), old age (> or =50 years) (OR=1.789, P=0.001), female gender (OR=1.739, P<0.001), and low body weight (<65 kg) (OR=1.493, P=0.027) were independent factors contributing to severe anemia. There was a significant linear correlation between the sustained virological response (SVR) rate and the time of severe anemia during therapy (r=0.774, P=0.003), especially among genotype 1 patients (r=0.960, P<0.001). CONCLUSION: Careful monitoring of hemoglobin level is necessary in patients who are old, female and have low body weight and platelet counts. Development of severe anemia was significantly correlated with the SVR.

Lu SN, Wang JH, Liu SL, Hung CH, Chen CH, Tung HD, Chen TM, Huang WS, Lee CM, Chen CC, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · Cancer. · Pubmed #17019738 links to  free full text

Abstract: BACKGROUND: The objective of this study was to examine the usefulness of platelet counts in the diagnosis of cirrhosis and for identifying high-risk individuals in a community-based hepatocellular carcinoma (HCC) screening program. METHODS: Pilot Study 1 determined the correlation between platelet counts and pathologic hepatic fibrosis scores among individuals with chronic hepatitis B virus (HBV) infection (n = 122 patients) and hepatitis C virus (HCV) infection (n = 244 patients). Pilot Study 2 investigated proportions of individuals with thrombocytopenia (<150 x 10(3)/mm(3)) among patients with HCC (n = 4042 patients). Pilot Study 3 demonstrated the correlation between platelet counts and ultrasonographic (US) parenchyma scores among anti-HCV-positive individuals (n = 75 patients). The core study was a 2-stage, community-based screening for HCC among residents age 40 years or older in townships with a high prevalence of anti-HCV (n = 4616 individuals) and in townships with a low prevalence of anti-HCV (n = 1694 individuals). Patients with thrombocytopenia were identified for US and alpha-fetoprotein screening. RESULTS: Among the individuals who were positive for anti-HCV, platelet counts decreased according to increased pathologic fibrosis scores or US scores for liver parenchyma disease: The best cutoff platelet count was 150 x 10(3)/mm(3) for a diagnosis of cirrhosis. The sensitivity and specificity were 68.2% and 76.4%, respectively, for pathologic cirrhosis and 76.2% and 87.8%, respectively, for US cirrhosis. Forty-eight percent of patients with HCC were thrombocytopenic. The proportion of thrombocytopenia was significantly greater in patients with HCV-related HCC (63%) than in patients with HBV-related HCC (42%). In the townships with high and low anti-HCV prevalence, the prevalence of thrombocytopenia was 17.9% and 6.1%, respectively, (P < .001), respectively. Twenty-five patients were diagnosed with HCC, and all of those patients resided in the high-prevalence township. CONCLUSIONS: Thrombocytopenia was a valid surrogate of cirrhosis and a valid marker for the identification of individuals at high-risk for HCC, especially in areas that had a high prevalence of HCV.