Ultrasound-Based Deep Learning Model for Detection and Classification of Focal Liver Lesions

( Seung Kak Shin ),( Young Jae Kim ),( Kwang Gi Kim ),( Oh Sang Kwon ),( Ju Hyun Kim ),( Yun Soo Kim ) 대한간학회 2023 춘·추계 학술대회 (The Liver Week) Vol.2023 No.1

Efficacy of Daclatasvir and Asunaprevir Treatment in Genotype 1b HCV Infected Patients: A Real Life and Multicenter Study

( Seung Kak Shin ),( Oh Sang Kwon ),( Chang Hwi Yoon ),( Young-joo Jin ),( Jin-woo Lee ),( Sangheun Lee ),( Ki Jun Han ),( Young Nam Kim ),( Tae Hun Kim ),( Yun Soo Kim ),( Duck Joo Choi ),( Ju Hyun K 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Combination of daclatasvir (DCV) and asunaprevir (ASV) has been approved in Korea for the treatment of genotype 1b (GT1b) hepatitis C virus (HCV) infected patients. The efficacy in virologic response, improvement of liver function and non-invasive fibrosis marker in liver cirrhosis (LC) were investigated. Methods: All HCV GT1b patients who were treated with DCV and ASV for at least 4 weeks from August 2015 to January 2017, were retrospectively enrolled. Virologic response was measured at 4 weeks (rapid virologic response, RVR), at 24 weeks (end of treatment response, ETR), and at 12 weeks after the end of treatment (sustained virologic response, SVR12). Liver function, aspartate transaminase to platelet ratio index (APRI), FIB-4 index, and fibrosis index (FI) were compared between before and after treatment (SVR12). Results: Patients with GT1b patients (n=474) were examined for resistance associated variants (RAVs). Sixty-seven patients had RAV. A total of 290 RAV-negative patients were treated with DCV and ASV for at least 4 weeks. Baseline characteristics were obtained: age (54±11 years), gender (male: 50.3%), LC (29.0%), treatment-naïve (74.8%), ALT (58.5±49.2 IU/L), HCV RNA (1,915,001±4,969,456 IU/mL). RVR (255/277, 92.1%), ETR (190/195, 97.4%), and SVR (146/152, 96.1%) rates were obtained. SVR rates were not significantly different between non-LC (102/104, 98.1%) and LC patients (44/48, 91.7%) (p=0.080). SVR rates were not significantly different between treatment- naïve (103/106, 97.2%) and treatment-experienced patients (43/46, 93.5%) (p=0.368). In LC patients (n=48), there were significant changes of albumin (3.8±0.8 to 4.0±0.5 g/dL, p=0.036), platelet count (109.6±52.6 to 120.3±58.5 x103/mm3, p=0.004), APRI (2.6±3.1 to 0.8±0.6, p=0.001), FIB-4 (7.6±6.5 to 2.9±1.6, p<0.001), and FI (3.1±1.1 to 2.9±1.2, p=0.058) after treatment. Conclusions: DCV and ASV treatment for HCV GT1b infected Korean subjects without RAV achieved high SVR rates. In addition, improvement of liver function and non-invasive fibrosis marker were noted in patients with LC.

Antifibrotic Effects of 8-Hydroxydeoxyguanosine by Inhibiting NOX Derived Oxidative Stress in Vitro and in Vivo Models of Liver Fibrosis

( Seung Kak Shin ),( Oh Sang Kwon ),( Jong Joon Lee ),( Duck Joo Choi ),( Yun Soo Kim ),( Ju Hyun Kim ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) is implicated in liver fibrosis. 8-hydroxydeoxyguanosine (8-OHdG) can have antioxidant effects by inhibiting Rac1. Rac1 is a known activator of NOX enzymes. The aim of this study was to investigate the role of NOX and the antifibrotic effects of 8-OHdG in vitro and in vivo models of liver fibrosis. Methods: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats (n=7), rats underwent bile duct ligation (BDL) (n=6), and BDL rats treated with 8-OHdG (60 mg/kg/day by gavage feeding) (n=6). All rats were sacrificed on day 21. Hepatic fibrosis in liver tissue was assessed. In vitro, human stellate cell line LX-2 was stimulated by angiotensin II (10uM). The ROS production was measured by confocal microscopy. The mRNA expressions in liver tissue and LX-2 cell were analyzed by quantitative real-time PCR. Results: 8-OHdG significantly attenuated the hydroxyproline level (620.6±169.1 vs 1110.3±357.9 ug/g liver tissue, p=0.019) and the degrees of collagen stain (2.04±0.86 vs 5.11±0.26 %, p<0.001). The NOX1 and NOX2 protein expression in liver tissue by immunofluorescence was attenuated in 8-OHdG treatment groups. 8-OHdG significantly attenuated the mRNA expression of NOX1 (7.3 vs 2.7 folds, p=0.022), NOX2 (10.5 vs 3.9 folds, p=0.001), α-SMA (6.2 vs 2.6 folds, p=0.017), TGF-β (7.7 vs 3.4 folds, p=0.001) collagen Iα (25.7 vs 9.0 folds, p<0.001). Angiotensin II induced increase of the DCF fluorescence intensity in LX-2 cells was attenuated by 8-OHdG. 8-OHdG significantly attenuated the mRNA expression of α-SMA (6.2 vs 1.2 folds, p=0.001) TGF-β (7.8 vs 1.5 folds, p<0.001) collagen Iα (13.3 vs 0.74 folds, p<0.001) in LX-2 cells treated with angiotensin II for 72 hours. Conclusions: NOX-derived ROS is a critical role in vitro and in vivo models of liver fibrosis. 8-OHdG ameliorates the liver fibrosis through the inhibition of NOX-derived oxidative stress.

Exogenous 8-Hydroxydeoxyguanosine Prevents Liver Fibrosis through the Inhibition of Rac1-NADPH oxidase Signaling in a Nonalcoholic Steatohepatitis Model

( Seung Kak Shin ),( Hye Jeong Cho ),( Hyosang Hwang ),( Dong Hae Chung ),( Oh Sang Kwon ),( Yun Soo Kim ),( Ju Hyun Kim ) 대한간학회 2021 춘·추계 학술대회 (KASL) Vol.2021 No.1

Usefulness of Linear Type Wireless Hand-Held Ultrasound for the Evaluation of Liver Surface Nodularity in Patents with Liver Cirrhosis

( Seung Kak Shin ),( Yun Soo Kim ),( Hannah Ra ),( Sangho Jeong ),( Hyung Nam Kim ),( Oh Sang Kwon ),( Duck Joo Choi ),( Ju Hyun Kim ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Sonographic liver surface nodularity (LSN) is a useful parameter for diagnosis of liver cirrhosis (LC). Recently, easy-to-use linear type wireless hand-held ultrasound (wireless US) has been introduced. We aimed to assess the performance of wireless US compared to conventional ultrasound system (conventional US) in evaluating the LSN, and to verify the usefulness of LSN measured by wireless US in diagnosing LC. Methods: We enrolled 104 patients who underwent wireless US (SONON 300L, 10 MHz linear transducer, Healcerion), conventional US (Logic E9, 9 MHz linear transducer, GE) and Fibroscan for evaluation of liver diseases between March 2017 and January 2018. LSN measurement (LSNM, defined as the length of curve line in liver surface matching the 2-cm linear segment in left lateral segment) was used to objectively evaluate the LSN. Diagnosis of LC was based on clinical criteria, and was compared with fibroscan results. Results: Among 104 patients, 54 (51.9%) patients were diagnosed with LC. The mean liver stiffness measurement (LSM) on fibroscan (28.1±22.3 vs. 6.7±4.8, P<0.001) and LSNM on conventional US (2.075±0.459 vs. 2.028±0.119, P<0.001) were significantly different between LC and non-LC group. The mean LSNMs (2.051±0.034 vs. 2.052±0.041, P=0.13) on between wireless and conventional US by paired t-test were not significantly different. The sensitivity, specificity, positive predictive value, and negative predictive value of high LSNMs (≥ 2.04) on wireless US in diagnosing LC were 88.9%, 90.0%, 90.6%, and 88.2%, respectively. The mean LSMs (25.7±22.8 vs. 9.6±10.6 kPa, P<0.001) were significantly different between high LSNMs (≥ 2.04) and low LSNMs (<2.04) group. Conclusions: The ability of liver surface nodularity evaluation with wireless US was not inferior to conventional US. Linear type wireless hand-held ultrasound can be a useful tool to easily identify the liver surface nodularity for diagnosis of LC.

Anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium-induced colitis model

Shin, Seung Kak,Cho, Jae Hee,Kim, Eui Joo,Kim, Eun-Kyung,Park, Dong Kyun,Kwon, Kwang An,Chung, Jun-Won,Kim, Kyoung Oh,Kim, Yoon Jae WJG Press 2017 WORLD JOURNAL OF GASTROENTEROLOGY Vol.23 No.25

<P><B>AIM</B></P><P>To evaluate the anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium (DSS)-induced colitis model.</P><P><B>METHODS</B></P><P>An acute colitis mouse model was induced by oral administration of 5% DSS in the drinking water for 7 d. In the treated group, rosuvastatin (0.3 mg/kg per day) was administered orally before and after DSS administration for 21 d. On day 21, mice were sacrificed and the colons were removed for macroscopic examination, histology, and Western blot analysis. In the <I>in vitro</I> study, IEC-6 cells were stimulated with 50 ng/mL tumor necrosis factor (TNF)-α and then treated with or without rosuvastatin (2 μmol/L). The levels of reactive oxygen species (ROS), inflammatory mediators, and apoptotic markers were measured.</P><P><B>RESULTS</B></P><P>In DSS-induced colitis mice, rosuvastatin treatment significantly reduced the disease activity index and histological damage score compared to untreated mice (<I>P</I> < 0.05). Rosuvastatin also attenuated the DSS-induced increase of 8-hydroxy-2’-deoxyguanosine and NADPH oxidase-1 expression in colon tissue. Multiplex ELISA analysis revealed that rosuvastatin treatment reduced the DSS-induced increase of serum IL-2, IL-4, IL-5, IL-6, IL-12 and IL-17, and G-CSF levels. The increased levels of cleaved caspase-3, caspase-7, and poly (ADP-ribose) polymerase in the DSS group were attenuated by rosuvastatin treatment. <I>In vitro</I>, rosuvastatin significantly reduced the production of ROS, inflammatory mediators and apoptotic markers in TNF-α-treated IEC-6 cells (<I>P</I> < 0.05).</P><P><B>CONCLUSION</B></P><P>Rosuvastatin had the antioxidant, anti-inflammatory and anti-apoptotic effects in DSS-induced colitis model. Therefore, it might be a candidate anti-inflammatory drug in patients with inflammatory bowel disease.</P>

HBV : Efficacy of Entecavir and Adefovir Combination Therapy in Patients with Multi-antiviraldrug resistant Hepatitis B Virus

( Seung Kak Shin ),( Young Kul Jung ),( Seung Jun Jang ),( Hae Lim Baek ),( Hyun Hwa Yoon ),( Soo Yong Park ),( Min Young Rim ),( Hyeonsu Park ),( In Ku Yo ),( Oh Sang Kwon ),( Yun Soo Kim ),( Duck Jo 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Multi-antiviral drug resistance is a major problem in the treatment of patients with chronic hepatitis B (CHB). Tenofovir disoproxil fumarate (TDF) is recommended for ADV or entecavir (ETV). However, until recently TDF was not available in Korea. ADV and ETV combination therapy may be a viable alternative to TDF in patients with either ADV or ETV resistance. This study investigated the efficacy of ADV and ETV combination therapy in patients with multidrug resistance. Methods: Forty-one patients were enrolled and were administered ADV and ETV combination therapy for at least 12 months. Blood was drawn at baseline and at 12, 24, 36, 48, and 60 months after commencing treatment, and virological response was analyzed. Results: After ADV and ETV combination therapy, ALT normalization was 68%, 73%, 80% 90%, and 93% in 12wks, 24wks, 36wks, 48wks, and 60 wks, respectively. HBV DNA reduction was -1.5, -1.8, -1.9, -1.8, and -1.9 log10IU/mL in 12wks, 24wks, 36wks, 48wks, and 60 wks, respectively. 29 of HBeAg positive patients showed the following low HBeAg seroconversion rate: 3%, 7%, and 10% in 24wks, 48wks, and 60wks, respectively. In addition, virological response group showed lower initial HBV DNA level (P=0.014) and lower HBeAg positive rate (P=0.016) compared with non-virological response group. Conclusions: ADV and ETV combination therapy could be considered in selected chronic hepatitis B patients who have low initial HBV DNA level and HBeAg negative status.

Partial Virological Response after 2 Years of Entecavir Therapy Increases the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Associated Cirrhosis

( Seung Kak Shin ),( Hyung Joon Yim ),( Jeong Han Kim ),( Chan Uk Lee ),( Jong Eun Yeon ),( Sang Jun Suh ),( Young Kul Jung ),( Yun Soo Kim ),( Ju Hyun Kim ),( Oh Sang Kwon ) 대한간학회 2021 Gut and Liver Vol.15 No.3

Background/Aims: The clinical significance of partial virological response (PVR) in patients undergoing antiviral therapy is not well known. This study investigated whether PVR after 2 years of entecavir (ETV) therapy is associated with hepatocellular carcinoma (HCC) development in cirrhotic patients. Methods: A total of 472 naïve patients with hepatitis B virus (HBV)-associated cirrhosis who were treated with ETV for at least 2 years were retrospectively enrolled. Clinical characteristics, laboratory data, PVR, and noninvasive fibrosis markers (aspartate aminotransferase to platelet ratio and FIB-4 index) at 2 years after ETV commencement were analyzed for HCC risk. Results: After excluding those who developed HCC within 2 years of ETV therapy, 359 patients (mean age, 51±10 years; male 64.3%) were examined. During a median follow-up of 82 months, 80 patients developed HCC. In the univariate analysis, older age (hazard ratio [HR], 1.056; p<0.001), PVR (HR, 2.536; p=0.002), higher aspartate aminotransferase (HR, 1.018; p=0.005), lower albumin level (HR, 0.463; p<0.001), lower platelet count (HR, 0.993; p=0.01), and higher FIB-4 index (HR, 1.141; p<0.001) at 2 years after ETV commencement were risk factors for HCC. In the multivariate analysis, older age (HR, 1.046; 95% confidence interval [CI], 1.022 to 1.072; p<0.001), PVR (HR, 2.358; 95% CI, 1.310 to 4.245; p=0.004), and higher FIB-4 index (HR, 1.103; 95% CI, 1.035 to 1.177; p=0.003) were independent risk factors. Conclusions: PVR and higher FIB-4 index after 2 years of ETV therapy were independent risk factors for HCC. Therefore, efforts to accomplish a complete virological response and reduce the FIB-4 index should be made. (Gut Liver 2021;15:430-439)

Entecavir Improves Liver Function and Fibrosis in Hepatitis B Virus-Associated Cirrhosis: A 6Years-Multicenter Study

( Seung Kak Shin ),( Oh Sang Kwon ),( Jeong Han Kim ),( Chan Uk Lee ),( Jong Eun Yeon ),( Sang Jun Suh ),( Young Kul Jung ),( Hyung Joon Yim ),( Duck Joo Choi ),( Yun Soo Kim ),( Ju Hyun Kim ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Previously we reported that entecavir (ETV) improves liver function and non-invasive fibrosis markers in patients with HBV-associated cirrhosis after 2 years of treatment (Shin et al. JGH, 2016). This study extended observational period (6 years) and aimed to verify same objects after 6 years of ETV treat-ment. Methods: Among 370 patients who were enrolled in 2 years-study of ETV, a total 283 naïve patients with HBV associated-cirrhosis was treated by ETV for at least 6 years in 4 tertiary institutions. For the evaluation of liver function or fibrosis, laboratory findings, model for end stage liver disease (MELD) score, Child-Pugh (CP) class, AST platelet ratio index (APRI), FIB- 4 index, fibrosis index (FI), and liver stiffness measurement (LSM) value were compared between the baseline and 6 years after ETV treatment. Results: The final 205 patients (mean age of 50±9 years; 64.2% male; 50.2% HBeAg-positive) were enrolled. The baseline ALT and HBV DNA levels were 139±205 IU/L and 6.9±1.2 log10 copies/mL, respectively. The ALT normalization and the undetectable HBV DNA rate after 6 years of ETV treatment were 87.3% and 99.0%, respectively. Changes in total bilirubin (1.9±2.7 to 1.1±0.6 mg/dL, P<0.001), albumin (3.7±0.6 to 4.2±0.4 g/dL, P<0.001), platelet count (105±44 to 124±53Í103/ mm3, P<0.001), and MELD score (8.5±4.6 to 5.9±4.6, P<0.001) were observed. The change of distribution in CP class (A:74.1%, B:21.0%, C:4.9% at baseline to A:96.1%, B:3.4%, C:0.5% at 6 years after ETV treatment) was observed. The changes in APRI score, FIB-4 index, and FI were from 3.7±5.4 to 0.8±0.7 (P<0.001), from 6.4±6.3 to 3.5±2.7 (P<0.001), and from 3.2±0.9 to 2.6±0.9 (P<0.001), respectively. The change in LSM value (n=55) was from 26.5±17.7 to 12.4±8.0 kPa (P<0.001). Conclusions: Long-term treatment with ETV improves liver function and fibrosis in patients with HBV-associated cirrhosis.

Role of FIB-4 Predicting Clinical Outcomes after HBsAg Seroclearance in Patients with Chronic Hepatitis B

( Seung Kak Shin ),( Ju Hyun Kim ),( Oh Sang Kwon ),( Duck Joo Choi ),( Yun Soo Kim ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The long term clinical outcomes, including development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after hepatitis B surface antigen (HBsAg) seroclearance in patients with high FIB-4 index remains unclear. This study aimed to determine the correlations between clinical outcomes after HBsAg seroclearance and high FIB-4 index at the time of HBsAg seroclearance in patients with chronic hepatitis B. Methods: Between November 2000 and January 2016, a total of 117 patients who achieved HBsAg seroclearance (n=96, non-cirrhotic; n=21, cirrhotic) were retrospectively reviewed. FIB-4 index was used to evaluate the liver fibrosis. LC was diagnosed based on clinical and radiological assessments. Results: The mean age at the time of HBsAg seroclearance was 50.1±10.5 years. Among 96 patients without evidence of cirrhosis at the time of HBsAg seroclearance, 11 (11.5%) patients developed LC. The median interval from HBsAg seroclearance to development of LC was 33 months (rage from 22 to 99 months). In univariate Cox regression analysis, platelet count (<150 x 103/mm3; HR 4.71; 95% CI 1.17-18.92; P=0.029) and FIB-4 index (≥1.70; HR 9.12; 95% CI 2.29-36.28; P=0.002) at the time of HBsAg seroclearance were significant predictive factors for development of LC after HBsAg seroclearance. During a median follow-up of 36 months after HBsAg seroclearance, HCC developed in 6 patients (5.1%) (n=3, cirrhotic; n=3, non-cirrhotic) and the 1-, 3-, and 6-year cumulative incidences of HCC were 0.9%, 2.6%, and 7.3%, respectively. The log-rank test revealed that the occurrence rate of HCC was significantly higher in the high FIB-4 index group (≥1.70) compared with that in the low FIB-4 index group (<1.70) (P=0.027). Conclusions: Patients with a high FIB-4 index at the time of HBsAg seroclearance are at risk of development of LC and HCC, and these patients require more careful surveillance after HBsAg seroclearance.