Kang Mo Kim

Increased risk of adefovir resistance in patients with lamivudine‐resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy

Although adefovir dipivoxil (ADV) has a unique profile of delayed and infrequent resistance in treatment‐naïve chronic hepatitis B patients, the association of ADV resistance with previous lamivudine (LAM) resistance is not well understood. We compared the emergence of the ADV‐resistant mutations rtA181V/T and rtN236T between LAM‐resistant patients and treatment‐naïve patients at 48 weeks of ADV monotherapy. Fifty‐seven LAM‐resistant patients and 38 treatment‐naïve patients were treated with 10 mg/d ADV for more than 48 weeks. Both baseline and 48‐week blood samples were analyzed for ADV‐resistant mutations via restriction fragment mass polymorphism analysis. Antiviral responses were evaluated according to changes in serum HBV DNA (measured via real‐time polymerase chain reaction) and alanine aminotransferase (ALT) levels and loss of hepatitis B e antigen (HBeAg). After 48 weeks, 10 (18%) of the 57 LAM‐resistant patients were found to have developed ADV‐resistant mutations, whereas none of the 38 treatment‐naïve patients developed such mutations (P < .01). Among LAM‐resistant patients, the reduction in serum HBV DNA levels was significantly lower in patients with ADV‐resistant mutations than in those without such mutations (−1.04 vs. −2.63 log10 copies/mL) (P = .01). However, the rates of serum ALT normalization (60% vs. 55%) and HBeAg loss (14% vs. 21%) were not significantly different between the 2 groups (P > .05). In conclusion, the emergence of the rtA181V/T and rtN236T mutations was more common in LAM‐resistant patients than in treatment‐naïve patients after 48 weeks of ADV therapy and was associated with reduced antiviral efficacy to drug treatment. (HEPATOLOGY 2006;43:1385–1391.)

Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis

BACKGROUND & AIMS The effect of entecavir (ETV) therapy on viral suppression and hepatic function in hepatitis B virus (HBV) patients with decompensated cirrhosis has not been established. We evaluated ETV as first-line monotherapy in these patients. METHODS We consecutively enrolled 70 HBV-infected patients with decompensated cirrhosis primarily treated with 0.5mg/day ETV, and evaluated the clinical outcomes by intention-to-treat analyses. We also compared the virological responses of 55 patients treated for 12 months (decompensated group) with those of 144 chronic hepatitis or compensated cirrhosis patients (compensated group). RESULTS The cumulative transplantation-free survival was 87.1% at 1year. ETV treatment for 12 months resulted in improved Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores. Sixty-six percent (36/55) of patients achieved CTP class A and 49% (27/55) showed improvement in the CTP score of 2 points after 12 months of ETV. The 1-year cumulative rates of HBV DNA negativity and HBeAg loss were 92.3% and 54.0%, respectively, by intention-to-treat analysis. The rates of HBV DNA negativity, HBeAg seroconversion/loss and ALT normalization at month 12 were similar for the decompensated and compensated groups. Cox regression analysis showed that pretreatment HBeAg seropositivity was a negative predictor of HBV DNA clearance during ETV therapy (hazard ratio, 0.514; 95% confidence interval 0.367-0.719; p<0.001). CONCLUSIONS One-year initial ETV therapy was similarly effective in both compensated and decompensated liver disease HBV patients. In addition, it improved underlying liver function in decompensated patients.

Which Response Criteria Best Help Predict Survival of Patients with Hepatocellular Carcinoma Following Chemoembolization? A Validation Study of Old and New Models

PURPOSE To identify differences in radiologic assessment methods and determine optimal imaging criteria for response evaluation in hepatocellular carcinoma (HCC) patients treated with chemoembolization. MATERIALS AND METHODS Institutional review board approval was obtained, and patient informed consent was waived. The present study included 332 patients with intermediate stage HCC and Child-Pugh A cirrhosis who underwent serial chemoembolization. All measurable target lesions of 1 cm or larger in diameter were uni- and bidimensionally measured both at baseline and during follow-up. Intermodel agreement among the guidelines of the World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), the European Association for the Study of the Liver (EASL), and modified RECIST (mRECIST) were examined. The most reliable model was selected on the basis of the correlation with survival prediction. RESULTS The κ values of comparisons among WHO, RECIST, and mRECIST guidelines were less than 0.20, whereas the κ value for the comparison of EASL and mRECIST guidelines was 0.94. In patients with a partial response (PR), stable disease (SD), or progressive disease (PD), compared with patients with a complete response (CR), hazard ratios (HRs) for survival were 2.99 (95% confidence interval [CI]: 2.14, 4.17), 3.49 (95% CI: 1.71, 7.10), and 15.63 (95% CI: 9.51, 25.69), respectively, for EASL criteria. In patients with a PR, SD, or PD, compared with patients with a CR, the HRs were 2.75 (95% CI: 1.96, 3.87), 6.32 (95% CI: 3.67, 10.90), and 16.06 (95% CI: 9.76, 26.43), respectively, for mRECIST guidelines (P<.001). The C index for the multivariate model was 0.76 (95% CI: 0.72, 0.79) for both EASL and mRECIST guidelines, thus exhibiting satisfactory capability to help predict survival. The Cox regression model revealed that both mRECIST and EASL guidelines were independent predictors of overall survival (P<.001 for both). CONCLUSION The enhancement models more accurately helped predict long-term survival in HCC patients treated with chemoembolization.

Non-invasive assessment of hepatic steatosis: Prospective comparison of the accuracy of imaging examinations

BACKGROUND & AIMS Despite increasing use of various imaging examinations for non-invasive assessment of hepatic steatosis (HS), their relative accuracy is unknown. The objective of this study is to prospectively compare the accuracy of computed tomography (CT), dual gradient echo magnetic resonance imaging (DGE-MRI), proton magnetic resonance spectroscopy ((1)H-MRS), and ultrasonography (US) for the diagnosis and quantitative estimation of HS. METHODS A total of 161 consecutive potential living liver donors underwent US (performed by two independent radiologists, US1 and US2), CT, DGE-MRI, (1)H-MRS, and liver biopsy on the same day. Using the histologic degree of HS as the reference standard, we compared the diagnostic performance of US1, US2, CT, DGE-MRI, and (1)H-MRS for diagnosing HS >or= 5% and HS >or= 30% and compared the accuracy of CT, DGE-MRI, and (1)H-MRS in the quantitative estimation of HS. RESULTS DGE-MRI and (1)H-MRS significantly outperformed CT and US for the diagnosis of HS5%. DGE-MRI showed a tendency of higher accuracy than the other examinations for diagnosing HS >or= 30%. The cross-validated sensitivity and specificity of DGE-MRI at the optimal cut-off were 76.7% and 87.1%, respectively, for diagnosing HS >or= 5% and 90.9% and 94%, respectively, for diagnosing HS >or= 30%. The cross-validated Bland-Altman 95% limits of agreement between the estimated degree of HS on imaging examinations and the histologic degree of HS, were the narrowest with DGE-MRI, yielding -12.7% to 12.7%. CONCLUSIONS Among CT, DGE-MRI, (1)H-MRS, and US, DGE-MRI is the most accurate method for the diagnosis and quantitative estimation of HS. Therefore, DGE-MRI may be the preferred imaging examination for the non-invasive assessment of HS.

Radiotherapy Plus Transarterial Chemoembolization for Hepatocellular Carcinoma Invading the Portal Vein: Long-Term Patient Outcomes

PURPOSE We have evaluated the clinical outcomes of patients after transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). METHODS AND MATERIALS A registry database of 412 patients treated with TACE and three-dimensional conformal radiotherapy for HCC with PVTT between August 2002 and August 2008 were analyzed retrospectively. The radiotherapy volume included the PVTT, with a 2- to 3-cm margin to cover adjacent HCC. Intrahepatic primary HCC was managed by TACE before or after radiotherapy. RESULTS Median patient age was 52 years old, and 88.1% of patients were male. Main or bilateral PVTT was observed in 200 (48.5%) patients. Median radiation dose was 40 Gy (range, 21-60 Gy) delivered in 2- to 5-Gy fractions. We found that 3.6% of patients achieved a complete response and that 24.3% of patients achieved a partial response. The response and progression-free rates of PVTT were 39.6% and 85.6%, respectively. Median patient survival was 10.6 months, and the 1- and 2-year survival rates were 42.5% and 22.8%, respectively. Significant independent variables associated with overall survival included advanced tumor stage, alpha-fetoprotein level, degree of PVTT, and response to radiotherapy. Forty-one patients (10.0%) showed grade 3-4 hepatic toxicity during or 3 months after completion of radiotherapy. Grades 2-3 gastroduodenal complications were observed in 15 patients (3.6%). CONCLUSIONS Radiotherapy is a safe and effective treatment for PVTT in patients with HCC. These results suggested that the combination of TACE and radiotherapy is a treatment option for relieving and/or stabilizing PVTT in patients with advanced HCC.

Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology.

A recent study in young Italian subjects suggested that the healthy thresholds for serum alanine aminotransferase (ALT) levels should be adjusted to 30 IU/L for men and 19 IU/L for women when assessing risk factors for nonalcoholic fatty liver disease. Our aim was to assess serum ALT concentrations in healthy Korean individuals and to determine the factors affecting ALT levels in these populations. We included 1,105 potential liver donors (643 men and 462 women) with biopsy‐proven normal livers. Median ages were 25 years in men and 30 years in women, with a median body mass index (BMI) of 22.3 kg/m2 in men and 21.4 kg/m2 in women. The calculated thresholds for ALT values in these subjects were 35 IU/L for men and 26 IU/L for women. Age and BMI were independently correlated with ALT levels in both sexes, whereas serum total cholesterol concentration was significant only in men and blood glucose level only in women (P < 0.05). When we chose a subgroup of 665 individuals (346 men and 319 women) using Prati criteria, modified by the BMI cutoff points for Asians (<23 kg/m2), we found that the healthy ALT values were 33 IU/L for men and 25 IU/L for women. The mean ALT concentrations for subjects within the Prati criteria were significantly lower than for those outside the criteria (16.7 versus 19.5 IU/L for men, 12.8 versus 14.9 IU/L for women; P < 0.001). Conclusion: The healthy ALT thresholds in biopsy‐proven normal Asians were clearly lower than the previously accepted thresholds, as has also been noted in Europeans. Age, BMI, and/or other metabolic parameters significantly affect ALT levels, even in subjects with normal livers. (HEPATOLOGY 2010.)

Diagnosis of hepatic steatosis and fibrosis by transient elastography in asymptomatic healthy individuals: a prospective study of living related potential liver donors

BackgroundThis prospective study aimed to assess the ability of transient elastography to identify histologic parameters, including steatosis, in asymptomatic healthy individuals such as potential liver donors, and to compare these findings with results in liver disease patients.MethodsForty-seven patients with abnormal liver function and/or hepatitis symptoms and 80 living related potential liver donors were consecutively enrolled, and liver biopsy and a Fibroscan test were performed in each subject. Histologic parameters were evaluated according to METAVIR scale by a single pathologist.ResultsIn liver disease patients, stiffness was significantly correlated with fibrosis stage (Spearman correlation coefficient, 0.700; P < 0.001), and the optimal stiffness cutoff values for F ≥ 2, F ≥ 3, and F = 4 were 7.35, 8.85, and 15.1 kPa respectively. In potential liver donors, however, stiffness was not correlated with fibrosis (0.023; P = 0.851). In the latter group, the area under the receiver-operating characteristics curve was 0.70 (95% confidence interval, 0.58–0.81), and the optimal stiffness cutoff value was 4.00 for F ≥ 2, which was lower than that in liver disease patients. Steatosis was not correlated with stiffness (0.088; P = 0.463) in potential liver donors.ConclusionsTransient elastography has limited value for detecting steatosis in asymptomatic healthy individuals, and the cutoff value for fibrosis should be reevaluated in these subjects.

Analysis of genetic and phenotypic heterogeneity in juvenile polyposis

BACKGROUND Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the PTCH, PTENand DPC4 (SMAD4)genes can cause GS, CS/BRRS, and JPS, respectively. AIMS To examine the contribution of mutations in PTCH,PTEN, and DPC4(SMAD4) to JPS. METHODS Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations inDPC4, PTEN, andPTCH. RESULTS No patient had a mutation in PTEN orPTCH. Five different germline mutations were detected in DPC4; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features. CONCLUSIONS Mutations in PTEN and PTCHare unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour DPC4 mutations (21% in this study) but there remains uncharacterised genetic heterogeneity in JPS.

Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion

Background and Aim:  This study aimed to evaluate the therapeutic efficacy and safety of repeated transarterial chemoembolization (TACE) with additional radiation therapy (RT) in hepatocellular carcinoma (HCC) with portal vein (PV) invasion.

HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability

Objective Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Design During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study. Results Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log10 IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05–1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan–Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66). Conclusions HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.