Levels and values of circulating endothelial progenitor cells, soluble angiogenic factors, and mononuclear cell apoptosis in liver cirrhosis patients.

BACKGROUND: The roles of circulating endothelial progenitor cell (EPC) and mononuclear cell apoptosis (MCA) in liver cirrhosis (LC) patients are unknown. Moreover, vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α are powerful endogenous substances enhancing EPC migration into circulation. We assessed the level and function of EPCs [CD31/CD34 (E(1)), KDR/CD34 (E(2)), CXCR4/CD34 (E(3))], levels of MCA, VEGF and SDF-1α in circulation of LC patients. METHODS: Blood sample was prospectively collected once for assessing EPC level and function, MCA, and plasma levels of VEGF and SDF-1α using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, in 78 LC patients and 25 age- and gender-matched healthy controls. RESULTS: Number of EPCs (E(1), E(2), E(3)) was lower (all p < 0.0001), whereas SDF-1α level and MCA were higher (p < 0.001) in study patients compared with healthy controls. Number of EPCs (E(2), E(3)) was higher but MCA was lower (all p < 0.05) in Child's class A compared with Child's class B and C patients, although no difference in VEGF and SDF-1α levels were noted among these patients. Chronic hepatitis B and esophageal varices bleeding were independently, whereas chronic hepatitis C, elevated aspartate aminotransferase (AST), and decompensated LC were inversely and independently correlated with circulating EPC level (all p < 0.03). Additionally, angiogenesis and transwell migratory ability of EPCs were reduced in LC patients than in controls (all p < 0.001). CONCLUSION: The results of this study demonstrated that level, angiogenic capacity, and function of circulating EPCs were significantly reduced, whereas plasma levels of SDF-1α and circulating MCA were substantially enhanced in cirrhotic patients.

A comparison of telbivudine and entecavir for chronic hepatitis B in real-world clinical practice.

OBJECTIVES: To evaluate the efficacy of telbivudine and entecavir in chronic hepatitis B (CHB) patients over a 1 year period. METHODS: Ninety-seven telbivudine-naive and 98 entecavir-naive CHB patients who had been treated for at least 1 year were enrolled. Serial serum hepatitis B virus (HBV) DNA levels were checked at baseline and at weeks 24 and 48 after treatment. RESULTS: Entecavir and telbivudine groups had similar baseline HBV DNA levels (5.9 ± 1.7 versus 6.0 ± 1.5 log copies/mL, P=0.529). The undetectable rate of HBV DNA after 1 year of treatment was significantly higher in the entecavir group than the telbivudine group (94.9% versus 82.0%, P=0.009). Resistance developed in 6.7% of the telbivudine-naive patients after 1 year compared with none of the entecavir-naive patients (P=0.009). However, there was a significant difference between the telbivudine and entecavir groups in hepatitis B e antigen (HBeAg) seroconversion 24 weeks after treatment (40% versus 12.5%, P=0.007). Multiple logistic regression analysis revealed that baseline alanine aminotransferase (ALT) >200 IU/L (P=0.008) was independently associated with HBeAg seroconversion. Applying the roadmap concept with ALT >2× upper limit of normal at baseline, telbivudine and entecavir had favourable outcomes in PCR negativity, ALT normalization, HBeAg seroconversion and resistance. CONCLUSIONS: In real-world clinical practice, telbivudine resulted in higher rates of HBeAg seroconversion and drug resistance at week 48 compared with entecavir. A combination with baseline ALT plus 24 week HBV DNA levels led to the lowest rates of resistance in HBeAg-positive telbivudine-naive patients and had the highest probability of HBeAg seroconversion in both entecavir- and telbivudine-naive patients.

Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan.

AIM: The aim of the present study was to assess the changes of liver stiffness (LS) and its associated factors in patients with chronic hepatitis C virus infection (HCV) after interferon (IFN)-based therapy. METHODS: Patients with chronic HCV who had previously undergone at least 20 weeks of IFN-based therapy were enrolled. The patients' initial LS measurement was taken at the time of enrollment, and a second LS measurement was made after an interval of at least 38 weeks. LS measurement was carried out with FibroScan, and changes of LS and its associated factors were analyzed. RESULTS: One hundred and forty-four patients, including 95 sustained virological response (SVR) patients and 49 non-sustained virological response (NSVR) patients, were enrolled. There was a significant decrease of LS among SVR patients (median, 0.6; P < 0.001). NSVR patients showed an increase of LS (median, 0.8; P = 0.557). For SVR patients, a high initial LS was the predictive factor of a rapid reduction of LS values. However, advanced fibrosis stage before therapy, higher body mass index (BMI) and longer time remission were predictive factors for slow reduction of LS values. CONCLUSIONS: LS decreases in sustained responders following IFN-based therapy in patients with chronic HCV. Advanced fibrosis, higher BMI, longer time for remission and lower initial LS value are predictive factors for a slow improvement of LS in sustained responders.

Evolution of full-length HBV sequences in chronic hepatitis B patients with sequential lamivudine and adefovir dipivoxil resistance.

BACKGROUND & AIMS: The aim of this study was to determine the evolution of full-length hepatitis B virus (HBV) sequences in chronic hepatitis B (CHB) patients with sequential lamivudine (LAM) and adefovir (ADV) resistance. METHODS: The full-length genomes of HBV were sequenced from 11 CHB patients before LAM treatment and at the emergence of LAM- and ADV-resistant HBV. RESULTS: Besides the known LAM-resistant polymerase gene mutations, 10 of 11 patients who had LAM-resistant HBV variants had additional amino acid changes in the reverse transcriptase (RT) domain, and ADV therapy reversed these additional changes to pre-LAM therapy status. Furthermore, new amino acid changes in the RT domain, distinct from the known ADV-resistant HBV variants, were selected at the emergence of ADV resistance in six of 11 patients. Seven patients had amino acid changes within the known T-cell or B-cell epitopes of HBV surface and core antigens at the emergence of LAM and/or ADV resistance. The frequency of pre-S deletions between nucleotide 3037-56 was higher at the emergence of ADV resistance compared with that at the emergence of LAM resistance (7/11 vs. 1/11; p=0.024). Combined LAM-ADV resistance was detected in one of 11 patients. This patient had resistant mutations to both drugs on the same viral genome by molecular cloning (5/24 polymerase gene clones). CONCLUSIONS: In addition to the known LAM- and ADV-resistant mutations accompanying the emergence of LAM and ADV resistance, the changes of nucleotide or amino acid sequences occurred commonly in the HBV surface antigen or RT domain and were scattered along the full-length HBV genomes.

A study on sequence variations in pre-S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan.

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.

FibroScan and ultrasonography in the prediction of hepatic fibrosis in patients with chronic viral hepatitis.

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.

Incidence of needle tract seeding and responses of soft tissue metastasis by hepatocellular carcinoma postradiotherapy.

AIM: To determine the incidence of needle tract seeding after fine needle aspiration (FNA) or percutaneous ethanol injection (PEI) and compare iatrogenic or spontaneous soft tissue metastasis (STM) by hepatocellular carcinoma (HCC) postradiotherapy (RT) in responses. METHODS: From November 1997 to January 2006, those who presented with STM by HCC after our invasive procedures or developed spontaneously were enrolled into this retrospective study. Metastatic lesions could be divided into procedure related (PR), which were located at the liver span and were related to invasive procedures, and non-procedure related (NPR), which were in extrahepatic areas. STM was treated with an electron or photon beam. RESULTS: A total of 39 HCC cases with developed STM were referred for RT, including 17 in the PR group and 22 in the NPR group. During the same period, a total of 18,227 person-times of FNA or PEI were performed on these HCC patients. The overall incidence of HCC with STM that was caused by invasive procedures was estimated at 0.13%. According to the Cox' regression model, the initial treatment modality influences the time duration after the initial diagnosis of HCC when STM has not occurred. None of these patients' soft tissue tumor increased in size during RT. The PR group had lower rates of bone metastasis (P=0.003) and coexisting extrahepatic metastasis (P=0.011) and a longer survival rate (P=0.003) than the NPR group. The estimated rates of 18-gauge and 22-gauge needle-induced HCC-related STM were 0.60% and 0.11%, respectively (P=0.064). CONCLUSION: The PR group bears a better prognosis than the NPR group post-RT.

Hepatitis C virus genotypes in southern Taiwan: prevalence and clinical implications.

The role of hepatitis C virus (HCV) genotypes in the development of hepatocellular carcinoma (HCC) is still controversial. To determine the distribution and clinical implications of HCV genotypes in southern Taiwan, we analysed 418 patients with chronic HCV infections. HCV genotypes were determined using an HCV Line Probe Assay. The predominant HCV genotype was 1b (45.5%), followed by 2a/2c (30.9%) and 2b (6.9%). The prevalence of genotype 1b in HCC patients (60.3%) was significantly higher than in those with liver cirrhosis (38.7%) and chronic hepatitis (38.7%) (P=0.003 and P<0.001, respectively). Patients with chronic HCV 2a/2c infection had higher alanine aminotransferase (ALT) levels than those with chronic HCV 1b infection (P<0.001). Univariate analysis revealed that disease severity was significantly correlated with older age, genotype 1b, lower ALT levels and lower viral load. Based on multiple logistic regression analysis, after adjusting for age and serum HCV RNA levels, HCV 1b infection was still a significant risk factor for HCC. In conclusion, the predominant genotypes in southern Taiwan were 1b and 2a/2c, and disease severity was associated with genotype 1b.

Comparison of prevalence for paraumbilical vein patency in patients with viral and alcoholic liver cirrhosis.

OBJECTIVES: The patent paraumbilical vein (PUV) is a venous collateral that is often found in patients with cirrhosis and portal hypertension. It can be effectively demonstrated by conventional ultrasonography (US). We conducted this prospective study to elucidate the prevalence and etiology of PUV patency for cirrhotic patients. METHODS: From August, 1997, to July, 1998, one of the authors (S.-N.L.) observed PUV patency for all cirrhotic patients during routine upper abdominal US examination. All cirrhotic patients diagnosed with portal hypertension were further analyzed. Portal hypertension was diagnosed by sonographic evidence of splenomegaly or ascites, or endoscopic varices. Cases presenting with hepatocellular carcinoma and sonographic evidence of prehepatic portal hypertension were excluded. Once a PUV patency with a diameter of > or = 3 mm was suspected based on conventional US, it was confirmed by color Doppler US. Of the 493 cirrhotic patients examined, 252 with portal hypertension and without hepatoma were enrolled in this study. RESULTS: Significant PUV patency was detected in 11.1% of the enrolled patients (28 of 252). With univariate analysis, a significantly higher prevalence was demonstrated for alcoholic patients (p < 0.0001), whereas prevalence was relatively low for those with chronic hepatitis B or C infection (p = 0.0159). A trend toward increased prevalence was noted with Child-Pugh classification (p = 0.001). Furthermore, a higher prevalence was noted in younger cirrhotic patients (p = 0.0037). Alcoholism was still a significant factor despite adjustment of Child-Pugh classification using multiple logistic regression, (OR = 3.88, 95% CI = 1.34-8.55). CONCLUSION: A significantly higher prevalence of PUV patency was demonstrated for patients with alcohol-induced liver cirrhosis in comparison to those with postviral cirrhosis.