Publications by authors named "Sang Bong Ahn"

59 Publications

Longitudinal renal changes in chronic hepatitis B patients treated with entecavir versus TDF: a REAL-B study.

Hepatol Int 2021 Nov 25. Epub 2021 Nov 25.

Department of Medicine, the University of Hong Kong, Hong Kong SAR, China.

Background And Aims: We aimed to compare the longitudinal changes in estimated glomerular filtration rate (eGFR) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF).

Methods: This is a retrospective study of 6189 adult treatment-naïve CHB patients initiated therapy with TDF (n = 2482) or ETV (n = 3707) at 25 international centers using multivariable generalized linear modeling (GLM) to determine mean eGFR (mL/min/1.73 m) and Kaplan-Meier method to estimate incidence of renal impairment (≥ 1 chronic kidney disease [CKD] stage worsening). We also examined above renal changes in matched ETV and TDF patients (via propensity score matching [PSM] on age, sex, diabetes mellitus [DM], hypertension [HTN], cirrhosis, baseline eGFR, and follow-up duration).

Results: In the overall cohort (mean age 49.7 years, 66.2% male), the baseline eGFR was higher for TDF vs. ETV group (75.9 vs. 74.0, p = 0.009). PSM yielded 1871 pairs of ETV or TDF patients with baseline eGFR ≥ 60 and 520 pairs for the eGFR < 60 group. GLM analysis of the overall (unmatched) cohort and PSM cohorts revealed lower adjusted mean eGFRs in TDF (vs. ETV) patients (all p < 0.01) during 10 years of follow-up. Among PSM eGFR ≥ 60 patients, the 5-year cumulative incidences of renal impairment were 42.64% for ETV and 48.03% for TDF (p = 0.0023). In multivariable Cox regression, TDF vs. ETV (adjusted HR 1.26, 95% CI 1.11-1.43) was associated with higher risk of worsening renal function.

Conclusion: Over the 10-year study follow-up, compared to ETV, TDF was associated with a lower mean eGFR and higher incidence of renal impairment.
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http://dx.doi.org/10.1007/s12072-021-10271-xDOI Listing
November 2021

BTT-105 ameliorates hepatic fibrosis in non-alcoholic fatty liver animal model.

FASEB J 2021 11;35(11):e21979

Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Republic of Korea.

BTT-105 (1-O-hexyl-2,3,5-trimethylhydroquinone), a hydroquinone derivative, is a potent anti-oxidant that was safe and tolerable in phase I clinical trial. This study examined the anti-fibrotic effect of BTT-105 in a mouse model of non-alcoholic fatty liver disease (NAFLD) along with the underlying mechanisms. In vivo, efficacy of BTT-105 evaluated from three kinds of NAFLD models (methionine/choline deficient diet (MCD), high fat diet (HF) and western diet (WD)). Metabolomics and transcriptomics profiling analysis in liver tissues were conducted. In vitro, anti-fibrotic effect of BTT-105 assessed in human hepatic stellated cells (HSCs) and primary mouse HSCs. BTT-105 improved NAFLD activity score in three kinds of NAFLD animal models (MCD, HF, and WD). BTT-105 also decreased levels of hepatic pro-collagen and collagen fibers deposition in liver tissue. Metabolome and transcriptome analysis revealed that BTT-105 decreased lipid metabolites and increased antioxidants in NAFLD mice. In HepG2 cells, BTT-105 enhanced Nrf2-ARE reporter activity in a dose-dependent manner and increased the levels of antioxidant gene expression. BTT-105 showed inhibition of HSCs activation and migration. Gene expression profiling and protein expression showed that BTT-105 increased Nrf2 activation as well as decreased PI3K-Akt pathway in activated HSCs. BTT-105 attenuated ameliorates steatohepatitis and hepatic fibrosis.
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http://dx.doi.org/10.1096/fj.202002656RRRDOI Listing
November 2021

On-treatment gamma-glutamyl transferase predicts the development of hepatocellular carcinoma in chronic hepatitis B patients.

Liver Int 2021 Oct 23. Epub 2021 Oct 23.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background & Aims: Gamma-glutamyl transferase (GGT) has been predictive of chronic hepatitis C-related hepatocellular carcinoma (HCC) development. Its role in the risk of HCC in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs) is elusive.

Methods: A total of 2172 CHB patients from East Asia were randomized into development and validation groups in a 1:2 ratio. Serum GGT levels before and 6 months (M6) after initiating NAs and the potential risk factors were measured. The primary endpoint was HCC development 12 months after NA initiation.

Results: The annual incidence of HCC was 1.4/100 person-years in a follow-up period of 11 370.7 person-years. The strongest factor associated with HCC development was high M6-GGT levels (>25 U/L; hazard ratio [HR]/95% confidence interval [CI]: 3.31/2.02-5.42, P < .001), followed by cirrhosis (HR/CI: 2.06/1.39-3.06, P < .001), male sex (HR/CI: 2.01/1.29-3.13, P = .002) and age (HR/CI: 1.05/1.03-1.17, P < .001). Among cirrhotic patients, the incidence of HCC did not differ between those with high or low M6-GGT levels (P = .09). In contrast, among non-cirrhotic patients, the incidence of HCC was significantly higher for those with M6-GGT level >25 U/L than for their counterparts (P < .001). Cox regression analysis revealed that the strongest factor associated with HCC development in non-cirrhotic patients was high M6-GGT levels (HR/CI: 5.05/2.52-10.16, P < .001), followed by age (HR/CI: 1.07/1.04-1.09, P < .001). Non-cirrhotic elderly patients with high M6-GGT levels had a similarly high HCC risk as cirrhotic patients did (P = .29).

Conclusions: On-treatment serum GGT levels strongly predicted HCC development in CHB patients, particularly non-cirrhotic patients, treated with NAs.
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http://dx.doi.org/10.1111/liv.15085DOI Listing
October 2021

Nationwide Data on the Characteristics of Linked-to-Care Chronic Hepatitis B in Korea.

J Clin Med 2021 Oct 9;10(20). Epub 2021 Oct 9.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA 94305, USA.

Linkage-to-care rate of chronic hepatitis B (CHB) is less well characterized. We aimed to evaluate the proportion, characteristics of CHB patients who are linked to care. We retrospectively analyzed insurance reimbursement claims data provided by the Korean National Health Insurance Service. CHB patients who had at least two clinic or hospital visits that were associated with a CHB diagnostic code during 2002-2006 were included. Those without a history of malignancy at baseline were followed up until 2018. Mean follow-up period was 14.5 ± 2.9 years. Among the participants, 553,085 patients (35.8%) were found to be linked to care. The rates were lower in men than women (35.7% vs. 36.0%, = 0.006). By age, it was highest for the 40's age group at 44.8% and lowest at 29.4% for the 20's age group (All < 0.0001). The linkage-to-care rate was higher in rural area than metropolitan area ( < 0.0001). The 15-year cumulative incidence of hepatocellular carcinoma and overall survival rates among linked-to-care CHB patients were 18.2% and 93.8%, respectively. Two thirds of CHB patients were not linked to care. Those who are male, dwelling in metropolitan areas, and not in life transition periods need to be targeted to improve the linkage-to-care rate in Korea.
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http://dx.doi.org/10.3390/jcm10204633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540784PMC
October 2021

An artificial intelligence model to predict hepatocellular carcinoma risk in Korean and Caucasian patients with chronic hepatitis B.

J Hepatol 2021 Oct 2. Epub 2021 Oct 2.

Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada.

Background & Aims: Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk.

Methods: Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development.

Results: In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p <0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p <0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up.

Conclusions: This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir.

Lay Summary: Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.
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http://dx.doi.org/10.1016/j.jhep.2021.09.025DOI Listing
October 2021

Dairy protein intake is inversely related to development of non-alcoholic fatty liver disease.

Clin Nutr 2021 10 25;40(10):5252-5260. Epub 2021 Aug 25.

Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin-si, Gyeonggi-do, 16995, Republic of Korea. Electronic address:

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is closely related to metabolic dysfunction, including insulin resistance, obesity, and metabolic syndrome. Dairy protein, rich in casein and whey protein, could help to reduce metabolic diseases. Therefore, we investigated the relationship between dairy protein intake and incident NAFLD.

Methods: We analyzed data for 5171 adults aged 40-69 years from the Korean Genome and Epidemiology Study.(KoGES) Participants were separated as men, women aged ≥50 years, and women aged <50 years and then divided into tertiles based on dairy protein intake. NAFLD was defined as NAFLD liver fat score >-0.640. Scores were calculated as 1.18 × metabolic syndrome (Yes: 1, No: 0) + 0.45 × diabetes mellitus (Yes: 2, No: 0) + 0.15 × serum insulin +0.04 × AST - 0.94 × (AST/ALT) - 2.89. Cox proportional hazards spline curves were drawn to visualize dose-response relationships between dairy protein intake and incident NAFLD. Multiple Cox hazard regression analysis was conducted to examine associations between dairy protein intake and incident NAFLD.

Results: The Cox proportional hazards spline curves revealed a negative linear relationship between dairy protein intake and incident NAFLD. The cumulative incidence of NAFLD significantly decreased with increasing tertiles of dairy protein intake in men and women aged ≥50 years. After adjusting for confounding factors, the hazard ratios and 95% confidence intervals for NAFLD in the middle and highest tertiles, compared to the lowest tertile, were 0.80 (0.67-0.96) and 0.71 (0.57-0.88) in men, 0.89 (0.72-1.09) and 0.72 (0.56-0.92) in women aged ≥50 years, and 1.01 (0.80-1.27) and 0.91 (0.67-1.24) in women aged <50 years, respectively.

Conclusions: We found that higher dairy protein intake was significantly and inversely associated with the risk of incident NAFLD in men and women aged ≥50 years. Consumption of milk and other dairy products could help prevent the development of NAFLD.
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http://dx.doi.org/10.1016/j.clnu.2021.08.012DOI Listing
October 2021

Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B.

Clin Gastroenterol Hepatol 2021 Sep 6. Epub 2021 Sep 6.

Hospital U Puerta de Hierro, IDIPHIM CIBERehd, Madrid, Spain.

Background & Aims: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC.

Methods: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort.

Results: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67).

Conclusions: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.
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http://dx.doi.org/10.1016/j.cgh.2021.09.001DOI Listing
September 2021

KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease.

Clin Mol Hepatol 2021 Jul 22;27(3):363-401. Epub 2021 Jun 22.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3350/cmh.2021.0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273632PMC
July 2021

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Department of Internal Medicine, Saga University Hospital, Saga, Japan.

Background & Aims: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines.

Methods: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years.

Results: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria.

Conclusion: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.
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http://dx.doi.org/10.1016/j.cgh.2021.05.062DOI Listing
June 2021

Optimal Hypoxic Preconditioning of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells (hES-MSCs) and Their Characteristics.

Int J Stem Cells 2021 May;14(2):221-228

Department of Internal Medicine, Eulji University School of Medicine, Seoul, Korea.

Background And Objectives: Hypoxia is frequently used to enhance stem cell function. However, the optimal level of hypoxia for growth and function of human embryonic stem cell-derived mesenchymal stem cells (hES-MSCs) is yet to be determined. The purpose of this study was to find the optimal level of hypoxia for hES-MSCs and characteristics of hES-MSCs cultured under these optimal hypoxic conditions.

Methods And Results: Cell viability and changes in the morphology of hES-MSCs were determined through cell proliferation and CCK-8 assay. The hES-MSCs were preconditioned under various hypoxic conditions (0.5∼5% O and 24∼72 h). The expression of cytokines in each culture condition was compared using cytokine array analysis. The morphology of hES-MSCs did not change under various hypoxic culture conditions. hES-MSCs viability after 48 h incubation in 2% O condition was higher than that in normoxic condition. HIF1 expression was increased up to six folds after 48 h of hypoxic preconditioning. HIF1 expression in hES-MSCs peaked after 48 h of incubation in 1% O condition. The expressions of PDGF-BB, IGFBP-6, VEGF-A, and angiogenin were increased after hES-MSCs were incubated for 48 h in 2% O condition.

Conclusions: The hES-MSCs viability and expressions of PDGF-BB, IGFBP-6, VEGF-A, and angiogenin increased after 48 h incubation in 2% O condition.
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http://dx.doi.org/10.15283/ijsc20096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138663PMC
May 2021

Twelve-month post-treatment parameters are superior in predicting hepatocellular carcinoma in patients with chronic hepatitis B.

Liver Int 2021 07 2;41(7):1652-1661. Epub 2021 Mar 2.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

Background & Aims: There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population.

Methods: We included two treatment-naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n = 1480, Korea prospective SAINT cohort) and the validation cohort (n = 426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method.

Results: We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-foetoprotein and platelet at 12 months showed the best performance (AUROC = 0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC = 0.844) and better than other existing prediction models including the APA, PAGE-B and GAG models (AUROC = 0.769 to 0.818).

Conclusions: We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487).
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http://dx.doi.org/10.1111/liv.14820DOI Listing
July 2021

NASH/Liver Fibrosis Prevalence and Incidence of Nonliver Comorbidities among People with NAFLD and Incidence of NAFLD by Metabolic Comorbidities: Lessons from South Korea.

Dig Dis 2021 3;39(6):634-645. Epub 2021 Feb 3.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA.

Background: NAFLD incidence, NASH prevalence, NAFLD fibrosis prevalence, incidence of metabolic comorbidities, and mortality data in the NAFLD population remain limited.

Aims: We used a meta-analytic approach to "stage" NAFLD among the Korean population.

Methods: We searched PubMed, Embase, Cochrane Library, and KoreaMed from inception until June 29, 2019, and calculated pooled estimates via the random-effects model.

Results: We screened 1,485 studies and analyzed 191 eligible studies: 179 (3,556,579 participants) for NAFLD prevalence and outcome analysis and 32 (1,089,785 participants) for NAFLD incidence analysis. NAFLD prevalence was 31.46% overall and 50-60% in those with metabolic risks. The incidence (per 1,000 person-years) of NAFLD was 42.8 overall and 70-77% in those with metabolic risk. The incidence (per 1,000 person-years) of new-onset T2DM, hypertension, cardiovascular disease, and chronic kidney disease was found to be 16.9, 47.9, 100.6, and 13.9, respectively. From biopsy data, 30.21% of the NAFLD population had moderate-to-severe steatosis (9 studies, 2,461 participants) and 52.27% had NASH (7 studies, 1,168 participants) and 85.41% had fibrosis
Conclusions: The overall prevalence of NAFLD was 31.46% with an incidence rate of 42.8 per 1,000 person-years. NASH prevalence was 52% but <15% had significant fibrosis. The prevalence and incidence of nonliver comorbidities was high especially for cardiovascular disease incidence. The burden of NAFLD is high in Korea. Health policy efforts need to be directed towards reversing the course of NAFLD disease.
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http://dx.doi.org/10.1159/000514953DOI Listing
November 2021

Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.

Hepatol Int 2021 Feb 4;15(1):71-81. Epub 2021 Jan 4.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Hepatitis Research Center, College of Medicine and Cohort Research Center and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.

Methods: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.

Results: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.

Conclusion: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.
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http://dx.doi.org/10.1007/s12072-020-10113-2DOI Listing
February 2021

HCC risk post-SVR with DAAs in East Asians: findings from the REAL-C cohort.

Hepatol Int 2020 Dec 4;14(6):1023-1033. Epub 2020 Dec 4.

Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.

Background: Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients.

Methods: To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups.

Results: In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p < 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p < 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005).

Conclusions: Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.
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http://dx.doi.org/10.1007/s12072-020-10105-2DOI Listing
December 2020

Type 2 Diabetes: A Risk Factor for Hospital Readmissions and Mortality in Australian Patients With Cirrhosis.

Hepatol Commun 2020 Sep 30;4(9):1279-1292. Epub 2020 Jun 30.

QIMR Berghofer Medical Research Institute Herston Australia.

Although there is evidence that type 2 diabetes mellitus (T2D) impacts adversely on liver-related mortality, its influence on hospital readmissions and development of complications in patients with cirrhosis, particularly in alcohol-related cirrhosis (the most common etiological factor among Australian hospital admissions for cirrhosis) has not been well studied. This study aimed to investigate the association between T2D and liver cirrhosis in a population-based cohort of patients admitted for cirrhosis in the state of Queensland, Australia. A retrospective cohort analysis was conducted using data from the Queensland Hospital Admitted Patient Data Collection, which contains information on all hospital episodes of care for patients with liver cirrhosis, and the Death Registry during 2008-2017. We used demographic, clinical data, and socioeconomic characteristics. A total of 8,631 patients were analyzed. A higher proportion of patients with T2D had cryptogenic cirrhosis (42.4% vs. 27.3%, respectively;  < 0.001) or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (13.8% vs. 3.4%, respectively;  < 0.001) and an admission for hepatocellular carcinoma (18.0% vs. 12.2%, respectively;  < 0.001) compared to patients without T2D. Patients with liver cirrhosis with T2D compared to those without T2D had a significantly increased median length of hospital stay (6 [range, 1-11] vs. 5 [range, 1-11] days, respectively;  < 0.001), double the rate of noncirrhosis-related admissions (incidence rate ratios [IRR], 2.03; 95% confidence interval [CI], 1.98-2.07), a 1.35-fold increased rate of cirrhosis-related admissions (IRR, 1.35; 95% CI, 1.30-1.41), and significantly lower survival ( < 0.001). Among hospitalized patients with cirrhosis, the cohort with T2D is at higher risk and may benefit from attention to comorbidities and additional support to reduce readmissions.
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http://dx.doi.org/10.1002/hep4.1536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471423PMC
September 2020

No Difference in Incidence of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection Treated With Entecavir vs Tenofovir.

Clin Gastroenterol Hepatol 2020 11 2;18(12):2793-2802.e6. Epub 2020 Mar 2.

Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background & Aims: Studies to evaluate risks of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with the nucelos(t)ide analogues entecavir or tenofovir have produced contradictory results. These differences are likely to be the result of censored data, insufficient observation periods, and different observation periods for patients treated with different drugs. We aimed to compare the incidence of HCC development between patients treated with oral entecavir or tenofovir and followed up for the same time periods.

Methods: We performed a retrospective study, collecting data from 1560 treatment-naive patients with chronic HBV infection who were first treated with entecavir (n = 753) or tenofovir (n = 807) from 2011 through 2015 at 9 academic hospitals in Korea. Clinical outcomes were recorded over a mean time period of 4.7 ± 1.0 years, from 92.4% of patients treated with tenofovir and 92.7% of patients treated with entecavir.

Results: Thirty-four patients in the entecavir group (4.5%) and 45 patients in the tenofovir group (5.6%) developed HCC during the follow-up period. The incidence of HCC did not differ significantly between groups, even in a 516-pair propensity score-matched population.

Conclusions: In a retrospective study of 1560 treatment-naive patients with chronic HBV infection, the incidence of HCC did not differ significantly between patients treated with entecavir vs tenofovir over the same observation period.

Clinical Trial: KCT0003487.
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http://dx.doi.org/10.1016/j.cgh.2020.02.046DOI Listing
November 2020

Role of innate lymphoid cells in chronic colitis during anti-IL-17A therapy.

Sci Rep 2020 01 15;10(1):297. Epub 2020 Jan 15.

Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea.

IL-17A is an important cytokine in intestinal inflammation. However, anti-IL-17A therapy does not improve clinical outcomes in patients with Crohn's disease. We aimed to evaluate the role of RORγt innate lymphoid cells (ILCs) in murine colitis models in the absence of IL-17A. An acute colitis model was induced with either dextran sulfate sodium (DSS) or trinitrobenzenesulfonic acid (TNBS) and a chronic colitis model was induced by CD4CD45RB T cell transfer from either wild-type C57BL/6 or Il17a mice. An anti-IL-17A antibody, secukinumab, was also used to inhibit IL-17A function in the colitis model. Flow cytometry was performed to analyze the population of RORγt ILCs in the colonic lamina propria of mice with chronic colitis. Acute intestinal inflammation due to DSS and TNBS was attenuated in IL-17A knockout mice, whereas chronic colitis was not relieved by T cell transfer from Il17a mice (% of original body weight: wild-type mice vs. Il17a mice, 81.9% vs. 82.2%; P = 0.922). However, the mean proportion of LinRORγt lymphocytes was higher after T cell transfer from Il17a mice than that after T cell transfer from wild-type mice (28.8% vs. 18.5%). The proportion of LinRORγt was also increased in Rag2 mice that received T cell transfer from wild-type mice when anti-IL-17A antibody was administered (31.7%). Additionally, Il6 and Il22 tended to be highly expressed after T cell transfer from Il17a mice. In conclusion, RORγt ILCs may have an important role in the pathogenesis of chronic colitis in the absence of IL-17A. Blocking the function of IL-17A may upregulate Il6 and recruit RORγt ILCs in chronic colitis, thereby upregulating IL-22 and worsening the clinical outcomes of patients with Crohn's disease.
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http://dx.doi.org/10.1038/s41598-019-57233-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962146PMC
January 2020

Effects of vitamin D supplements in patients with chronic hepatitis C: a randomized, multi-center, open label study.

Korean J Intern Med 2020 09 12;35(5):1074-1083. Epub 2019 Nov 12.

Department of Internal Medicine, Eulji University School of Medicine, Seoul, Korea.

Background/aims: We aimed to assess the role of vitamin D supplementation in the response to pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV) treatment in patients with chronic hepatitis C (CHC).

Methods: Our study was a multi-center, randomized controlled trial in 11 hospitals. CHC patients were randomly assigned (1:1) to two groups namely, PEGIFN-α plus RBV (control group) or PEG-IFN-α plus RBV + vitamin D (800 IU daily) (vitamin D group). The primary end-point was the rate of sustained virologic response (SVR).

Results: One hundred forty eight CHC patients were randomly assigned to two groups. Seventy-one patients received the PEG-IFN-α plus RBV and 77 patients received the PEG-IFN-α plus RBV + vitamin D. A total of 105 patients completed the study (control group, 47 vs. vitamin D group, 58). Baseline characteristics were mostly similar in both the groups. There was a modest but non-significant increase in SVR in the vitamin D group compared to the control group with the intention to treat analysis (64.0% vs. 49.3 %, p = 0.071) as well as in the per protocol analysis (control group vs. vitamin D group: 74.5% vs. 84.5%, p = 0.202). Fifty-two patients (73.2%) in the control group and 63 patients (81.8%) in the vitamin D group experienced at least one adverse event. The drop-out rate due to adverse effects was not different between both groups (control group vs. vitamin D group: 19.7% vs. 10.4%, p = 0.111).

Conclusion: Vitamin D supplement did not increase SVR in treatment naïve patients with CHC irrespective of genotype.
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http://dx.doi.org/10.3904/kjim.2018.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487303PMC
September 2020

Validation of the Korean Stroop Test in Diagnosis of Minimal Hepatic Encephalopathy.

Sci Rep 2019 05 29;9(1):8027. Epub 2019 May 29.

Department of Arts & Technology, Hanyang University, Seoul, 04763, Republic of Korea.

The burden of minimal hepatic encephalopathy (MHE) is significant, but no universal criteria for diagnosis have been established. We aimed to validate the Korean Stroop Test for MHE screening. Chronic hepatitis B-related liver cirrhosis patients were recruited prospectively from 13 centers. The Korean Stroop Test consisted of two Stroop-off states (color and word) and two Stroop-on states (inhibition and switching). Accuracy adjusted psychomotor speed (rate correct score) of these tests were analyzed. Sex- and age- adjusted rate correct scores of these tests were rated as the Korean Stroop Score (K-Stroop score). MHE was diagnosed when Portosystemic Encephalopathy Syndrome Test (PHES) scores were below -4. A total of 220 liver cirrhosis patients and 376 healthy controls were enrolled. Prevalence of MHE was 20.6% in cirrhosis patients. Rate correct scores and the K-Stroop score showed significant differences between healthy controls, cirrhosis patients without MHE, and cirrhosis patients with MHE. The rate correct score of the K-Stroop score was 0.74 (95% Confidence Interval: 0.66-0.83, P < 0.001). Female gender and the K-Stroop score were significant for MHE diagnosis. The Korean Stroop Test is simple and valid for screening of MHE.
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http://dx.doi.org/10.1038/s41598-019-44503-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541633PMC
May 2019

Randomized, Double-blind, Placebo-controlled Study of a Multispecies Probiotic Mixture in Nonalcoholic Fatty Liver Disease.

Sci Rep 2019 04 5;9(1):5688. Epub 2019 Apr 5.

R&D center Microbiome, Cell Biotech, Gyeongi, Korea.

The intestinal microbiota is closely associated with the development of obesity and nonalcoholic fatty liver disease (NAFLD). This study investigated the effects of probiotic treatment on visceral fat area (VFA) and intrahepatic fat (IHF) fraction in NAFLD. Sixty-eight obese NAFLD patients (>5% proton density fat fraction [PDFF] on magnetic resonance imaging [MRI]) were randomized to probiotic and placebo groups for 12 weeks. The probiotic mixture included 6 bacterial species. VFA and IHF were measured using the MRI-PDFF technique. Body weight and total body fat were reduced in the probiotic group but not in the placebo group. The mean IHF fraction was reduced after 12 weeks of treatment in the probiotic group compared to that at baseline (from 16.3 ± 15.0% to 14.1 ± 7.7%, p = 0.032) but was not reduced in the placebo group. The decrease in IHF (mean difference: -2.61%, p = 0.012) was also greater in the probiotic group than in the placebo group. Reduction of triglyceride was greater in the probiotic treatment group than in the placebo group (mean difference: -34.0 mg/dl, p = 0.0033). However, the changes in IHF percentage and triglyceride levels were not different between placebo and control groups after adjusting for changes in body weight. Treatment with probiotics for 12 weeks resulted in significant reduction in IHF and body weight in obese NAFLD patients.
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http://dx.doi.org/10.1038/s41598-019-42059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450966PMC
April 2019

Radiation protection effect of mobile shield barrier for the medical personnel during endoscopic retrograde cholangiopancreatography: a quasi-experimental prospective study.

BMJ Open 2019 03 20;9(3):e027729. Epub 2019 Mar 20.

Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Republic of Korea.

Objective: To investigate the effectiveness of radiation protection offered by a newly designed mobile shield barrier for medical personnel during endoscopic retrograde cholangiopancreatography (ERCP).

Design: Quasi-experimental prospective study.

Setting: ERCP procedures conducted between October 2016 and June 2017 at a single secondary referral hospital that performs approximately 250 therapeutic ERCP procedures annually.

Interventions: The mobile shield barrier was a custom-made 2 mm Pb shielding plate (width: 120 cm, height: 190 cm) with a 0.5 mm Pb window (width: 115 cm, height: 60 cm) on its upper part was used. Four wheels were attached to the bottom to allow easy moving.

Primary And Secondary Outcome Measures: The radiation doses were measured during ERCP using personal thermoluminescence dosimetry (TLD) badges on both sides of the mobile shield barrier (patient's side: TLD1 and medical staff's side: TLD2). The radiation doses were also measured on the outer surface of the thyroid shield of the endoscopist (TLD3), and on the chest area inside the protective apron of the endoscopist (TLD4) and the main assistant (TLD5). The TLD was changed and reported once every 3 months. The radiation dose measured by TLD badges were compared.

Results: During the study period, a total of 128 ERCP procedures were performed. The mean fluoroscopy time per procedure was 244.9±257.0 s and the mean number of digital radiographs per procedure was 3.7±1.0. TLD1 (outside the barrier) had a mean radiation dose of 26.85±3.47 mSv and all the other TLDs (inside the barrier) had less than 1 mSv (p<0.001). In the post hoc analysis, the difference between TLD1 and others showed a statistical significance; however, there were no significant differences between the TLDs inside the barrier.

Conclusion: Our mobile shield barrier was useful to reduce the radiation exposure of medical personnel during ERCP.
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http://dx.doi.org/10.1136/bmjopen-2018-027729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527993PMC
March 2019

Mismatched effects of receptor interacting protein kinase-3 on hepatic steatosis and inflammation in non-alcoholic fatty liver disease.

World J Gastroenterol 2018 Dec;24(48):5477-5490

Department of Translational Medicine, Hanyang University College of Medicine, Seoul 04763, South Korea.

Aim: To validate the effects of receptor interacting protein kinase-3 (RIP3) deletion in non-alcoholic fatty liver disease (NAFLD) and to clarify the mechanism of action.

Methods: Wild-type (WT) and RIP3 knockout (KO) mice were fed normal chow and high fat (HF) diets for 12 wk. The body weight was assessed once weekly. After 12 wk, the liver and serum samples were extracted. The liver tissue expression levels of RIP3, microsomal triglyceride transfer protein, protein disulfide isomerase, apolipoprotein-B, X-box binding protein-1, sterol regulatory element-binding protein-1c, fatty acid synthase, cluster of differentiation-36, diglyceride acyltransferase, peroxisome proliferator-activated receptor alpha, tumor necrosis factor-alpha (TNF-α), and interleukin-6 were assessed. Oleic acid treated primary hepatocytes from WT and RIP3KO mice were stained with Nile red. The expression of inflammatory cytokines, including chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and TNF-α, in monocytes was evaluated.

Results: RIP3KO HF diet fed mice showed a significant gain in body weight, and liver weight, liver to body weight ratio, and liver triglycerides were increased in HF diet fed RIP3KO mice compared to HF diet fed WT mice. RIP3KO primary hepatocytes also had increased intracellular fat droplets compared to WT primary hepatocytes after oleic acid treatment. RIP3 overexpression decreased hepatic fat content. Quantitative real-time polymerase chain reaction analysis showed that the expression of very-low-density lipoproteins secretion markers (microsomal triglyceride transfer protein, protein disulfide isomerase, and apolipoprotein-B) was significantly suppressed in RIP3KO mice. The overall NAFLD Activity Score was the same between WT and RIP3KO mice; however, RIP3KO mice had increased fatty change and decreased lobular inflammation compared to WT mice. Inflammatory signals (CXCL1/2, TNF-α, and interleukin-6) increased after lipopolysaccharide and pan-caspase inhibitor (necroptotic condition) treatment in monocytes. Neutrophil chemokines (CXCL1, and CXCL2) were decreased, and TNF-α was increased after RIP3 inhibitor treatment in monocytes.

Conclusion: RIP3 deletion exacerbates steatosis, and partially inhibits inflammation in the HF diet induced NAFLD model.
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http://dx.doi.org/10.3748/wjg.v24.i48.5477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319133PMC
December 2018

Optimal cutoff value for assessing changes in intrahepatic fat amount by using the controlled attenuation parameter in a longitudinal setting.

Medicine (Baltimore) 2018 Dec;97(50):e13636

Biostatistical Consulting and Research Laboratory, Hanyang University, School of Medicine, Seoul, Korea.

The controlled attenuation parameter (CAP) has shown a good correlation with the intrahepatic fat amount in cross-sectional studies. However, there is no study on whether the change of CAP scores can also show good correlation in a longitudinal setting. Therefore, we investigated the correlation between CAP and magnetic resonance imaging-estimated proton density fat fraction (MR PDFF) through serial examination in a longitudinal setting.Sixty-five patients with nonalcoholic fatty liver disease were evaluated with MR PDFF and transient elastography including CAP at baseline and 3 months later.The CAP and MR PDFF at baseline showed a strong correlation in assessing hepatic steatosis (r = 0.66, P < .001). After treatment, the correlation between the change in CAP after treatment and the intrahepatic fat change (%) on MR PDFF was not satisfactory (r = 0.37, P = .005) in the longitudinal setting. The optimal cutoff value of the change in CAP for discriminating an improvement or an aggravation in intrahepatic fat percentage (>1% change in MR PDFF) was selected as 38 dB/m (area under the receiver operating characteristic curve = 0.559). For CAP changes > 38 dB/m, the predictive value was 14/16 (87.5%), whereas for changes < 38 dB/m, the predictive value was 12/41 (29.3%). Thereby, the accuracy of the method using the change in CAP was only 26/57 (46%). In addition, Cohen's kappa value was not significant (κ=0.11, P = .186).Careful interpretation of the steatosis change based on the CAP score is needed when the absolute change value is < 38 dB/m in a longitudinal setting.
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http://dx.doi.org/10.1097/MD.0000000000013636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320035PMC
December 2018

Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients: A Randomized, Multicenter, Phase IIIb Open-Label Study (POTENT Study).

Chin Med J (Engl) 2018 Jul;131(14):1645-1651

Clinical Research Center, Asan Medical Center, Seoul 05505, Korea.

Background: Until now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late-add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment.

Methods: Between June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono-treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis.

Results: HBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA <2000 U/L (28.8% vs. 28.8%, t = 0.10, P = 1.000) was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) was not different in the two groups (12.1% vs. 16.7%, t = 1.83, P = 0.457). Baseline HBV-DNA level (7 logU/ml vs. 7.5 logU/ml, t = 1.70, P = 0.019) and hepatitis B surface antigen titer (3.6 logU/ml vs. 4.0 logU/ml, t = 2.19, P = 0.020) were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively.

Conclusions: The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens.

Trial Registration: ClinicalTrials.gov, NCT01220596; https://clinicaltrials.gov/ct2/show/NCT01220596?term=NCT01220596&rank=1.
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http://dx.doi.org/10.4103/0366-6999.235880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048918PMC
July 2018

Duodenal Niemann-Pick C1-like 1 expression was negatively correlated with liver X receptor expression in nonalcoholic fatty liver disease.

Korean J Intern Med 2019 Jul 23;34(4):777-784. Epub 2018 Feb 23.

College of Pharmacy, The Catholic University of Korea, Bucheon, Korea.

Background/aims: Intestinal cholesterol absorption includes intestinal Niemann-Pick C1-like 1 (NPC1L1) and is an important target pathway in nonalcoholic fatty liver disease (NAFLD). We investigated the expression of NPC1L1 and its correlation with liver X receptor (LXR) expression in peripheral mononuclear (PMN) cells in patients with NAFLD.

Methods: We evaluated intestinal expression of NPC1L1 in 25 NAFLD patients and 28 healthy controls. We calculated the mRNA expression levels of LXR and farnesoid X receptor (FXR), which are master players of cholesterol metabolism in PMN cells. The protein expression of ABCA1, ABCG5/8, NPC1L1, SREBP, LXR, FXR, and CD36 was measured on tissue samples from the duodenum and ileum.

Results: The expression of LXR (p = 0.01) and FXR (p = 0.03) in PMN cells was increased in the NAFLD group compared to the control group. Duodenal NPC1L1 decreased in the NAFLD group compared to the healthy controls (3.38 ± 1.4 vs. 2.42 ± 1.2, p = 0.05). NPC1L1 expression in the duodenum was negatively correlated with LXR expression in PMN cells. Expression of LXR and FXR in the ileum was also negatively correlated with the expression of LXR in PMN cells.

Conclusion: Duodenal NPC1L1 expression was decreased in NAFLD and was negatively correlated with LXR expression in PMN cells.
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http://dx.doi.org/10.3904/kjim.2017.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610185PMC
July 2019

Fermented Soymilk Alleviates Lipid Accumulation by Inhibition of SREBP-1 and Activation of NRF-2 in the Hepatocellular Steatosis Model.

J Microbiol Biotechnol 2018 Feb;28(2):236-245

Eulji Medi-Bio Research Institute (EMBRI), Eulji University, Daejeon 34824, Republic of Korea.

Ingredients of soy and fermented soy products have been widely utilized as food supplements for health-enhancing properties. The aim of this study was to evaluate the effects of fermented soymilk (FSM) and soymilk (SM) on free fatty acid-induced lipogenesis in the hepatocellular steatosis model. HepG2 cells were incubated with palmitic acid (PA) for 24 h to induce lipogenesis and accumulation of intracellular lipid contents. The PA-treated cells were co-incubated with FSM, SM, genistein, and estrogen, respectively. Lipid accumulation in the PA-treated HpG2 cells was significantly decreased by co-incubation with FSM. Treatment of HepG2 cells with PA combined with genistein or estrogen significantly increased the expression of SREBP-1. However, FSM co-incubation significantly attenuated SREBP-1 expression in the PA-treated HepG2 cells; in addition, expression of NRF-2 and phosphorylation of ERK were significantly increased in the PA and FSM co-incubated cells. PA-induced ROS production was significantly reduced by FSM and SM. Our results suggested that the bioactive components of FSM could protect hepatocytes against the lipid accumulation and ROS production induced by free fatty acids. These effects may be mediated by the inhibition of SREBP-1 and the activation of NRF-2 via the ERK pathway in HepG2 cells.
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http://dx.doi.org/10.4014/jmb.1707.07061DOI Listing
February 2018

Validation of a Paper and Pencil Test Battery for the Diagnosis of Minimal Hepatic Encephalopathy in Korea.

J Korean Med Sci 2017 Sep;32(9):1484-1490

Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Korea.

The aim of this study was to validate a new paper and pencil test battery to diagnose minimal hepatic encephalopathy (MHE) in Korea. A new paper and pencil test battery was composed of number connection test-A (NCT-A), number connection test-B (NCT-B), digit span test (DST), and symbol digit modality test (SDMT). The norm of the new test was based on 315 healthy individuals between the ages of 20 and 70 years old. Another 63 healthy subjects (n = 31) and cirrhosis patients (n = 32) were included as a validation cohort. All participants completed the new paper and pencil test, a critical flicker frequency (CFF) test and computerized cognitive function test (visual continuous performance test [CPT]). The scores on the NCT-A and NCT-B increased but those of DST and SDMT decreased according to age. Twelve of the cirrhotic patients (37.5%) were diagnosed with MHE based on the new paper and pencil test battery. The total score of the paper and pencil test battery showed good positive correlation with the CFF (r = 0.551, P < 0.001) and computerized cognitive function test. Also, this score was lower in patients with MHE compared to those without MHE (P < 0.001). Scores on the CFF (32.0 vs. 28.7 Hz, P = 0.028) and the computer base cognitive test decreased significantly in patients with MHE compared to those without MHE. Test-retest reliability was comparable. In conclusion, the new paper and pencil test battery including NCT-A, NCT-B, DST, and SDMT showed good correlation with neuropsychological tests. This new paper and pencil test battery could help to discriminate patients with impaired cognitive function in cirrhosis (registered at Clinical Research Information Service [CRIS], https://cris.nih.go.kr/cris, KCT0000955).
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http://dx.doi.org/10.3346/jkms.2017.32.9.1484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546968PMC
September 2017

Comparison of efficacy of low-carbohydrate and low-fat diet education programs in non-alcoholic fatty liver disease: A randomized controlled study.

Hepatol Res 2018 Feb 4;48(3):E22-E29. Epub 2017 Jul 4.

Department of Internal Medicine, Eulji University, Seoul, South Korea.

Aim: Composition of macronutrients is important in non-alcoholic fatty liver disease (NAFLD). Diet education programs that mainly emphasize reducing fat consumption have been used for NAFLD patients. We compared the efficacy of conventional low-fat diet education with low-carbohydrate diet education in Korean NAFLD patients.

Methods: One hundred and six NAFLD patients were randomly allocated to low-fat diet education or low-carbohydrate education groups for 8 weeks. Liver chemistry, liver / spleen ratio, and visceral fat using abdominal tomography were measured.

Results: Intrahepatic fat accumulation decreased significantly in the low-carbohydrate group compared to low-fat group (liver/spleen 0.85 vs. 0.92, P < 0.05). Normalization of ALT activity at week 8 was 38.5% for the low-carbohydrate and 16.7% for the low-fat group (P = 0.016). Not only liver enzyme, but also low density lipoprotein cholesterol and blood pressure levels significantly decreased in the low-carbohydrate group. Total energy intake was also further decreased in the low-carbohydrate group compared to the low-fat group. Although body weight changes were not different between the two groups, the carbohydrate group had a lower total abdominal fat amount.

Conclusions: A low-carbohydrate diet program is more realistic and effective in reducing total energy intake and hepatic fat content in Korean NAFLD patients. This trial is registered with the National Research Institute of Health: KCT0000970 (https://cris.nih.go.kr/cris/index.jsp).
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http://dx.doi.org/10.1111/hepr.12918DOI Listing
February 2018

A High Ki67/BCL2 Index Could Predict Lower Disease-Free and Overall Survival in Intestinal-Type Gastric Cancer.

Eur Surg Res 2017 9;58(3-4):158-168. Epub 2017 Mar 9.

Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea.

Background: The heterogeneity of gastric cancer makes the identification of potential prognostic indicators particularly important. The Ki67 and BCL2 proteins are known prognostic markers for different types of cancer. Ki67 is associated with cell proliferation, whereas BCL2 has antiproliferative roles. A combined marker based on these opposite functions might provide improved prognostic information in gastric cancer.

Method: Ki67 and BCL2 expression was assessed in 276 gastric adenocarcinoma tissue microarrays. A Ki67/BCL2 index based on the relative expression of each protein was divided into low- and high-risk groups using receiver operating characteristic curves.

Results: A high Ki67/BCL2 index significantly correlated with advanced stage, recurrence, intestinal type, high histologic grade, and lymphatic and perineural invasion (all p < 0.05). Univariate and multivariate analyses revealed a significant relationship between disease-free or overall survival and the Ki67/BCL2 index in intestinal-type gastric cancer (all p < 0.05).

Conclusions: A combined marker using Ki67 and BCL2 could be a useful indicator for predicting survival in patients with intestinal-type gastric cancer.
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http://dx.doi.org/10.1159/000448945DOI Listing
November 2017

Invasion Depth Measured in Millimeters is a Predictor of Survival in Patients with Distal Bile Duct Cancer: Decision Tree Approach.

World J Surg 2017 Jan;41(1):232-240

Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do, Republic of Korea.

Background: AJCC staging system is unreliable for predicting survival in distal bile duct (DBD) cancer patients, due to inter-observer variation. Measured depth of invasion (DOI) is suggested to be more accurate to predict patients' clinical outcome in extra-hepatic cholangiocarcinomas, but its significance in DBD cancer and cutoff values are still debatable. This study aimed to identify the optimal cutoff value of DOI in relation to prognosis in DBD cancer patients.

Methods: Data of 179 patients with DBD adenocarcinoma treated in three institutions were investigated. Under microscopic review, DOI was measured. The relationships between the clinicopathological parameters and the groups based on DOI (≤3; 3-10; >10 mm) were evaluated, and the survival times of each group based on DOI and T classification were compared.

Results: Deeply invading tumors exhibited a greater tendency toward the infiltrative type, high histological grade, AJCC stage, and pancreatic, duodenal, lymphovascular and perineural invasion. The measured DOI was significantly correlated with worse relapse-free and overall survival (all p < 0.05). In multivariate analyses, the DOI remained as one of the prognostic factors (all p < 0.05), while T classification was not a significant prognostic factor. The new prognostic models (low, intermediate, and high risk) that applied DOI and nodal metastasis showed significant difference in recurrence and survival rate (all p < 0.05).

Conclusions: On the basis of the proposed cutoff value, the DOI could be clear and meaningful, overcoming the vagueness of the T classification for predicting clinical outcomes in patients with DBD carcinoma.
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http://dx.doi.org/10.1007/s00268-016-3687-7DOI Listing
January 2017
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