Yoo-Kyung Cho

Sequential accumulation of the basal core promoter and the precore mutations in the progression of hepatitis B virus-related chronic liver disease.

Objectives: Despite the pathogenic role of the basal core promoter (BCP) and the precore mutations in chronic hepatitis B virus (HBV) infection, their role in the progression of liver disease is still controversial. We analyzed whether the accumulation of these mutations might enhance the progression of HBV-related chronic liver disease. Methods: Forty consecutive patients at each clinical status were analyzed. Clinical statuses were as follows: HBeAg-positive asymptomatic carrier (HBeAg+ ASC) (defined as HBeAg+, anti-HBe–, HBV-DNA+ by hybridization, normal ALT); inactive HBsAg carrier; chronic hepatitis B; liver cirrhosis. The genotype and the BCP/precore regions were determined by PCR using genotype specific primers and direct sequencing, respectively. Results: All patients except one were infected with genotype C. The A to T mutation at nucleotide 1762 and/or G to A mutation at nucleotide 1764 were found in 30% in HBeAg+ ASC, 65.7% in inactive HBsAg carrier, 95% in chronic hepatitis B, and 90% in liver cirrhosis (p < 0.001). The prevalence of the G to A mutation at nucleotide 1896 was 5% in HBeAg+ ASC, 22.5% in inactive HBsAg carrier, 32.5% in chronic hepatitis B, and 50% in liver cirrhosis, respectively (p < 0.001). The T to C/A mutation at nucleotide 1753 in the BCP and G to A mutation at nucleotide 1899 in the precore were more frequent in liver cirrhosis than in the other clinical statuses (p < 0.05). Conclusion: Sequential accumulation of mutations in the BCP/precore has an important role in the progression of HBV-related liver disease.

Gender disparity in distribution of the major hydrophilic region variants of hepatitis B virus genotype C according to hepatitis B e antigen serostatus

Hepatitis B virus (HBV) e antigen (HBeAg) seroconversion during chronic HBV infection is known to play an important role in disease progression and patient response to antiviral agents. The aim of the present study was to analyze gender disparity in distribution of major hydrophilic region (MHR) variants according to HBeAg serostatus. Prevalence of MHR variants from 68 Korean patients with chronic hepatitis (31 HBeAg‐positive and 37 HBeAg‐negative) was examined in terms of HBeAg serostatus and sex by direct sequencing analysis of the MHR. Gender disparity was observed in the distribution of MHR variants according to HBeAg serostatus. In male patients, the prevalence of MHR variants was significantly higher in HBeAg negative patients than in HBeAg positive patients [58.8% (10/17 patients) vs. 14.3% (3/21 patients), P = 0.004]. However, the same was not true in female patients [55.0% (11/20 patients) vs. 60.0% (6/10 patients), P = 1.000)]. In addition, 2 mutation types (L110I and G145A) related to HBeAg serostatus were found. In conclusion, HBeAg seroconversion in male chronic patients infected with genotype C could lead to mutations of MHR, major target to host immune response, which might in turn contribute to HBV persistence and immune evasion. J. Med. Virol. 83:405–411, 2011.

Comparison of the Clinical Characteristics of Patients with Small Bowel and Gastric Anisakiasis in Jeju Island

Background/Aims Anisakiasis is frequent in Jeju Island because of the peoples habit of ingesting raw fish. This study evaluated the clinical characteristics of patients with small bowel anisakiasis and compared them with those of patients with gastric anisakiasis. Methods We retrospectively reviewed the medical records of 109 patients diagnosed with anisakiasis between May 2003 and November 2011. Results Of the 109 patients diagnosed with anisakiasis, those with suspicious anisakiasis (n=38) or possible anisakiasis (n=12) were excluded. The age and gender distributions did not differ between patients with small bowel anisakiasis (n=30; age, 45±13 years) and those with gastric anisakiasis (n=29; age, 46±10 years). The mean duration of hospitalization was 5.4±4.3 days for patients with small bowel anisakiasis and 0.5±1.7 days for patients with gastric anisakiasis. Small bowel anisakiasis was accompanied by leukocytosis (76.7% vs 25.5%, p=0.003) and elevated C-reactive protein levels (3.4±3.2 mg/dL vs 0.5±0.3 mg/dL, p=0.009). Contrast-enhanced abdominopelvic computed tomography showed small bowel wall thickening with dilatation in 93.3% (28/30) of patients and a small amount of ascites in 80.0% (24/30) of patients with small bowel anisakiasis. Conclusions Compared with gastric anisakiasis patients, small bowel anisakiasis patients had a longer hospitalization time, higher inflammatory marker levels, and small bowel wall thickening with ascites.

Small cell carcinoma of the liver and biliary tract without jaundice

An 80-year-old woman presenting with chest pain was found to have a large, lobulated soft tissue mass in the liver and nearby tissues on abdominal computed tomography (CT). The tumor had invaded the common hepatic artery and main portal vein. Jaundice developed 4 wk later, at which point, a pancreas and biliary CT scan revealed a large mass in the right lobe of the liver and a hilar duct obstruction, which was found to be a small cell carcinoma. Despite its rarity, liver and bile duct small cell carcinoma should be considered in the differential diagnosis of atypical chest pain without jaundice.

Molecular characteristics and functional analysis of full-length hepatitis B virus quasispecies from a patient with chronic hepatitis B virus infection

It has been hypothesized that naturally occurring mutations in HBV may play a role in the pathogenesis of HBV-related disease. We determined the molecular characteristics of naturally occurring HBV isolates and performed a functional analysis of full-length hepatitis B virus quasispecies from a patient with chronic hepatitis B. The 10 HBV clones isolated were identified as HBV genotype B4 and subtype adw. In most clones, amino acid substitutions and nucleotide changes occurred in a specific region of the core protein, X protein and in the core promoter. In the core protein, cI3L, cL60M, and cI97L were detected in 8 of 10 clones and cP130T was detected in all 10 clones. In the X protein, xI127M was detected in 5 clones. In the basal core promoter, the A1762T/G1764A mutation was found only in 1 clone. An 11-bp nucleotide insertion between nucleotides 1772 and 1773, was found in 2 clones. Six clones that were replication-competent exhibited variation in the level of replicating capacity in vitro even though the average genetic distance between the HBV clones was only 0.5% (range: 0.3-0.7%). Among the replication-competent 6 clones, 5 clones showed higher replication competency compared with clone B9 (reference clone used in this study) in Huh7 cells. However, 4 clones showed lower replication competency compared with clone B9 in HepG2 cells. In conclusion, the HBV virus exhibits genetic variation in the form of quasispecies with different mutation patterns, and these quasispecies may be recognized by distinct viral replication patterns even in patients with subtle genetic mutation.

Response to Adefovir Depends on Mutation Patterns in Precore Region, Basal Core Promoter and Reverse Transcriptase, and On-Treatment Responses in Lamivudine-Resistant Chronic Hepatitis B Patients

Objective: In vitro studies showed that mutations in the basal core promoter (BCP) or precore (PC) region restore the replication inefficiency of the lamivudine-resistant mutant. The aim of this study was to clarify the effect of molecular characteristics on the antiviral response to adefovir in patients with lamivudine-resistant chronic hepatitis B (CHB). Methods: Sixty-six lamivudine-resistant patients who were treated with adefovir monotherapy were studied. Sequences of BCP, PC region and reverse transcriptase were determined before adefovir therapy. In patients with virologic breakthrough, reverse transcriptase sequencing was performed. Results: The cumulative probabilities of virologic response were 23.3, 46, 52.7 and 59.5% at years 1, 2, 3 and 4, respectively. PC mutation, the absence of compensatory mutations (rtL80I/V or rtV173L), and a decrease in serum hepatitis B virus (HBV) DNA by 3 log or greater at 6 months were independent predictors of virologic response. The cumulative probabilities of virologic breakthrough were 0, 12.9, 30.7 and 44.5% at years 1, 2, 3 and 4, respectively. BCP mutation and a less than 3 log decrease in serum HBV DNA at 6 months were 2 independent risk factors for virologic breakthrough. Conclusion: Response to adefovir depends on mutation patterns in the BCP, PC region and reverse transcriptase, and on-treatment decreases in serum HBV DNA in lamivudine-resistant CHB patients.

Distribution of hepatitis C virus genotypes in Jeju Island

BACKGROUNDS/AIMS The hepatitis C virus (HCV) genotype affects clinical outcomes of HCV infection, in terms of the response to antiviral therapy and progression of chronic liver diseases, and shows geographic differences in distribution. The aim of this study was to elucidate the HCV genotypes in patients with chronic HCV infection in Jeju, which is an island off the Korean peninsula. METHODS The study population consisted of 162 patients with anti-HCV antibodies and HCV-RNA. HCV genotypes were determined using genotype specific primers. RESULTS HCV genotype 2a predominated (62.3%), followed by genotype 1b (34.0%) and 2b (3.7%). The prevalence of genotypes differed significantly with age, with HCV genotypes 1 and 2 being more frequent in older and younger subjects (P=0.035), respectively. HCV-RNA levels were higher in patients with genotype 1 than in those with genotype 2 (P=0.001). HCV genotype was not significantly related to sex, clinical diagnosis and potential risk factors. CONCLUSIONS HCV genotype 2a is most common in Jeju, followed by genotype 1b. Our results suggest that the distribution of the HCV genotype differs between regions in Korea.

Predictors of spontaneous viral clearance and outcomes of acute hepatitis C infection

Background/Aims This study evaluated the predictors of spontaneous viral clearance (SVC), as defined by two consecutive undetectable hepatitis C virus (HCV) RNA tests performed ≥12 weeks apart, and the outcomes of acute hepatitis C (AHC) demonstrating SVC or treatment-induced viral clearance. Methods Thirty-two patients with AHC were followed for 12-16 weeks without administering antiviral therapy. Results HCV RNA was undetectable at least once in 14 of the 32 patients. SVC occurred in 12 patients (37.5%), among whom relapse occurred in 4. SVC was exhibited in 8 of the 11 patients exhibiting undetectable HCV RNA within 12 weeks. HCV RNA reappeared in three patients (including two patients with SVC) exhibiting undetectable HCV RNA after 12 weeks. SVC was more frequent in patients with low viremia than in those with high viremia (55.6% vs. 14.3%; P=0.02), and in patients with HCV genotype non-1b than in those with HCV genotype 1b (57.1% vs. 22.2%; P=0.04). SVC was more common in patients with a ≥2 log reduction of HCV RNA at 4 weeks than in those with a smaller reduction (90% vs. 9.1%, P<0.001). A sustained viral response was achieved in all patients (n=18) receiving antiviral therapy. Conclusions Baseline levels of HCV RNA and genotype non-1b were independent predictors for SVC. A ≥2 log reduction of HCV RNA at 4 weeks was a follow-up predictor for SVC. Undetectable HCV RNA occurring after 12 weeks was not sustained. All patients receiving antiviral therapy achieved a sustained viral response. Antiviral therapy should be initiated in patients with detectable HCV RNA at 12 weeks after the diagnosis.

Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND Adefovir (ADV) resistance is more frequent in lamivudine (LMV)-resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naïve patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy. METHODS We performed a clonal analysis of HBV reverse transcriptase in treatment-naïve (n = 3) and LMV-resistant patients before ADV therapy (n = 14). Dynamic changes in the viral population (n = 9) during ADV therapy were also analyzed. RESULTS Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naïve patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naïve patients (p = 0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n = 6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up. CONCLUSION The high rate of ADV resistance in patients with LMV-resistance might be attributable to preexisting rtA181V/T mutant virus.

New scoring system for predicting relapse after lamivudine-induced hepatitis B e-antigen loss in chronic hepatitis B patients.

Aim:  In endemic areas of hepatitis B virus (HBV) infection, lamivudine‐induced hepatitis B e‐antigen (HBeAg) loss is not durable. We developed a scoring system to predict the relapse after lamivudine‐induced HBeAg loss.