Showing papers by "Kwang Hyub Han published in 2008"

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Abstract: Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon α2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier “Asian-Pacific consensus statement on the management of chronic hepatitis B” was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.

Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis.

Abstract: BACKGROUND. Patients with advanced hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have a particularly grave prognosis. In the current study, an attempt was made to localize chemoradiation therapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in patients with locally advanced HCC with PVT and good reserve liver function. The objective of the current study was to evaluate the therapeutic effect of localized CCRT followed by HAIC as a new treatment modality for these patients. METHODS. Between January 1998 and December 2003, 40 patients were recruited. Concurrent regional chemotherapy using an intra-arterial implanted port plus localized external beam radiotherapy was performed with a total of 45 gray (Gy) over 5 weeks with conventional fractionation and hepatic arterial infusion of 5-fluorouracil (5-FU), which was administered during the first and fifth weeks of radiotherapy. One month after localized CCRT, HAIC with 5-FU and cisplatin was administered every 4 weeks. RESULTS. One month after localized CCRT, an objective response was observed on the intention-to-treat analysis in 18 of 40 patients (45%). The actuarial 3-year overall survival rate was 24.1% and the median survival time was 13.1 months from the start of radiation treatment. Responders after localized CCRT demonstrated significantly better survival (P = .033) than nonresponders. CONCLUSIONS. The substantial response rate as well as median survival time noted in the current study encourages the use of this new approach in patients with locally advanced HCC with PVT. Cancer 2008. © 2008 American Cancer Society.

MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Abstract: A single-nucleotide polymorphism (SNP) in the promoter region of MDM2, SNP 309, is associated with hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus infection. The effect of p53 codon 72 polymorphism Arg72Pro on HCC risk remains inconsistent. This study evaluated the association of MDM2 and p53 polymorphisms with the presence and early onset of HCC in Korean patients with chronic hepatitis B virus (HBV) infection. In total, 583 consecutive patients with chronic HBV infection were classified according to the presence (n = 287) or absence (n = 296) of HCC. The MDM2 SNP 309 and p53 Arg72Pro were genotyped using restriction fragment length polymorphism method. The MDM2 G/G and p53 Pro/Pro genotypes were more frequent in HCC group than in non-HCC group (P < 0.001 and P = 0.004, respectively). Multivariate analysis for the presence of HCC revealed that the odds ratio (OR) for MDM2 G/G over T/T was 4.89 (P < 0.001) and that of p53 Pro/Pro over Arg/Arg was 3.03 (P = 0.006). Combined MDM2 G/G and p53 Pro/Pro had a synergistic effect on HCC risk, with an OR of 20.78 (P < 0.001). The mean age of tumor onset in patients with MDM2 G/G genotype was 50.9 years compared with 55.1 with T/T genotype (P = 0.018) and that with p53 Pro/Pro was 49.7 years compared with 52.9 with Arg/Arg (P = 0.040). Thus, MDM2 SNP 309 and p53 Arg72Pro are associated with the early development of HCC in Korean patients with chronic HBV infection.

Prediction of microvascular invasion before curative resection of hepatocellular carcinoma

Abstract: Background The accurate staging of hepatocellular carcinoma (HCC) is important in establishing treatment strategies and prognosis. Among tumor factors, microvascular invasion, one of TNM staging components and prognostic factors, is underestimated preoperatively, due to inaccuracy of imaging modalities. We investigated preoperative predictors of microvascular invasion. Methods We reviewed 190 consecutive HCC patients given curative resection from 1999 to 2006. All were treatment-naive and monitored every 3 months after resection. Tumor recurrence, survivals, and clinicopathological factors associated with microvascular invasion were analyzed. Results The 5-year disease-free survival (DFS) rate was 39.4%(median follow-up duration: 35 months). On resection pathology, 38.9% (74/190 patients) had microvascular invasion undetected preoperatively, using liver spiral computed tomography (CT) or angiography. Independent predictors of microvascular invasion were tumor size (P = 0.043), number (P = 0.011), and Edmondson grade (P = 0.001). Patients with Edmondson grade 1 and size <5 cm had no microvascular invasion, while those with grade ≥2 had higher incidences (7/18 patients, 38.8%) even in small tumor (<2 cm). When tumors recurred, presence of microvascular invasion independently increased incidences of multiple tumors, portal vein invasion, and diffuse-infiltrative patterns significantly. Conclusions Preoperative predictors of microvascular invasion are tumor size, number, and Edmondson grade, which may be useful for making clinical decisions in both non-surgical and surgical candidates. J. Surg. Oncol. 2008;97:246–252. © 2007 Wiley-Liss, Inc.

High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels.

Abstract: Current treatment guidelines suggest that antiviral therapy be considered for chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite alanine aminotransferase (ALT) levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels. Between January 2003 and June 2006, 105 consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, had detectable serum HBV DNA (>10(5) copies/mL) in a direct hybridization assay and normal or slightly elevated serum ALT levels (≤2 × ULN) for at least 12 months were included in a prospective study. Histological assessment was based on the METAVIR scoring system. Significant histology was defined as fibrosis stage ≥F2 or necroinflammation grade ≥A2. Among the 105 CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels for at least 12 months, significant fibrosis (F2-F4 fibrosis) was observed in 63 patients (60.0%) and the actual significant histology was found in 65 patients (61.9%). On multivariate analysis, serum ALT levels and age at which they entered the study were independent factors associated with significant histology. Odds ratios for significant histology increased progressively according to serum ALT levels and age. In conclusion, a large proportion of CHB patients with genotype C, high viral load and ALT ≤2 × ULN had significant liver disease on liver biopsy and should be considered for antiviral therapy.

Hepatocellular carcinoma presenting with bone metastasis: clinical characteristics and prognostic factors

Abstract: The survival of patients with hepatocellular carcinoma (HCC) has been prolonged with improvements in various diagnostic tools and treatment modalities. Consequently, bone metastases from HCC are diagnosed more frequently. We investigated the clinical features, prognosis, treatment outcomes, and prognostic factors of HCC presenting with bone metastasis. Between June 2000 and April 2007, we recruited 37 consecutive HCC patients presenting with bone metastasis. These patients were divided into an untreated control group (n = 16) and a treated group (n = 21). The mean age of the patients was 61.1 years (male:female, 31:6). The most common cause of HCC was hepatitis B virus infection (56.8%). Twenty-two patients (59.5%) were of Child-Pugh class A and 15 (40.5%) were of Child-Pugh class B. Spinal metastasis was most common and noted in 21 patients (56.7%). The treatment modalities in the treated group included intra-arterial chemotherapy in nine patients (42.8%), systemic chemotherapy in five (23.8%), and both intra-arterial and systemic chemotherapy in seven (33.4%). The median survival of all patients was 6.2 months (range 0.7–46.6); that of untreated control group and the treated group was 2.9 (range 0.7–42.2) and 9.7 (range 0.9–46.6) months, respectively, with no significant difference (log-rank test, P = 0.081). Cox regression analysis revealed that the presence of ascites at the initial presentation was the only prognostic factor (P = 0.016). Although our study showed that locoregional and/or systemic chemotherapy did not provide significant survival prolongation compared to supportive care in patients with HCC initially accompanied by bone metastasis, a more large-scaled randomized study might be required.

Prediction of postoperative hepatic insufficiency by liver stiffness measurement (FibroScan®) before curative resection of hepatocellular carcinoma: a pilot study

Abstract: Background Liver stiffness measurement (LSM) using transient elastography (FibroScan®) reflects the degree of hepatic fibrosis This prospective study investigated how well LSM predicts the development of hepatic insufficiency after curative liver resection surgery for hepatocellular carcinoma

Epidemiology of hepatocellular carcinoma in Japan and Korea

Abstract: The worldwide burden of liver cancer has been estimated at 671,000 new cases for the year 2005. Hepatocellular carcinoma (HCC) accounts for between 85 and 90% of primary liver cancer and is one of the

New diagnostic method for liver fibrosis and cirrhosis.

Abstract: Liver fibrosis, i.e. excessive accumulation of extracellular matrix proteins, occurs in most types of chronic liver diseases. The prognosis and management of chronic liver diseases depend on the degre

Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model

Abstract: Angiotensin blockade such as with an angiotensin II receptor blocker (ARB) or angiotensinconverting enzyme inhibitor (ACEI) has antifibrotic properties. The aim of this study was to evaluate and compare the antifibrotic effect between ARBs and ACEIs. Common bile duct-ligated (BDL) adult Sprague-Dawley rats were allocated to five groups (each group, n = 8) as follows: G1, BDL without drug; G2, BDL + captopril 100 mg/kg per day; G3, BDL + ramipril 10 mg/kg per day; G4, BDL + losartan 10 mg/kg per day; G5, BDL + irbesartan 15 mg/kg per day. Four weeks post-BDL, hepatic fibrosis was analyzed histomorphologically using Batts and Ludwig scores. α-Smooth muscle actin (α-SMA) expression by immunohistochemical staining, hydroxyproline contents of liver tissue by spectrophotometry, and angiotensin receptor, collagen, procollagen, and transforming growth factor β (TGF-β) expressions were evaluated by real-time reverse transcriptase-polymerase chain reaction. Angiotensin receptor expression was also determined by Western blotting. Batts and Ludwig scores were 3.8, 2.6, 2.4, 1.8, and 1.6 in G1, G2, G3, G4, and G5, respectively. Histologically, ARB groups (G4, G5) showed significant suppression of hepatic fibrosis compared with ACEI groups or the control. Expressions of α-SMA (%) and the content of hydroxyproline (μg liver tissue) were significantly lower in ARB groups (G4, G5) than in ACEI groups (G2, G3) (P < 0.05). Also, ARB reduced the expression of angiotensin receptor, collagen, procollagen, and TGF-β1 compared with ACEI. Western blot analysis showed that the expression of angiotensin receptor was inhibited in both ARB and ACEI groups. Both ARB and ACEI attenuate hepatic fibrosis through inhibiting hepatic stellate cell activation, and the inhibitory effect of ARBs on hepatic fibrosis is superior to that of ACEIs in the BDL rat model.

Natural history of hepatitis B virus–related cirrhotic patients hospitalized to control ascites

Abstract: Background and Aim: Few studies have assessed the natural history of hepatitis B virus (HBV)–related cirrhotic ascites. We investigated the natural history of patients with HBV-related cirrhotic ascites hospitalized to control ascites and determined their prognosis, including survival rates and prognostic factors affecting survival. Methods: Between January 1996 and December 2005, 203 consecutive patients with HBV-related cirrhotic ascites were followed for a median of 80.7 months (range, 15–149) after their first significant ascitic decompensation that required hospitalization. Results: The mean age of all patients was 52.6 years. Male gender predominated (male/female, 138/65). A subgroup analysis of 165 patients who had ascitic decompensation as their first episode of hepatic decompensation revealed that gastrointestinal variceal bleeding developed after a median interval of 8 months following ascitic decompensation in 31 (18.8%) patients, hepatic encephalopathy occurred at 9 months in 53 (32.1%), spontaneous bacterial peritonitis appeared at 12.7 months in 24 (14.5%), hepatorenal syndrome occurred at 8.1 months in five (3%), and hepatocellular carcinoma was observed at 21.2 months in 10 (6.1%). The overall median survival was 12.4 months. The 1- and 3-year survival rates were 50.7 and 18.7%. The prognostic factors that independently correlated with survival at the time of ascitic decompensation were Child–Pugh classification B/C (P = 0.030), serum white blood cell (WBC; P = 0.035), serum creatinine (Cr; P = 0.039), serum sodium (Na; P = 0.010), and antiviral therapy (P = 0.040). Conclusions: The prognosis of HBV-related cirrhotic patients with ascitic decompensation is poor. Child–Pugh class, serum WBC/Cr/Na, and antiviral therapy primarily influenced survival.

Prevalence and genotype distribution of hepatitis C virus among apparently healthy individuals in Mongolia: a population-based nationwide study.

Abstract: Background and Aims: Hepatitis C virus (HCV) is one of the major causes of liver cirrhosis and hepatocellular carcinoma (HCC) in Mongolia. However, there are no data concerning nationwide prevalence of HCV infection in Mongolia. We intended to investigate the population-based prevalence of HCV infection and genotype distribution among 1512 apparently healthy individuals in this country. Methods: Between April 2003 and December 2005, sera from 1512 residents of Ulaanbaatar and 12 provinces were collected by two-stage cluster random sampling, and anti-HCV was tested. Anti-HCV-positive samples were tested for HCV RNA by reverse transcription polymerase chain reaction, and HCV genotype was determined. Results: The mean age of the subjects was 46.2±17.8 years, and 812 (53.7%) were male. Overall, the prevalence of anti-HCV was 15.6% (236/1512) and HCV RNA was detected in 167 subjects (11.0%), with the most common genotype being 1b (165/167, 98.8%). When the HCV RNA-positive subjects were categorized by decade of age, the prevalence in each age group was as follows: 2.5% in subjects ≤10 years of age, 4.5% in teens, 10.1% in 20's, 12.5% in 30's, 24.2% in 40's, 29.0% in 50's and 32.6% in subjects ≥61 years of age. The seroprevalence of anti-HCV in a risk group, nurses, was not significantly different from the general population in each decade of age (P>0.05). Conclusions: Approximately 11.0% of apparently healthy population had detectable HCV RNA in Mongolia, and the predominant genotype of HCV was 1b. Preventive and therapeutic strategies for chronic hepatitis C are urgently warranted in this HCV-endemic area.

Clinical Features and Treatment Outcomes of Upper Gastrointestinal Bleeding in Patients with Cirrhosis

Abstract: With recent progress in treatment modalities, mortality from upper gastrointestinal (UGI) bleeding has decreased appreciably. The aim of this study was to establish how UGI bleeds are managed in Korean patients with cirrhosis and to evaluate treatment outcomes. A total of 479 episodes of acute UGI bleeding in 464 patients with cirrhosis were included during a six-month period at nine tertiary medical centers. Treatment outcomes were assessed by failure to control bleeding, rebleeding and mortality. The source of bleeding was esophagogastric varices in 77.7% of patients, nonvariceal lesions in 15.9%, and undefined in 6.5%. For control of bleeding, endoscopic and pharmacologic treatments were used in 74.7% and 81.9% of patients, respectively. Variceal ligation was a major technique for endoscopic treatment (90%), and terlipressin and somatostatin were the main pharmacologic agents used (96.4%). Initial hemostasis was achieved in 86.8% of cases, but rebleeding occurred in 3.8% and 16.8% of cases within five days and six weeks of hemorrhage, respectively. Five-day and six-week mortality were 11.3% and 25.9%, respectively. Survival of patients with variceal bleeding seems to be remarkably improved than previous reports, which may suggest the advances in hemostatic methods for control of variceal hemorrhage.

Hepatic splenosis preoperatively diagnosed as hepatocellular carcinoma in a patient with chronic hepatitis B: a case report.

Abstract: We report on a case of hepatic splenosis. A 32-yr-old man underwent a splenectomy due to trauma at the age of 6. He had been diagnosed as being a chronic hepatitis B-virus carrier 16 yr prior to the surgery. The dynamic computer tomography (CT) performed due to elevated serum alpha-fetoprotein (128 ng/mL) demonstrated two hepatic nodules, which were located near the liver capsule. A nodule in Segment IVa had a slight enhancement during both the arterial and portal phases, and another nodule in Segment VI showed a slight enhancement only in the portal phases. Dynamic magnetic resonance imaging (MRI) of the mass in Segment VI showed enhanced development in the arterial phases and slight hyperintensivity to the liver parenchyma in the portal phases. These imaging findings suggested a hypervascular tumor in the liver, which could be either focal nodular hyperplasia, adenoma, or hepatocellular carcinoma (HCC). Even though these lesions were diagnosed as HCC, some of the findings were not compatible with typical HCC. On dynamic CT and MRI, all lesions showed a slight arterial enhancement and did not show early venous washout. All lesions were located near the liver capsule. These findings, along with a history of splenectomy, suggested a diagnosis of hepatic splenosis.

Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with chronic hepatitis B.

Abstract: Goals: We aimed to determine whether the presence of large liver cell dysplasia (LLCD) and/or small LCD (SLCD) in chronic hepatitis B is a risk factor for hepatocellular carcinoma (HCC) development. Background: A close relationship between LLCD/SLCD and hepatitis B virus has been observed and SLCD has been proposed to be a putative precursor of HCC, whereas the significance of LLCD is still controversial. Study: One hundred eighty-one patients with chronic hepatitis B who underwent needle liver biopsy were evaluated for the presence of LLCD/SLCD. The predictive value of LLCD/SLCD for HCC development was assessed. Results: LLCD and SLCD were present at initial biopsy in 82 (45%) and 17 (9%) patients, respectively. During the mean follow-up of 115 ± 48 months, 19 (10%) cases were diagnosed of HCC, of which 13 (76%) and 3 (17%) cases had demonstrated LLCD and SLCD, respectively, at initial evaluation. The patients with LLCD showed a significantly higher cumulative probability of HCC development than those without LLCD (P=0.016). The risk of HCC development in the presence of LLCD was approximately 3-fold, with positive and negative predictive values of 15.9% and 94.9%, respectively. The patients with SLCD showed no significant difference in cumulative probability of HCC development compared with those without (P> 0.05). Conclusions: LLCD in chronic hepatitis B is considered to be one of the risk factors for HCC development and its presence may help to identify a high-risk subgroup of patients requiring more intensive screening for HCC.

[Measurement of hepatic venous pressure gradient in liver cirrhosis: relationship with the status of cirrhosis, varices, and ascites in Korea].

Abstract: BACKGROUND/AIMS The relationships between the hepatic venous pressure gradient (HVPG) and the status of cirrhosis, complications of portal hypertension and the severity of cirrhosis are not clear. The aim of this study was to determine the relationships between HVPG and the complications or status of cirrhosis. METHODS The HVPG, gastroesophageal varices, Child-Pugh score, Model for End-Stage Liver Disease (MELD) score, presence of ascites, recent bleeding history and the status of cirrhosis were assessed in a cohort of 172 patients (156 males, 16 females) with liver cirrhosis. RESULTS The HVPG was 15.6+/-5.1 (mean+/-SD) mmHg (4-33 mmHg) and was significantly higher in patients in the decompensated stage than in those in the compensated stage (16.6+/-4.3 vs. 10.8+/-6.1 mmHg, respectively; P 0.05). HVPG was significantly higher in Child's B cirrhosis (n=87, 15.6+/-4.7 mmHg) and Child's C cirrhosis (n=36, 18.4+/-4.7 mmHg) than in Child's A cirrhosis (n=49, 13.7+/-5.1 mmHg; P<0.01). HVPG also was strongly correlated with the MELD score (P<0.01). The time required to measure the HVPG was 11.2+/-6.4 min, and only three cases of minor complication occurred during the procedure. CONCLUSIONS HVPG was correlated with the severity of liver cirrhosis, presence of ascites, and risk of variceal bleeding in patients with liver cirrhosis.

Fatal spontaneous bacterial peritonitis by Leclercia adecarboxylata in a patient with hepatocellular carcinoma.

Abstract: lation, or absence of fragmental pericardium with appendage herniation. TTE or TEE, MRI and cardiac catheterisation are effective diagnostic modalities for left atrial aneurysms. TTE is a noninvasive and convenient diagnostic tool (8,11). The anatomical relationship between an aneurysm and adjacent structures can be studied thoroughly. TEE is an alternative diagnostic approach when image study of TTE is inadequate (11). Moreover, TEE is an excellent tool for identifying the presence of an intracardiac thrombus (2), and is beneficial when studying pulmonary venous return. Magnetic resonance imaging is another effective noninvasive imaging study. With three-dimensional reconstruction, an MRI provides further information regarding the extent and size of an aneurysm, its relationship to adjacent structures, presence of compression to the left ventricle, and abnormal pulmonary venous drainage (11,12,15). Cardiac catheterisation was previously used for the definitive diagnosis of left atrial aneurysms. Trans-septal catheterisation or pulmonary angiogram in the levophase show that contrast enters the atrium with aneurysmal sac (6,8,10,16). Although cardiac catheterisation may be unnecessary when echocardiographic or MRI studies diagnose left atrial aneurysm and provide sufficient preoperative information (11,12,15), excluding other cardiac abnormalities such as systemic-to-pulmonary shunt is prudent. Surgical intervention is recommended even for asymptomatic patients as major complications, such as tachycardia, heart failure, or peripheral systemic embolisms, can develop. Following resection of an aneurysm, most reported cases obtained good results (2,6,7,12,14,16). In this case, no anti-dysrhythmic agents were needed after surgery. In conclusion, aneurysm of the left atrium could be associated with the paroxysmal atrial flutter and should be suspected when chest radiography shows abnormal atrium bulging. TTE should be used as the initial step for differential diagnosis. Other imaging studies, including TEE, computer tomography and MRI, also provide useful information.

Combination therapy of thymosin alpha-1 and lamivudine for HBeAg positive chronic hepatitis B: A prospective randomized, comparative pilot study.

Abstract: Background and Aim: Monotherapy of lamivudine, interferon-alpha (IFN-α), and thymosin alpha-1 (Tα1) is unlikely to be sufficient for the eradication of a chronic hepatitis B virus (HBV) infection. The aim of our study is to elucidate whether the combination of Tα1 and lamivudine is superior to lamivudine monotherapy in hepatitis B e antigen (HBeAg) positive naive patients with chronic hepatitis B. Methods: Sixty-seven patients were assigned to two different groups in a randomized manner. The combination group (n = 34) received Tα1 (1.6 mg subcutaneously, twice a week) and lamivudine (100 mg orally, daily) for 24 weeks, followed by continuous lamivudine therapy. The monotherapy group (n = 33) received lamivudine monotherapy continuously. Results: The incidence of HBeAg seroconversion at 24 weeks was 26.5% (9/34) in the combination group and 6.1% (2/33) in the monotherapy group (P = 0.024). However, there was no statistically significant difference between 26.5% (9/34) in the combination group and 12.1% (4/33) in the monotherapy group at 52 weeks (P = 0.138). The emergence of viral breakthrough gradually increased to 35.3% (12/34) in the combination group, and to 21.2% (7/33) in the monotherapy group at 52 weeks (P = 0.201). Conclusions: The combination treatment of Tα1 and lamivudine did not have an obvious benefit of virological and biochemical response as compared to the lamivudine monotherapy during the combination period. In addition, after the cessation of Tα1 treatment, the combination therapy did not prevent the occurrence of viral and biochemical breakthroughs.

Chronic HBV infection with persistently normal ALT b. not to treat

Abstract: Chronic hepatitis B (CHB) is a lifelong, progressive and potentially fatal disease if not properly treated. Fortunately, successful therapy with antiviral agents resulted in sustained improvements in virologic, biochemical, histologic features of disease and clinical outcome. Although the recent development of a new and potent anti-hepatitis B virus (HBV) agents may offer many therapeutic options against HBV, there are still unsolved issues and areas for the optimal antiviral therapy. The various clinical courses and different status of the diseases, the variable response to antiviral agents, and the lack of long-term outcome of antiviral treatment contribute to the difficulties in establishment of ideal guidelines, particularly in some special patient groups [1]. It is very important to establish optimal guidelines for whom to treat and when to start, as well as how to treat in Asian patients with CHB. An individual patient’s alanine aminotransferase (ALT) level is an important factor in the decision to initiate the treatment of CHB because the elevated ALT levels indicate immune-mediated inflammation to eliminate HBV-infected hepatocytes and a higher rate of hepatitis B virus e antigen (HBeAg) seroconversion [1–3]. However, up to 40–50% of all HBeAg-positive patients may have normal ALT levels for prolonged periods [4]. The primary goal of treatment for CHB is to induce sustained suppression of HBV replication and to prevent progression of disease. APASL guidelines recommended that HBeAg-positive patients with HBV DNA levels of ≥20,000 IU/ml (≥105 copies/ml) and elevated ALT levels should be considered for treatment. However, the following issues remain unsettled: Should patients with an ALT level of less than two times upper limit of normal (ULN) be treated, and if so when and how? At that time, APASL guidelines recommended that patients with persistently normal or minimally elevated ALT should not be treated except in cirrhotic patients, but need adequate follow-up [1]. The newer therapeutic options have been shown to offer clinical benefits over lamivudine and may represent better therapeutic choices. Emerging evidence suggests that the more appropriate HBV DNA threshold for the treatment of HBeAg-negative patients is ≥2,000 IU/ml (≥104 copies/ml) [2, 3]. This review discusses the key issues and current challenges in the management of chronic HBV infection with persistently normal ALT (PNALT), which is usually defined as ALT remaining normal for at least 2 years in periodic biochemical examinations, to treat or not to treat [5].

[Serum hyaluronic acid level: correlation with quantitative measurement of hepatic fibrosis in a cirrhotic rat model]

Abstract: BACKGROUNDS/AIMS The serum level of hyaluronic acid (HA) has been suggested as a useful serologic marker for hepatic fibrosis. However, the relationship between serum HA levels and quantitative markers of fibrosis from liver tissue has not been reported. The aim of this study was to determine the correlation between serum HA level and quantitative measurement of hepatic fibrosis in a cirrhotic rat model. METHODS Cirrhosis was produced by common bile duct ligation (BDL) in adult Sprague-Dawley rats. The animals were classified into four groups: (1) G1, sham operated (n=5); (2) G2, BDL for 2 weeks (n=6); (3) G3, BDL for 3 weeks (n=6); and (4) G4, BDL for 4 weeks (n=6). Hepatic fibrosis was analyzed histomorphologically using the Batts and Ludwig scoring system. Serum HA level and hepatic hydroxyproline content were quantified. The gene expressions in the liver of procollagen, collagen, and transforming growth factor-beta (TGF-beta) were measured by reverse transcriptase-polymerase chain reaction. RESULTS In groups G1, G2, G3, and G4, the Batts and Ludwig scores (mean+/-SD) were 0, 1.3+/-0.5, 2.6+/-0.5, and 3.4+/-0.5, respectively (P<0.05), serum HA levels were 12.5+/-3.2, 30.0+/-4.3, 228.6+/-157.7, and 391.3+/-207.7 ng/mL (P<0.05), and the concentration of hydroxyproline was 12.4+/-2.8, 17.6+/-3.8, 17.9+/-2.4, and 33.4+/-3.4 microg/g liver tissue, and it was significantly higher in group G4 than in the other groups (P<0.05). The gene expressions of collagen, procollagen, and TGF-beta1 in the liver were also significantly higher in group G4 compared with the other groups (P<0.05). Direct linear correlations were observed between serum HA level and hepatic hydroxyproline content, hepatic gene expressions of collagen, procollagen, TGF-beta1, and histomorphological grade of hepatic fibrosis (P<0.001). CONCLUSIONS These results indicate that serum HA is a useful and noninvasive serologic marker for the evaluation of advanced hepatic fibrosis.

Clinical course of virologic breakthrough after emergence of YMDD mutations in HBeAg-positive chronic hepatitis B.

Abstract: Objective: High rate of resistance to lamivudine is a major problem in treating chronic hepatitis B (CHB) patients. We investigated the course of virologic breakthrough (VB) after e

Clinical outcomes of systemic chemotherapy in hepatocellular carcinoma patients with multiple lung metastases

Abstract: systemic chemotherapy only, and 8 patients received highly supportive care. The treatment responses and median survival times for the modalities were analyzed and compared. Results: The median age of the 52 analyzed patients (45 males) was 52.4 years. The most common etiology of HCC was chronic hepatitis B virus infection (n=44, 84.6%) followed by hepatitis C virus infection (n=2, 3.8%), with the etiology being unknown in 6 cases (11.5%). The treatment modality had no significant effect on the treatment response rate (P=0.432) or median survival time (133, 66, 74, and 96 days for primary tumor treatment with systemic chemotherapy, primary tumor treatment only, systemic chemotherapy only, and highly supportive care, respectively; P=0.067). Conclusions: We found that systemic chemotherapy was not effective in treating HCC presenting with multiple lung metastases. Improving the effectiveness of systemic treatment and selecting patients who would benefit from such treatment remains a major challenge. (Korean J Hepatol 2008;14:360-370)

MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Abstract: A single-nucleotide polymorphism (SNP) in the promoter region of MDM2, SNP 309, is associated with hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus infection. The effect of p53 codon 72 polymorphism Arg72Pro on HCC risk remains inconsistent. This study evaluated the association of MDM2 and p53 polymorphisms with the presence and early onset of HCC in Korean patients with chronic hepatitis B virus (HBV) infection. In total, 583 consecutive patients with chronic HBV infection were classified according to the presence (n = 287) or absence (n = 296) of HCC. The MDM2 SNP 309 and p53 Arg72Pro were genotyped using restriction fragment length polymorphism method. The MDM2 G/G and p53 Pro/Pro genotypes were more frequent in HCC group than in non-HCC group (P < 0.001 and P = 0.004, respectively). Multivariate analysis for the presence of HCC revealed that the odds ratio (OR) for MDM2 G/G over T/T was 4.89 (P < 0.001) and that of p53 Pro/Pro over Arg/Arg was 3.03 (P = 0.006). Combined MDM2 G/G and p53 Pro/Pro had a synergistic effect on HCC risk, with an OR of 20.78 (P < 0.001). The mean age of tumor onset in patients with MDM2 G/G genotype was 50.9 years compared with 55.1 with T/T genotype (P = 0.018) and that with p53 Pro/Pro was 49.7 years compared with 52.9 with Arg/Arg (P = 0.040). Thus, MDM2 SNP 309 and p53 Arg72Pro are associated with the early development of HCC in Korean patients with chronic HBV infection.

Clinical Features and Treatment Outcomes of Upper Gastrointestinal Bleeding in Patients with Cirrhosis

Abstract: With recent progress in treatment modalities, mortality from upper gastrointestinal (UGI) bleeding has decreased appreciably. The aim of this study was to establish how UGI bleeds are managed in Korean patients with cirrhosis and to evaluate treatment outcomes. A total of 479 episodes of acute UGI bleeding in 464 patients with cirrhosis were included during a six-month period at nine tertiary medical centers. Treatment outcomes were assessed by failure to control bleeding, rebleeding and mortality. The source of bleeding was esophagogastric varices in 77.7% of patients, nonvariceal lesions in 15.9%, and undefined in 6.5%. For control of bleeding, endoscopic and pharmacologic treatments were used in 74.7% and 81.9% of patients, respectively. Variceal ligation was a major technique for endoscopic treatment (90%), and terlipressin and somatostatin were the main pharmacologic agents used (96.4%). Initial hemostasis was achieved in 86.8% of cases, but rebleeding occurred in 3.8% and 16.8% of cases within five days and six weeks of hemorrhage, respectively. Five-day and six-week mortality were 11.3% and 25.9%, respectively. Survival of patients with variceal bleeding seems to be remarkably improved than previous reports, which may suggest the advances in hemostatic methods for control of variceal hemorrhage.