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Background/Aims We used next-generation sequencing (NGS) to analyze resistance-associated substitutions (RASs) and retreatment outcomes in patients with chronic hepatitis C virus (HCV) infection who failed direct-acting antiviral agent (DAA) treatment in South Korea. Methods Using prospectively collected data from the Korean HCV cohort study, we recruited 36 patients who failed DAA treatment in 10 centers between 2007 and 2020; 29 blood samples were available from 24 patients. RASs were analyzed using NGS. Results RASs were analyzed for 13 patients with genotype 1b, 10 with genotype 2, and one with genotype 3a. The unsuccessful DAA regimens were daclatasvir+asunaprevir (n=11), sofosbuvir+ribavirin (n=9), ledipasvir/sofosbuvir (n=3), and glecaprevir/pibrentasvir (n=1). In the patients with genotype 1b, NS3, NS5A, and NS5B RASs were detected in eight, seven, and seven of 10 patients at baseline and in four, six, and two of six patients after DAA failure, respectively. Among the 10 patients with genotype 2, the only baseline RAS was NS3 Y56F, which was detected in one patient. NS5A F28C was detected after DAA failure in a patient with genotype 2 infection who was erroneously treated with daclatasvir+asunaprevir. After retreatment, 16 patients had a 100% sustained virological response rate. Conclusions NS3 and NS5A RASs were commonly present at baseline, and there was an increasing trend of NS5A RASs after failed DAA treatment in genotype 1b. However, RASs were rarely present in patients with genotype 2 who were treated with sofosbuvir+ribavirin. Despite baseline or treatment-emergent RASs, retreatment with pan-genotypic DAA was highly successful in Korea, so we encourage active retreatment after unsuccessful DAA treatment.

Abstract This prospective, 12-center study investigated the etiology and clinical characteristics of acute viral hepatitis (AVH) during 2020–2021 in South Korea, and the performance of different diagnostic methods for hepatitis E virus (HEV). We enrolled 428 patients with acute hepatitis, of whom 160 (37.4%) were diagnosed with AVH according to predefined serologic criteria. The clinical data and risk factors for AVH were analyzed. For hepatitis E patients, anti-HEV IgM and IgG were tested with two commercial ELISA kits (Abia and Wantai) with HEV-RNA real-time RT-PCR. HAV, HEV, HBV, HCV, Epstein-Barr virus (EBV), cytomegalovirus, and herpes simplex virus accounted for AVH in 78.8% (n = 126), 7.5% (n = 12), 3.1% (n = 5), 1.9% (n = 3), 6.9% (n = 11), 1.2% (n = 2), and 0.6% (n = 1) of 160 patients (median age, 43 years; men, 52.5%; median ALT, 2144 IU/L), respectively. Hospitalization, hemodialysis, and intensive care unit admission were required in 137 (86.7%), 5 (3.2%), and 1 (0.6%) patient, respectively. Two patients developed acute liver failure (1.3%), albeit without mortality or liver transplantation. Ingestion of uncooked clams/oysters and wild boars’ blood/bile was reported in 40.5% and 16.7% of patients with HAV and HEV, respectively. The concordance rate between the anti-HEV-IgM results of both ELISA kits was 50%. HEV RNA was detected in only 17% of patients with HEV. The diagnosis of HEV needs clinical consideration due to incomplete HEV diagnostics.

Membranous obstruction of the inferior vena cava (MOVC) is a rare subset of Budd-Chiari syndrome (BCS) with a subacute onset that is often complicated by cirrhosis and hepatocellular carcinoma (HCC). Here we report a case of recurrent HCC in a patient with cirrhosis and BCS that was treated with several episodes of transarterial chemoembolization followed by surgical tumorectomy, whereas the MOVC was successfully treated with balloon angioplasty followed by endovascular stenting. The patient was followed up for 9.9 years without anticoagulation and experienced no stent thrombosis. After the tumorectomy, the patient was HCC-free for 4.4 years of follow-up.

Abstract Transarterial chemoembolization (TACE) is often used as a locoregional therapy for early hepatocellular carcinoma (HCC) when local ablation or resection are not feasible, but incomplete response and recurrence are commonly observed. In this study, we sought to determine the association between metformin administration and TACE outcomes for single nodular HCC in patients with type 2 diabetes mellitus (T2DM). The retrospective cohort analysis included 164 T2DM patients with single nodular HCC who underwent TACE as an initial treatment, and 91 were exposed to metformin before and after TACE. Propensity score (PS) matching was used to balance covariates. Logistic regression analysis was used to determine the predictors of tumor response after TACE, and Cox regression analysis assessed independent predictors of local tumor recurrence (LTR) in patients with complete response after TACE. Metformin use was associated with significantly higher objective response rate (ORR) in the overall and PS-matched cohort (79.1% vs. 60.3 and 78.7% vs. 57.5%; p = 0.008 and p = 0.029, respectively). Logistic regression analysis showed that metformin use was an independent predictor of ORR in all and PS-matched patients (odds ratio = 2.65 and 3.06; p = 0.016 and 0.034, respectively). Cox regression analysis showed metformin administration was an independent predictor for lower LTR in all and PS-matched patients (hazard ratio = 0.28 and 0.27; p = 0.001 and 0.007, respectively). Metformin administration is associated with better initial response and lower local recurrence after TACE for single nodular HCC in T2DM.

Abstract The role of hepatocellular carcinoma (HCC) surveillance is being questioned in alcoholic cirrhosis because of the relative low HCC risk. This study aimed to assess the risk and predictors of HCC in Korean patients with alcoholic cirrhosis by using competing risk analysis. A total of 745 patients with alcoholic cirrhosis were recruited at a university-affiliated hospital in Korea and randomly assigned to either the derivation (n = 507) and validation (n = 238) cohort. Subdistribution hazards model of Fine and Gray was used with deaths and liver transplantation treated as competing risks. Death records were confirmed from Korean government databases. A nomogram was developed to calculate the Alcohol-associated Liver Cancer Estimation (ALICE) score. The cumulative incidence of HCC was 15.3 and 13.3% at 10 years for derivation and validation cohort, respectively. Age, alpha-fetoprotein level, and albumin level were identified as independent predictors of HCC and incorporated in the ALICE score, which discriminated low, intermediate, and high risk for HCC in alcoholic cirrhosis at the cut-off of 60 and 100. The risk of HCC can be stratified by using a combination of readily available clinical parameters (age, AFP level, and albumin level) in patients with alcoholic cirrhosis.

Background/Aims This study aimed to evaluate the cost-effectiveness of hepatitis C virus (HCV) screening compared to no screening in the Korean population from societal and healthcare system perspectives. Methods A published decision-tree plus Markov model was used to compare the expected costs and quality-adjusted life years (QALY) between one-time universal HCV screening and no screening in the population aged 40–65 years using the National Health Examination (NHE) program. Input parameters were obtained from analyses of the National Health Insurance claims data, Korean HCV cohort data, or from the literature review. The population aged 40–65 years was simulated in a model spanning a lifetime from both the healthcare system and societal perspectives, which included the cost of productivity loss due to HCV-related deaths. The incremental cost-effectiveness ratio (ICER) between universal screening and no screening was estimated. Results The HCV screening strategy had an ICER of $2,666/QALY and $431/QALY from the healthcare system and societal perspectives, respectively. Both ICERs were far less than the willingness-to-pay threshold of $25,000/QALY, showing that universal screening was highly cost-effective compared to no screening. In various sensitivity analyses, the most influential parameters on cost-effectiveness were the antibodies to HCV (anti-HCV) prevalence, screening costs, and treatment acceptance; however, all ICERs were consistently less than the threshold. If the anti-HCV prevalence was over 0.18%, screening could be cost-effective. Conclusions One-time universal HCV screening in the Korean population aged 40–65 years using NHE program would be highly cost-effective from both healthcare system and societal perspectives.

Background/Aims The risk factors for the development of primary biliary cholangitis (PBC) is unclear. This study aimed to investigate the risk factors associated with PBC in Korea through a questionnaire survey. Methods Consecutively enrolled 103 PBC patients from six referral hospitals and 100 age- and sex-matched community controls participated in this study. A standardized questionnaire survey including demographics, lifestyle, individual and familial medical history and reproductive history was prospectively collected and analyzed. Results The PBC patients had a mean age of 58.3 years and a female proportion of 86.4%. The age- and sex-matched controls had a similar educational level and economic status to the PBC patients. Among the lifestyle factors, the multivariable analysis showed smoking including both first-hand and second-hand (odds ratio [OR], 2.03; 95% confidence interval [CI], 1.06 to 3.93), history of autoimmune diseases (OR, 2.46; 95% CI, 1.06 to 6.35), and family history of PBC (OR, 17.76; 95% CI, 1.77 to 2,418.74) were significantly associated with PBC, whereas alcohol intake was negatively associated with PBC. Among reproductive factors, the number of induced abortions was significantly associated with PBC, while the number of full-term deliveries was negatively associated with PBC. Conclusions A family history of PBC, accompanying autoimmune diseases, and smoking were significantly associated with PBC. More induced abortions and less full-term deliveries were associated with PBC in women. In contrast, mild to moderate alcohol intake was negatively associated with PBC. Further studies are warranted to validate the results of this study and to search for clues about the pathogenesis of PBC.

Background/Aims The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival. Methods Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017. Results The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients. Conclusions The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

Background and aimApparently healthy individuals with elevated serum alpha-fetoprotein (AFP) levels (>7 ng/mL) for unknown causes visit clinics. We investigated their clinical characteristics, outcomes, and relationship with body fat deposition and muscle mass.MethodsThe case group included asymptomatic 137 individuals with "elevated AFP level" (R772) diagnostic code from 2009 to 2018 in a tertiary hospital. The control group enrolled 274 age- and sex-matched patients with ResultsThe case group (mean age 47.5 years, male 35.8%) showed higher AFP levels (10.3 vs 2.5 ng/mL, pConclusionElevated AFP levels in asymptomatic individuals may play a role in expressing a protective phenotype against hepatic steatosis, myosteatosis, and sarcopenia. AFP levels in patients with elevated AFP were stable during follow-up without liver injury or cancer development. Interaction between AFP expression and steatosis warrants further study.

OBJECTIVES Injection drug use is a major risk factor for hepatitis C virus (HCV) infection; however, limited data on this topic are available in Korea. Thus, this study aimed to investigate the epidemiological and clinical characteristics, treatment uptake, and outcomes of HCV infection among people who inject drugs (PWID). METHODS We used the data from the Korea HCV cohort, which prospectively enrolled patients with HCV infection between 2007 and 2019. Clinical data and results of a questionnaire survey on lifetime risk factors for HCV infection were analyzed according to a self-reported history of injection drug use (PWID vs. non-PWID group). RESULTS Among the 2,468 patients, 166 (6.7%) were in the PWID group, which contained younger patients (50.6±8.2 vs. 58.2±13.1 years) and a higher proportion of male (81.9 vs. 48.8%) than the non-PWID group. The distribution of PWID showed significant regional variations. Exposure to other risk factors for HCV infection was different between the groups. The proportion of patients with genotype non-2 infection was higher in the PWID group. Treatment uptake was higher in the PWID group in the interferon era; however, it was comparable between the groups in the direct-acting antiviral era. The rate of sustained virological response did not significantly differ between the groups. CONCLUSIONS As of 2019, PWID constituted a minority of HCV-infected people in Korea. The epidemiological characteristics, but not treatment uptake and outcomes, were different between the PWID and non-PWID groups. Therefore, active HCV screening and treatment should be offered to PWID in Korea.

Background/Aims: To investigate a reported outbreak of presumed hepatitis E virus (HEV) infection in a Korean food manufacturing facility and to explore the association between anti-HEV immunoglobulin M (IgM) positivity and coronavirus disease 2019 (COVID-19) infection or vaccination. Methods: Twenty-four cases of anti-HEV IgM positivity were reported among 646 workers at the facility in 2022. An epidemiological investigation was conducted, comprising HEV-RNA testing of blood and environmental samples, analysis of group meal records, and an association between anti-HEV IgM positivity and confirmed COVID-19 infection or vaccination. Results: All 24 patients were asymptomatic, with cases spread sporadically across the facility. HEV RNA was not detected in the serum or environmental samples. Four out of 340 meals (1.2%) showed a significantly higher proportion of anti-HEV positivity in each meal intake group than in the non-intake group on certain days. Although the cumulative rate of COVID-19 infection showed no difference, the anti-HEV IgM positive group showed significantly higher proportions of >2 doses of COVID-19 vaccination (83.3% vs 48.7%, p=0.021), vaccination within 90 days (45.8% vs 19.7%, p=0.008), and having the Moderna vaccine administered as the last vaccine (75.0% vs 14.5%, p<0.001) than those of the anti-HEV negative group. In four multivariable models, three or more COVID-19 vaccinations and the Moderna vaccine as the last vaccine were consistently associated with anti-HEV IgM positivity, while the specific day group meal intake was also a significant factor. Conclusions: This epidemiological investigation showed that anti-HEV IgM positivity may occur as a false-positive result related to COVID-vaccination over three times and use of the Moderna vaccine, although a portion of true HEV infection may not be excluded. [ABSTRACT FROM AUTHOR]

Background/Aims Non-selective β-blockers (NSBBs) are used for primary prevention of esophageal variceal hemorrhage (VH) in patients with portal hypertension, but a significant number of patients develop VH while on NSBB therapy. In this study, we sought to determine whether liver volume can predict the risk of primary prophylaxis failure in cirrhotic patients on NSBB therapy. Methods A retrospective cohort of 309 patients on prophylactic propranolol was analyzed. Liver volume was measured in portal venous phase images of multidetector computed tomography. Predictors of VH were assessed using a Cox proportional hazards model with competing-risks analysis. A nomogram was developed for estimation of the risk of primary prophylaxis failure. Results During a median follow-up of 36 months, 37 patients on propranolol developed VH. Liver volume index, the ratio of measured-to-expected liver volume, was an independent predictor of VH (adjusted hazard ratio [HR], 2.70; 95% confidence interval [CI], 1.37 to 5.33; p = 0.004) as were the presence of large varices and the absence of ascites. A nomogram-based volume score of > 0.6 was predictive of prophylaxis failure (HR, 7.54; 95% CI, 2.88 to 19.73; p < 0.001). Time-dependent receiver operating characteristic curve analysis revealed that a nomogram-based risk score had significantly better discriminatory power than the North Italian Endoscopy Club index in predicting prophylaxis failure at 6 and 8 years. Conclusions Liver volume index is an independent predictor of first VH and a nomogram-based volume score stratifies the VH risk in cirrhotic patients on propranolol prophylaxis.

Abstract Alcohol increases the risk of both hepatocellular carcinoma (HCC) and colorectal neoplasia. In this hospital-based case-control and retrospective cohort study, we sought to determine whether development of colorectal neoplasia increases the risk of HCC in patients with alcoholic liver disease (ALD). In the phase I case-control analysis, the association between history of colorectal cancer (CRC) and HCC development was assessed in patients with ALD by logistic regression modeling (n = 1,659). In the phase II retrospective cohort analysis, the relative risk of HCC development was compared in ALD patients with respect to the history of CRC by a Cox model (n = 1,184). The history of CRC was significantly associated with HCC in the case-control analysis (adjusted odds ratio, 1.82; 95% CI, 1.06–3.15; P

Background/Aim This study aimed to establish the real-world effectiveness and safety of grazoprevir/elbasvir (EBR/GZR) therapy in South Korea. Methods A total of 242 patients with chronic hepatitis C virus (HCV) genotype 1 or 4 infection who started EBR/GZR were consecutively enrolled from seven tertiary hospitals. Retrospective analysis of the fractions of patients that achieved sustained virological response (SVR) was performed, and the incidence of adverse events was noted. Results The mean age of enrolled patients was 59.0 ± 12.6 years and 47.5% were males. Patients with HCV genotype 1b accounted for 93.8% (n = 227), and patients with HCV of unspecified genotype 1 accounted for 5.8% (n = 14). Hypertension was the most common comorbid disease (29.8%) followed by diabetes (22.7%) and chronic kidney disease (CKD, 12.4%). SVR rates of treatment-naïve and treatment-experienced patients were 85.5% (182/213) and 93.1% (27/29), respectively, in the intention-to-treat analyses, whereas in the per-protocol analyses, those were 97.8% (179/183) and 100% (28/28), respectively. Fewer patients with HCV genotype 1 of unspecified subtype achieved SVR (81.8%, n = 11) compared to the patients with SVR infected with genotype 1b (99%, n = 198, p < 0.001). All patients with CKD showed SVR. Itching (12%) and dyspepsia (4.1%) were common adverse events. Of the four patients who discontinued the antiviral therapy, one experienced mild fatigue but neither treatment withdrawal was because of an adverse event. Conclusions EBR/GZR showed high real-world effectiveness and safety in Korean patients with chronic HCV infection regardless of the previous antiviral treatment, liver cirrhosis, or CKD status.

Background & Aims: Personalised risk prediction of the development of hepatocellular carcinoma (HCC) among patients with liver cirrhosis on potent antiviral therapy is important for targeted screening and individualised intervention. This study aimed to develop and validate a new model for risk prediction of HCC development based on deep learning, and to compare it with previously reported risk models. Methods: A novel deep-learning-based model was developed from a cohort of 424 patients with HBV-related cirrhosis on entecavir therapy with 2 residual blocks, including 7 layers of a neural network, and it was validated using an independent external cohort (n = 316). The deep-learning-based model was compared to 6 previously reported models (platelet, age, and gender-hepatitis B score [PAGE-B], Chinese University HCC score [CU-HCC], HCC-Risk Estimating Score in CHB patients Under Entecavir [HCC-RESCUE], age, diabetes, race, etiology of cirrhosis, sex, and severity HCC score [ADRESS-HCC], modified PAGE-B score [mPAGE], and Toronto HCC risk index [THRI]) using Harrell's concordance (c)-index. Results: During a median 5.2 yr of follow-up (inter-quartile range 2.8–6.9 yr), 86 patients (20.3%) developed HCC. The deep-learning-based model had a Harrell's c-index of 0.719 in the derivation cohort and 0.782 in the validation cohort. Goodness of fit was confirmed by the Hosmer-Lemeshow test (p >0.05). Moreover, this model in the validation cohort had the highest c-index among the 6 previously reported models: PAGE-B (0.570), CU-HCC (0.548), HCC-RESCUE (0.577), ADRESS-HCC (0.551), mPAGE (0.598), and THRI (0.587) (all p

Hepatic hemangioma represents the most common benign primary hepatic neoplasm. Although most such tumors are small and asymptomatic, giant hepatic hemangioma is frequently symptomatic, and requires intervention. Moreover, diffuse multiple hepatic hemangiomatosis occupying almost the entire liver is extremely rare in adults, and the optimal management for this condition is unclear. We report a case of a rapidly growing, symptomatic giant hepatic hemangioma with diffuse hepatic hemangiomatosis in a 50-year-old female patient who was treated by living-donor liver transplantation. This case shows malignant behavior of a benign hemangioma that required liver transplantation. Although this case could not meet the criteria for transplantation according to the MELD (model for end-stage liver disease) score system, it should be considered as an exceptional indication for deceased-donor liver allocation. Further studies of the mechanism underlying hemangioma growth are warranted.

Autoimmune liver diseases including autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are rare diseases. The aim of this review is to examine the epidemiology and clinical characteristics of AIH and PBC in South Korea. There were 4,085 patients registered as AIH in the Rare Intractable Disease Registry of Korea between 2009-2013, with a median age of 56 years and female-to male ratio of 6.4. The age-adjusted incidence and prevalence of AIH were 1.07/100,000/year and 4.82/100,000 persons, respectively. Among the patients, 1.1% underwent liver transplantation, and case fatality was 2.18%. Liver cirrhosis at diagnosis was accompanied in 23%; liver biopsy was performed in 75.2%, and prednisolone therapy or prednisolone and azathioprine combination therapy was done in 73% with a remission rate of 86%. There were 2,824 patients with PBC (≥20 years) registered in Korea between 2009-2013 with a median age of 57 years and female-to male ratio of 6.2. The age-adjusted incidence and prevalence of PBC were 0.86/100,000/year and 4.75/100,000 persons, respectively. Among the patients, 2.5% underwent liver transplantation, and case fatality was 2.2% with a 5-year transplantation-free survival of 95.4%. Ursodeoxycholic acid (UDCA) was prescribed in 90% of the patients with a UDCA inadequate response rate of 30%. In conclusion, AIH and PBC are rare but mostly treatable diseases if diagnosed in the early stages. However, scarce data, low awareness, delayed diagnosis and non-availability of 2nd line therapeutics are important issues to be solved. Therefore, governmental support for research and drug development and nationwide cooperative studies are warranted.

Background We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines. Methods A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of “stemness”-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)–related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers. Results Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p

Abstract Background Health care workers (HCWs) are at high risk for occupational blood exposures (OBEs) and transmission of bloodborne pathogens. This study elucidated the incidence rate and epidemiological characteristics of OBEs among HCWs and investigated the pathogen transmission rate for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Methods Self-reported OBEs from January 1, 2011 to December 31, 2015 were obtained from the electronic recording system. OBE incidence densities per 100 person-years and per 100 bed-years were calculated with a 5-year trend analysis. OBE characteristics and pathogen transmission rates were evaluated. Results Among 10,452 HCWs and 1072 average yearly beds, 1076 OBEs were reported. OBE incidence rate was 5.6 cases per 100 person (full-time equivalent)-years and 20.3 per 100 bed-years. Incidence rate decreased and was significantly associated with a decrease of beds served per HCW. Housekeeping showed the highest OBE rate (14.8%) followed by doctors (8.5%) and nurses (6.2%). OBEs occurred in wards, emergency rooms, and operating rooms (38.1%, 13.3% and 12.2%, respectively) via percutaneous (86.7%) and mucocutaneous exposures (13.2%). Of OBEs associated with HBV (n = 133), HCV (n = 126), and HIV (n = 25), only one led to an infection (HCV; transmission rate of 0.8%). Neither HBV nor HIV infection occurred. Conclusions OBE incidence rate in a Korean university hospital was 5.6 cases per 100 person-years and 20.3 per 100 bed-years and was related to HCW workload and work proficiency. Though the actual bloodborne pathogen transmission rate was low, efforts to prevent OBE should be made for hospital safety.

Background & aimsElastography point quantification is a convenient method for measuring liver stiffness. It can be performed simultaneously with conventional ultrasonography. This study aimed to evaluate its diagnostic performance for assessing hepatic fibrosis in patients with autoimmune liver disease (AILD), including autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).MethodsThe diagnostic performance of elastography point quantification (ElastPQ) was evaluated and compared with that of serum fibrosis markers, including the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4), using the receiver operating characteristics analysis with histologic evaluation as the reference standard.ResultsIn 49 AIH patients, sensitivity and specificity of ElastPQ were 93.6% and 44.4%, respectively, for significant fibrosis (≥ F2, cutoff 4.47 kPa), and 63.6% and 86.8% for cirrhosis (F4, cutoff 9.28 kPa). In 41 PBC patients, they were 81.8% and 73.3%, respectively, for significant fibrosis (≥ F2, cutoff 5.56 kPa), and 100% and 81.6%, respectively, for advanced fibrosis (≥ F3, cutoff 6.04 kPa). The areas under the receiver operating characteristic curves of ElastPQ for significant fibrosis (0.77, 95% CI 0.67-0.86) and cirrhosis (0.81, 95% CI 0.65-0.96) were higher than those of APRI and FIB-4 in AILD patients. According to the multivariable analysis, histological activity, steatosis, and body max index (BMI) were not significant factors that influenced the result of ElastPQ.ConclusionsElastPQ exhibited better diagnostic performance-without the influence of confounding factors-for assessing hepatic fibrosis in AILD patients than serum fibrosis markers.

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic disorders caused by defects in biliary epithelial trans-porters. It mostly presents as low y-glutamyltransferase cholestasis. Recently, USP53 has been identified as one of the novel genes associated with PFIC. Herein, we report a 21-year-old Korean male patient with a late-onset PFIC. Initial work-up, including whole genome sequencing, did not find any associated gene. However, reviewing sequencing data identified novel compound heterozygous variants in splicing site of USP53 (NM_001371395.1:c.972+3_972+6del, and c.973-1G>A). The patient's bilirubin level fluctuated during the disease course. At 4.5 years after the initial presentation, the patient's symptom and high bilirubin level were normalized alter administration of high-dose ursodeoxycholic acid. Recognition of this disease entity is important for prompt diagnosis and management. USP53 is recommended for the work-up of low y-glutamyltransferase cholestasis. [ABSTRACT FROM AUTHOR]

Background/Aims Glypican-3 (GPC3) protein is highly expressed in hepatocellular carcinoma (HCC) tissue. It has been suggested as a diagnostic biomarker, but its inconsistent performance means that it requires further assessment. We therefore investigated the diagnostic value of the plasma GPC3 level compared to the alpha-fetoprotein (AFP) level as a diagnostic biomarker of HCC. Methods We enrolled 157 consecutive patients with newly diagnosed HCC and 156 patients with liver cirrhosis (LC) as the control group. GPC3 plasma levels were measured using two commercially available enzyme-linked immunosorbent assays (ELISAs, named as Assay 1 and 2), and AFP levels were measured using an enzyme-linked chemiluminescent immunoassay. The diagnostic accuracy was analyzed using the receiver operating characteristics (ROC) curve. Results Plasma GPC3 levels in HCC patients were very low (0–3.09 ng/mL) in Assay 1, while only 3 of the 157 patients (1.9%) showed detectable GPC3 levels in Assay 2. The median GPC3 level was not significantly elevated in the HCC group (0.80 ng/mL) compared with the LC group (0.60 ng/mL). The area under the ROC curve (AUC) for GPC3 was 0.559 in Assay 1. In contrast, the median AFP level was significantly higher in HCC (27.72 ng/mL) than in LC (4.74 ng/mL), with an AUC of 0.729. Conclusion The plasma level of GPC3 is a poor diagnostic marker for HCC, being far inferior to AFP. The development of a consistent detection system for the blood level of GPC3 is warranted.

The aim of this study was to determine whether dynamic computed tomography (CT)-measured liver volume predicts the risk of hepatocellular carcinoma (HCC) when the CT scans do not reveal evidence of HCC in chronic hepatitis B (CHB) patients on surveillance.This retrospective multicentre cohort study included 1,246 patients who received entecavir and regular HCC surveillance in three tertiary referral centres in South Korea. Liver volumes were measured on portal venous phase CT images. A nomogram was developed based on Cox independent predictors and externally validated. Time-dependent receiver operating characteristic (ROC) analysis was performed for comparison with previous prediction models.Patients who received dynamic CT studies during surveillance had significantly higher risk for HCC compared to patients without CT studies (hazard ratio [HR] = 3.1; p < 0.001). Expected/measured liver volume ratio was an independent predictor of HCC (HR = 4.2; p = 0.002) in addition to age, sex and cirrhosis. The nomogram based on the four predictors discriminated risks for HCC (HR = 4.1 and 6.0 in derivation and validation cohort, respectively, for volume score > 150; p < 0.001). Time-dependent ROC analysis confirmed better performance of the volume score compared to HCC prediction models with conventional predictors (integrated area under curve = 0.758 vs. 0.661-0.712; p < 0.05).CT-measured liver volume is an independent predictor of future HCC, and nomogram-based liver volume score may stratify the risks of HCC in CHB patients who showed negative CT findings for HCC during surveillance.

Background/AimsVitamin E improves the biochemical profiles and liver histology in nonalcoholic steatohepatitis, but the role of vitamin E is not clearly defined in the management of nonalcoholic fatty liver disease (NAFLD) which includes both simple steatosis and steatohepatitis. Co-morbid metabolic syndrome increases the probability of steatohepatitis in NAFLD. In this study, we aimed to determine the short-term effects of vitamin E and off-treatment durability of response in a propensity-score matched cohort of NAFLD patients with metabolic syndrome.MethodsA retrospective cohort was constructed by retrieving 526 consecutive NAFLD patients from the electronic medical record data warehouse of a tertiary referral hospital in South Korea. Among them, 335 patients (63.7%) had metabolic syndrome and were eligible for vitamin E therapy. In order to assess the effect of vitamin E, propensity score matching was used by matching covariates between control patients (n=250) and patients who received vitamin E (n=85).ResultsThe PS-matched vitamin E group (n=58) and control group (n=58) exhibited similar baseline metabolic profiles. After 6 months of vitamin E therapy, the mean ALT levels decreased significantly compared to PS-matched control (P

Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis, hepatocellular carcinoma, and liver-related mortality. The new antiviral drugs against HCV, direct acting antivirals, result in >90% cure rate. This review aimed to summarize the current prevalence, clinical characteristics, outcomes, and treatment response associated with HCV infection, and countermeasures for optimal HCV control in South Korea. Based on a literature review, the current anti-HCV prevalence in the Korean population is 0.6 to 0.8%, with increasing prevalence according to age. The major HCV genotypes in Korean patients were genotype 1b and genotype 2. Successful antiviral treatment leads to significantly reduced liver related complications and mortality. However, only about one third of the individuals with HCV infection seem to be managed under the current national health insurance system, suggesting a remarkable rate of underdiagnoses and subsequent loss of opportunity to cure. A recent study in South Korea showed that targeted population screening for HCV infection is cost-effective. To prevent recently developed clusters of HCV infection in some clinics, mandatory surveillance rather than sentinel surveillance for HCV infection is required and governmental countermeasures to prevent reuse of syringes or other medical devises, and public education should be maintained. Moreover, one-time screening for a targeted population should be considered and a cost-effectiveness study supporting an optimal screening strategy is warranted.

The epidemiologic shift of hepatitis A virus (HAV) infection in the South Korean population resulted in a peak outbreak of hepatitis in 2009. The aim of this study was to clarify the seropositivity of anti-HAV antibody (anti-HAV) and its demographic characteristics before and after the peak outbreak from 2005 to 2014.This retrospective study analyzed the anti-HAV data of all individuals from 1,795 medical institutions referred to a major central laboratory from January 2005 through December 2014, as a sentineal tool for monitoring annual variation of anti-HAV positivity. The prevalence of anti-HAV was adjusted for age and area with the standard population based on the 2010 Census data.A total of 424,245 individuals were included in this study. The overall age-adjusted anti-HAV prevalence decreased from 65.6% in 2005 to 62.2% in 2014. During the 10-year period, the seroprevalence continuously decreased in persons aged 30 to 39 years (69.6% to 32.4%) and those aged 40 to 49 years (97.9% to 79.3%) due to the cohort effect. In contrast, it increased in persons aged 10 to 19 years (15.4% to 35.2%), while it was the lowest (8.7%) in 2010 before rebounding to 20.2% in 2014 in persons aged 20 to 29 years due to a vaccination effect.Although the HAV vaccination rate increased, the anti-HAV seropositivity in South Korea decreased from 65.6% to 62.2% in this study population. In particular, the immunity of young adults was still low, and an outbreak of HAV is possible in the near future. Therefore, continuous monitoring and optimal preventive measures to prevent future outbreaks should be considered.

Little is known about population-based epidemiology and disease burden of autoimmune hepatitis (AIH). The aim of this study was to investigate the prevalence, incidence, comorbidity and direct medical cost of AIH in South Korea.The data was from the nationwide, population-based National Health Insurance Service claims database and the Rare Intractable Disease registration program. Age and gender-specific prevalence rates were calculated, and data on comorbidity, diagnostic tests, prescribed drugs, and medical costs were retrieved for patients registered under the disease code K75.4 (AIH) from 2009 to 2013.A total of 4,085 patients with AIH were identified between 2009 and 2013 with a female-to-male ratio of 6.4. The age-adjusted prevalence rate was 4.82/100,000 persons and gender adjusted prevalence rates were 8.35 in females and 1.30 in males. The age-adjusted calculated incidence rate was 1.07/100,000 persons (gender-adjusted 1.83 in females and 0.31 in males). Ascites, variceal bleeding, and hepatocellular carcinoma were found in 1.4%, 1.3%, and 2.2% of the patients, respectively. Forty-six patients (1.1%) underwent liver transplantation during the study period. Case-fatality was 2.18%. Corticosteroid and azathioprine were prescribed in 44.1% and 38.0% of prevalent patients with AIH in 2013, respectively. The nationwide total direct medical cost was less than 4.0 million USD, and the average cost for each patient was 1,174 USD in 2013.This is the first report on the nationwide epidemiology of AIH in Korea, and it showed a lower prevalence than that of Western countries with considerable disease burden.

Background/AimsThe prevalence of hepatitis C virus (HCV) infection in Korea exhibits significant geographic variation, with it being higher in Busan and Jeonam than in other areas. The reason for this intranational geographic difference was investigated in this study by conducting a comparative analysis of the risk factors related to HCV infection among three geographic areas: the capital (Seoul), Busan, and the province of Jeolla.MethodsIn total, 990 patients with chronic HCV infection were prospectively enrolled at 5 university hospitals located in Seoul (n=374), Busan (n=264), and Jeolla (n=352). A standardized questionnaire survey on the risk factors for HCV infection was administered to these three groups of patients, and a comparative analysis of the findings was performed.ResultsThe analysis revealed significant regional differences in exposure to the risk factors of HCV infection. By comparison with patients in Seoul as a control group in the multivariate analysis, patients in Busan had significantly more experience of invasive medical procedures, acupuncture, cosmetic procedures, and multiple sex partners. In contrast, patients in Jeolla were significantly older, and they had a higher prevalence of hepatocellular carcinoma, a lower prevalence of multiple sex partners, and had experienced fewer invasive procedures.ConclusionsThere was a significant geographic difference in the exposure to potential risk factors of HCV infection between patients from the three studied regions. This may explain the regional variation of the prevalence of HCV infection in Korea, and should be taken into account when planning strategies for the prevention and management of HCV infection.

Background/AimsPortal-vein thrombosis (PVT) develops in 10-25% of cirrhotic patients and may aggravate portal hypertension. There are few data regarding the effects of anticoagulation on nonmalignant PVT in liver cirrhosis. The aim of this study was to elucidate the safety, efficacy, and predictors of response to anticoagulation therapy in cirrhotic patients.MethodsPatients with liver cirrhosis and nonmalignant PVT were identified by a hospital electronic medical record system (called BESTCARE). Patients with malignant PVT, Budd-Chiari syndrome, underlying primary hematologic disorders, or preexisting extrahepatic thrombosis were excluded from the analysis. Patients were divided into two groups (treatment and nontreatment), and propensity score matching analysis was performed to identify control patients. The sizes of the thrombus and spleen were evaluated using multidetector computed tomography.ResultsTwenty-eight patients were enrolled in this study between 2003 and 2014: 14 patients who received warfarin for nonmalignant PVT and 14 patients who received no anticoagulation. After 112 days of treatment, 11 patients exhibited significantly higher response rates (complete in 6 and partial in 5) compared to the control patients, with decreases in thrombus size of >30%. Compared to nonresponders, the 11 responders were older, and had a thinner spleen and fewer episodes of previous endoscopic variceal ligations, whereas pretreatment liver function and changes in prothrombin time after anticoagulation did not differ significantly between the two groups. Two patients died after warfarin therapy, but the causes of death were not related to anticoagulation.ConclusionsWarfarin can be safely administered to cirrhotic patients with nonmalignant PVT. The presence of preexisting portal hypertension is a predictor of nonresponse to anticoagulation.

Background/AimsThe distribution of hepatitis C virus (HCV) genotypes varies geographically. In Korea, genotypes 1 and 2 comprise more than 90% of HCV infections, while genotype 6 is very rare. This study compared the clinical and epidemiological characteristics of patients with genotype 6 HCV infection with those infected with HCV genotypes 1 and 2.MethodsThis was a prospective, multicenter HCV cohort study that enrolled 1,173 adult patients, of which 930 underwent HCV genotype analysis, and only 9 (1.0%) were found to be infected with genotype 6 HCV. The clinical and epidemiological parameters of the genotypes were compared.ResultsThe patients with genotype 6 HCV had a mean age of 41.5 years, 77.8% were male, and they had no distinct laboratory features. A sustained virologic response (SVR) was observed in four (67%) of six patients who received antiviral therapy. Risk factors such as the presence of a tattoo (n=6, 66.7%), more than three sexual partners (n=3, 33.3%), and injection drug use (n=3, 33.3%) were more common among genotype 6 patients than among genotypes 1 or 2.ConclusionsThe epidemiology and treatment response of patients infected with genotype 6 HCV differed significantly from those with genotypes 1 or 2, warranting continuous monitoring.

Alpha-fetoprotein (AFP) is the most widely used serum biomarker for hepatocellular carcinoma (HCC), despite its limitations. As complementary biomarkers, protein induced by vitamin K absence (PIVKA-II), osteopontin (OPN), and Dickkopf-1 (DKK-1) have been proposed. This study aimed to perform a head-to-head comparison of the diagnostic performance of AFP, PIVKA-II, OPN and DKK-1 as single or in combination to seek the best biomarker or panel, and to investigate the clinical factors affecting their performance.Using 401 stored plasma samples obtained from 208 HCC patients and 193 liver cirrhosis control patients, plasma AFP, PIVKA-II, OPN and DKK-1 levels were measured by ELISA, and receiver operating characteristic curve analyses were performed for each biomarker and for every combination of two to four markers.Of the four biomarkers, AFP showed the highest area under the curve (0.786). The sensitivity and specificity for each single biomarker was 62% and 90.2% (AFP>20 ng/mL), 51.0% and 91.2% (PIVKA-II>10 ng/mL), 46.2% and 80.3% (OPN>100 ng/mL), and 50.0% and 80.8% (DKK-1>500 pg/mL), respectively. Among the combinations of two biomarkers, AFP>20 ng/mL or DKK-1>500 pg/mL showed the best diagnostic performance (sensitivity 78.4%, specificity 72.5%). Triple or quadruple combination did not improve the diagnostic performance further. The patient's age, etiology and tumor invasiveness of HCC affected the performance of each marker.AFP was the most useful single biomarker for HCC diagnosis, and the combined measurement of AFP and DKK-1 could maximize the diagnostic yield. Clinical decision should be based on the consideration of various factors affecting the diagnostic performance of each biomarker. Efforts to seek novel HCC biomarkers should be continued.

Epidemiological data indicate that type 2 diabetes is associated with increased risk of hepatocellular carcinoma (HCC). However, risk stratification for HCC has not been fully elucidated in diabetic population. The aim of this study was to identify potential predictors of HCC in diabetic patients without chronic viral hepatitis. A cohort of 3,544 diabetic patients without chronic viral hepatitis or alcoholic cirrhosis was established and subjects were randomly allocated into a derivation and a validation set. A scoring system was developed by using potential predictors of increased risk of HCC from the Cox proportional hazards model. The performance of the scoring system was tested for validation by using receiver operating characteristics analysis. During median follow-up of 55 months, 36 cases of HCC developed (190 per 100,000 person-years). The 5- and 10-year cumulative incidences of HCC were 1.0%, and 2.2%, respectively. Multivariate Cox regression analysis showed that age > 65 years, low triglyceride levels and high gamma-glutamyl transferase levels were independently associated with an increased risk of HCC. DM-HCC risk score, a weighted sum of scores from these 3 parameters, predicted 10-year development of HCC with area under the receiver operating characteristics curve of 0.86, and discriminated different risk categories for HCC in the derivation and validation cohort. In conclusion, old age, low triglyceride level and high gamma-glutamyl transferase level may help to identify individuals at high risk of developing HCC in diabetic patients without chronic viral hepatitis or alcoholic cirrhosis.

Although alpha-fetoprotein (AFP) is the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance, disease activity may also increase AFP levels in chronic hepatitis B (CHB). Since nucleos(t)ide analog (NA) therapy may reduce not only HBV viral loads and transaminase levels but also the falsely elevated AFP levels in CHB, we tried to determine whether exposure to NA therapy influences AFP performance and whether selective application can optimize the performance of AFP testing in CHB during HCC surveillance. A retrospective cohort of 6,453 CHB patients who received HCC surveillance was constructed from the electronic clinical data warehouse. Covariates of AFP elevation were determined from 53,137 AFP measurements, and covariate-specific receiver operating characteristics regression analysis revealed that albumin levels and exposure to NA therapy were independent determinants of AFP performance. C statistics were largest in patients with albumin levels ≥ 3.7 g/dL who were followed without NA therapy during study period, whereas AFP performance was poorest when tested in patients with NA therapy during study and albumin levels were < 3.7 g/dL (difference in C statics = 0.35, p < 0.0001). Contrary to expectation, CHB patients with current or recent exposure to NA therapy showed poorer performance of AFP during HCC surveillance. Combination of concomitant albumin levels and status of NA therapy can identify subgroup of CHB patients who will show optimized AFP performance.