Association between Non-Alcoholic Fatty Liver Disease Incidence and Colorectal Cancer

( Se Hwa Kim ),( Haein Bak ),( Sungwon Jang ),( Ha Seok Lee ),( Chan Uk Lee ),( Young Sun Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Kwan Soo Byun ),( Minjin Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases(CLD) globally(prevalence of 25.2%). Recently, It is stipulated that NAFLD may be an independent risk factor for developing colorectal cancer(CRC). We analyzed the prevalence of NAFLD in patients with CRC and the effect of NAFLD on the prognosis of CRC. Methods: Total 293 patients with CRC were enrolled from March 2003 to April 2018. Patients who had other CLD including chronic viral hepatitis B/C, autoimmune hepatitis, and primary biliary cholangitis and significant alcohol abuse (more than 140 g/week in women and 210 g/week in men) were excluded. Hepatic steatosis was evaluated by non-enhanced computed tomography (CT) scan. We measured values of regions of interest (ROI) for 3 times in liver and spleen, respectively. We diagnosed NAFLD when the average ROI of liver 10 less than it of spleen. 123 healthy controls who took non-enhanced CT scan were also analyzed. Results: The median age was 65.0(interquartile range[IQR] 54.0-73.0 years), and median Body mass index(BMI) was 24.02 (IQR 21.4-26.1). The median BMI of CRC patients without NAFLD was 23.75(IQR 21.3-25.7), and CRC patients with NAFLD was 25.16(IQR 21.8-27.0). The prevalence of Hypertension was 49.8%(146/293) in CRC group, and 35.77%(4/123) in control group (P=0.009). The prevalence of Diabetes Mellitus was 32.08% (94/293) in CRC group, and 16.26%(20/123) in control group(P=0.001). The prevalence of NAFLD was significantly higher in CRC group(24.57%, 72/293) than in the healthy group. (13%, 16/123) (P=0.008). Overall survival did not showed significant difference between NAFLD group and non-NAFLD group (P=0.706 by log-rank test). Conclusions: The prevalence of NAFLD in patients with CRC is significantly higher than control group. But the overall survival didn’t show singnificant difference. Further studies are needed to specify the effect of NAFLD on CRC prognosis in terms of recurrence and progression.

Serum miRNA as a Useful Diagnostic Biomarker for Diagnosis of NASH and a Clue for Disease Progression Pathway in NAFLD Patients

( Young-sun Lee ),( Jeong-an Gim ),( Haein Bak ),( Sehwa Kim ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Jong Eun Yeon ),( Soon Ho Um ),( Kwan Soo Byun ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Non-alcoholic steatohepatitis (NASH), as subtype of non-alcoholic fatty liver disease (NAFLD), is progressive disease that can result in advanced fibrosis and cirrhosis. The aim of this study was to evaluate diagnostic value using serum miRNA to For distinguish ing NASH from simple steatosis (SS). Methods: RNA extraction and small RNA sequencing were done using sera from 24 patients who were diagnosed with NAFLD by biopsy. miRNA expression levels were compared between 12 SS patients and 12 NASH patients. After selecting miRNAs showing significantly increased expression in NASH group comparing to SS group, diagnostic accuracies of each miRNA and a combination of miRNAs were analysed. For functional relationship between specific signalling pathway and miRNAs that were significantly elevated in sera of NASH patients compared to those in sera of SS patients, miEAA database was used. Results: A total of 2,588 mature miRNA reads were obtained from miRDeep2 Quantifier module. Expression levels of 26 miRNAs were significantly increased in NASH group than in SS group, whereas those of 12 miRNAs were significantly decreased in NASH group than in SS group. Among 38 significant miRNAs, eight miRNAs that showed high expression within the top 25% of all miRNAs were selected and compared. Only four miRNAs showed meaningful area under receiver operating characteristic (AUROC) values for NASH diagnosis (P<0.05). When AUROC values for diagnosis of NASH were compared between a combination of 8 miRNAs (AUROC: 0.924; 95% CI: 0.739-0.992) and a combination of 4 miRNAs (AUROC: 0.875; 95% CI: 0.676-0.973), there was no significant difference (P=0.26). Among 26 miRNAs that showed significantly increased expression in NASH group, 10 miRNAs were included in 17 miRNA group, such as adipocytokine signalling pathway and thyroid hormone signalling pathway (Figure). Conclusions: Combination of serum circulating miRNAs could be used as novel biomarker for diagnosis of NASH. The expression of circulating miRNAs is correlated with specific signalling pathway.

MR-Based Non-Alcoholic Steato Hepatitis (MASH) Score in Patients with Non-Alcoholic Fatty Liver Disease

( Young-sun Lee ),( Ji Eun Lee ),( Haein Bak ),( Sehwa Kim ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Baekhui Kim ),( Jeong Woo Kim ),( Chang Hee Lee ),( Jong Eun Yeon 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: As prevalence of NAFLD accounts for up to 30% of the general population worldwide, non-invasive evaluation of disease severity of NAFLD and non-invasive diagnosis of NASH are important issues. The objective of this prospective cross-sectional study was to develop a diagnostic scoring system that could improve the accuracy of NASH diagnosis by combining multiparametric MR and clinical indicators. Methods: This study included 130 patients who were diagnosed NAFLD by liver biopsy from October 2016 to July 2019. All patients were examined for medical history, laboratory tests, and multiparametric MR consisting of MRI proton density fat fraction, MR spectroscopy, T1 mapping, and MR elastography (MRE). Scoring model was developed using logistic regression. Internal validation was performed using bootstrapping. Results: NASH patients were older (59 years vs. 46 years, P<0.001) and had lower BMI (28.23 kg/㎡ vs. 31.19 kg/㎡, P=0.032) than nonalcoholic fatty liver (NAFL) patients. NASH group showed higher prevalence of diabetes/impaired fasting glucose, hypertension, and dyslipidemia. Four categorical variables and 19 continuous variables were evaluated for NASH diagnostic model. Diabetes/IFG and hypertension among categorical variables and age, BMI, hemoglobin, platelet count, T1 mapping, and MRE among continuous variables met the criterion of P-value ≤ 0.1. Variable interactions were identified between BMI and hemoglobin, between platelet count and diabetes/IFG, and between platelet count and MRE. Finally, equation for MR-based NASH (MASH) score was obtained using four demographic factors, two laboratory variables, and two MRI parameters (Figure 1). MASH score showed satisfactory accuracy for NASH diagnosis (C-statistics: 0.892; 95% CI: 0.834-0.950; P<0.001). When MASH score of 0.73 was set as a cut-off for NASH diagnosis, its sensitivity was 0.67 and its specificity was 0.90 (PPV = 0.89, 47/53). When MASH score of 0.37 was set as a cut-off for NASH exclusion, its sensitivity was 0.90 and its specificity was 0.78 (NPV = 0.87, 47/54). Only 17% (22/130) of patients were located in the gray zone (Table 1). Internal validation using 1000 bootstrapping also showed satisfactory accuracy for NASH diagnosis (C-statistics: 0.909; 95% CI: 0.855-0.964; P<0.001). Conclusions: MASH score is a novel non-invasive biomarker for the diagnosis of NASH in patients with NAFLD. Further external validation is required for its clinical application.

NAFLD Is Associated with High Prevalence and High Recurrence Rate in Patients with Breast Cancer

( Young-sun Lee ),( Sung Won Chang ),( Ha Seok Lee ),( Haein Bak ),( Sehwa Kim ),( Min-jin Lee ),( Chan Uk Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Jong Eun Yeon 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Breast cancer is most common cancer in women worldwide. The incidence of breast cancer is correlated with metabolic component including diabetes, hypertension, and obesity. Likewise breast cancer, metabolic components are important risk factors for development of NAFLD. In this study, we analyzed the prevalence of NAFLD in patients with breast cancer and the effect of NAFLD on the prognosis of breast cancer. Methods: Patients with breast cancer were enrolled from January 2007 to June 2017. Patients who had other chronic liver were excluded. Hepatic steatosis was evaluated by non-enhanced CT scan. We diagnosed NAFLD when the mean attenuation of the liver is lower than 40 HU or 10 HU lower than that of the spleen. 123 healthy controls who took non-enhanced CT scan were also analyzed. Results: Total 1587 patients were enrolled from January 2007 to June 2017. The prevalence of NAFLD in patients with breast cancer was 15.8% (251/1587) and it was significantly higher comparing with healthy control (8.9%, 11/123)(P=0.036). After propensity score matching, the difference of NAFLD prevalence was still significant between control group (8.9%, 11/123) and breast cancer patients (17.9%, 22/123) (P=0.040). In breast cancer patients, overall survival did not showed significant difference between NAFLD group and non-NAFLD group (P=0.304) (Figure A). However, recurrence-free survival was significantly higher in patients without NAFLD comparing with those with NAFLD (P=0.009) (Figure B). Among breast cancer patients received endocrine treatment, NAFLD group showed higher cumulative incidence of significant liver injury comparing with non-NAFLD group (P<0.001). Conclusions: The prevalence of NAFLD in patients with breast cancer is significantly high compared to healthy control group. Moreover, breast cancer patients with NAFLD showed poor prognosis in terms of recurrence. Therefore, diagnostic evaluation to determine whether or not NAFLD is present would be important in managing patients with breast cancer.

Clinical Significance of Serum Exosomal miRNA in Liver Fibrogenesis of Non-alcoholic Fatty Liver Disease

( Soo Min Bang ),( Eun Jung Ko ),( Yoonseok Lee ),( Haein Bak ),( Sehwa Kim ),( Young-sun Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Jong Eun Yeon ),( Soon Ho Um ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Fatty liver disease in non-significant amount of alcoholic drinker (Non-alcoholic fatty liver disease (NAFLD)) is on the rise worldwide as obesity and diabetes increase. Among histologic changes, the degree of liver fibrosis is the most important factor for predicting long term outcomes. Although liver biopsy is the gold standard for diagnosis, it is difficult to be done in routine clinical practice due to the risk of serious complications and variabilities of sampling and interpretation. The aim of this study was to explore clinical significance of serum exosomal miRNA in liver fibrogenesis of NAFLD patients. Methods: A total of 41 biopsy-proven NAFLD patients were included. Exosomes were isolated from serum samples and exosomal miRNAs were analyzed with GeneChip miRNA 4.0 array (Affymetrix, U.S.A). Expression levels of miRNAs in liver tissues of the same patient who had been tested for serum exosomal miRNA were analyzed. To define the role of miRNA in liver fibrogenesis, hepatocytes or stellate cells were transfected with miRNA of interest. Results: NAFLD patients with significant fibrosis (Group 1) were older than those with non-significant fibrosis (Group 2). The percentage of patients who had metabolic syndrome was higher in Group 1. In addition, Group 1 patients had lower platelet counts and prolonged PT INR. A total of 86 serum exosomal miRNAs showed significant differences in expression between the two groups. Of these, 42 miRNAs showed significantly higher expression while 44 miRNAs showed significantly lower expression in Group 1 than in Group 2. MiR4668-5p, 3613-3p, 8075, 619-5p, 1184 showed higher expression levels in Group 1 than in Group 2. When human stellate cells (LX2 cells) were transfected with miR4668-5p inhibitors or miR4668-5p mimics, TGF-b, collagen1A1, and a-SMA mRNA expression levels were significantly decreased by miR 4668-5p inhibitors. However, their expression levels or significantly increased after transfections with miR4668-5p mimics. Conclusions: Serum exosomal miRNAs showed significantly altered expression in NAFLD patients with significant fibrosis. Although additional researches are required, serum exosomal miRNA might have a diagnostic value for advanced fibrosis or serve as therapeutic targets for liver fibrogenesis in NAFLD patients.

The Direct Comparison between 7th AJCC Staging System and 8th AJCC Staging System for Prediction of Survival with Korean Multicenter HCC Patients

( Young-sun Lee ),( Sung Won Chang ),( Ha Seok Lee ),( Haein Bak ),( Sehwa Kim ),( Min-jin Lee ),( Chan Uk Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Jong Eun Yeon 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: AJCC staging is the most commonly used staging system in most solid tumors, and recent AASLD hepatocellular carcinoma (HCC) guideline also endorsed this AJCC staging system based on status of tumor, node, and metastasis. Recently, 8th edition of AJCC staging system was released in December 2016. This study aimed to compare prediction of survival in HCC patients between 7th AJCC staging system and 8th AJCC staging system. Methods: From 2004 to 2013, 2211 newly diagnosed HCC patients were consecutively enrolled in three Korea University medical centers and the medical records of patients were retrospectively reviewed. Each patients were classified following both of 7th AJCC staging system and 8th AJCC staging system. Results: Chronic hepatitis B (1523, 68.9%) was main attributable factor in development of HCC, followed by chronic hepatitis C (256, 11.6 %) and alcohol consumption (241, 10.9%). 1514 patients (68.5%) died during study period and median overall survival (OS) was 24.7 months. According to 7th AJCC staging system, 894 (40.4%) patients were included into stage I; 459 patients (20.8%) into stage II; 180 patients (8.1%) into stage IIIa; 354 patients (16.0%) into stage IIIb; 3 patients (0.1%) into stage IIIc; 119 patients (5.4%) into stage IVa; and 202 patients (9.1%) into stage IVb. According to 8th AJCC staging system, 400 (18.1%) patients were categorized into stage IA; 498 patients (22.5%) into stage IB; 442 patients (20.2%) into stage II; 193 patients (8.7%) into stage IIIa; 357 patients (16.1%) into stage IIIb; 119 patients (5.4%) into stage IVa; and 202 patients (9.1%) into stage IVb. Both 7th staging system and 8th staging system show distinct survival outcomes according to each stage. Although 7th AJCC staging system significantly well predicted 1 year of survival than 8th AJCC staging system (AUROC; 0.796 vs 0.784, P=0.013), AUROCs of 3 year and 5 year were similar in 7th and 8th AJCC staging system (0.754 vs 0.752 in 3 year, P=0.601; 0.744 vs 0.742 in 5 year, P=0.643). Conclusions: Both 7th and 8th AJCC staging system show distinct survival outcome according to each stage. Moreover, both 7th and 8th AJCC staging system are similar in prediction of survival outcomes.

Role of tenofovir disoproxil fumarate in prevention of perinatal transmission of hepatitis B virus from mother to child: a systematic review and meta-analysis

( Young-sun Lee ),( Ha Seok Lee ),( Ji Hoon Kim ),( Sung Won Chang ),( Myung Han Hyun ),( Haein Bak ),( Sehwa Kim ),( Min-jin Lee ),( Chan Uk Lee ),( Young Kul Jung ),( Yeon Seok Seo ),( Hyung Joon Yi 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.1

Background/Aims: To prevent the perinatal transmission of hepatitis B virus (HBV) from mother to child, administration of an antiviral agent during pregnancy has been attempted in women who are either hepatitis B e antigen positive or have a high viral load. In this systematic review and meta-analysis with randomized controlled trials, we analyzed the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing the perinatal transmission of HBV in pregnant women who have high HBV DNA titers. Methods: Multiple comprehensive databases (PubMed, EMBASE, and Cochrane databases) were searched for studies evaluating the efficacy of TDF for the prevention of perinatal transmission of HBV. Results: Two studies (one open label study and one double blind study) were included and analyzed. Intention-to-treat analysis (527 pregnancies) showed that the preventive effect of TDF was not significant (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.13 to 2.17; p = 0.38, I² = 81%). However, the per-protocol analysis showed that TDF significantly reduced perinatal transmission (OR, 0.10; 95% CI, 0.01 to 0.77; p = 0.03, I² = 0%). There was no significant difference between the TDF group and the control group with respect to maternal and fetal safety outcomes. Conclusions: In pregnant women who have high HBV DNA titers, TDF can reduce the perinatal transmission from mother to child without significant adverse events.