Diagnostic Performance of Noninvasive Tests in Patients with MetALD in a Health Check-up Cohort.

BACKGROUND AND AIMS: Noninvasive tests (NITs) for liver fibrosis have been recognized for their clinical utility in metabolic dysfunction-associated steatotic liver disease (MASLD). However, their diagnostic efficacy in detecting liver fibrosis is notably reduced in patients with alcohol-related liver disease. Therefore, ascertaining the reliability of NITs in patients with MASLD with increased alcohol intake (MetALD) is essential. METHODS: In this cross-sectional study, we reviewed data from 7,918 health check-up participants who underwent both magnetic resonance elastography (MRE) and ultrasound for the diagnosis of hepatic steatosis. The participants were categorized into MASLD and MetALD groups, and the performance of fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) were assessed. Advanced hepatic fibrosis (F3) was defined as MRE ≥ 3.6 kPa. RESULTS: The prevalence of MetALD was 5.8% in this health check-up cohort, and 1.5% of these patients exhibited advanced hepatic fibrosis. Both MetALD and MASLD displayed similar metabolic profiles and hepatic fibrosis burdens. The diagnostic performance of FIB-4 and NFS for MRE ≥ 3.6 kPa showed no noticeable differences in the area under the receiver operating characteristic values between the two groups (0.85 vs. 0.80 in FIB-4). Moreover, the sensitivity (71.4%), specificity (77.3%), and both positive (4.6%) and negative (99.4%) predictive values of NITs for MetALD closely mirrored those observed for MASLD. CONCLUSION: The newly defined MetALD exhibited a high FIB-4 performance, demonstrating reasonable sensitivity and negative predictive value for the initial screening of advanced hepatic fibrosis in MetALD. IMPACT AND IMPLICATIONS: In this cross-sectional study, data from 7,918 participants who underwent MRE were analyzed to assess the performance of fibrosis-4 (FIB-4) and nonalcoholic fatty liver disease fibrosis scores in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with increased alcohol intake (MetALD). We found that the newly identified MetALD group had high diagnostic accuracy with FIB-4, similar to the MASLD population. These results highlight the potential of FIB-4 as a reliable screening tool for MetALD, even when specific subgroups are considered. Therefore, FIB-4 is a valuable screening tool for identifying advanced fibrosis in the MetALD population.

Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study.

BACKGROUND & AIMS: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. METHODS: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. RESULTS: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar. CONCLUSIONS: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

Personalized Antiviral Drug Selection in Patients With Chronic Hepatitis B Using a Machine Learning Model: A Multinational Study.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy. METHODS: This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group. RESULTS: The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1). DISCUSSION: Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively.

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

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.

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

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.

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

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.

Efficacy and safety of direct-acting antiviral therapy for hepatitis C virus in elderly patients (≥65 years old): A systematic review and meta-analysis.

Direct-acting agents (DAAs) have launched a new era of hepatitis C virus (HCV) treatment. As aged individuals comprise a large percentage of HCV-infected patients, the effectiveness and safety of DAAs in the elderly have come under scrutiny. This meta-analysis aimed to evaluate the efficacy and safety of DAAs in elderly patients. After a systematic search in PubMed (MEDLINE), Embase, OVID MEDLINE, the Cochrane Library and other databases, two investigators reviewed relevant abstracts and selected manuscripts for examination. The sustained virologic response (SVR) and adverse event (AE) rates were calculated with a random-effects model. Ninety studies evaluating SVR rates of elderly patients (≥65 years old) receiving DAAs were selected. DAAs in elderly patients exhibited a notable SVR rate of 96% (95% confidence interval [CI]: 95%-97%), accompanied by comparable rates in subgroup analyses. The comparison of SVR rates in elderly and non-elderly patients indicated no significant discrepancy (odds ratio [OR] 1.01, 95% CI: 1.00-1.01). The overall event rate of AEs was 45% (95% CI: 31%-60%), though AE rates varied by subgroups. Furthermore, AEs were comparatively more frequent (OR 1.15, 95% CI: 1.04-1.28) in the elderly than non-elderly, especially in subgroups such as SAE (OR 1.89, 95% CI: 1.52-2.36) and dose reduction in ribavirin (OR 1.90, 95% CI: 1.53-2.36). However, in the ribavirin (RBV)-free regimen, there was no significant difference in the incidence of AEs between the elderly and non-elderly groups. DAAs have high efficacy in elderly patients. Considering the possibility of AE, the RBV-free regimen should be given prior consideration for the treatment of elderly patients with HCV.

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

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.

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

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.

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

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).

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

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

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

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.

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

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).

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

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.

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

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.

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

Associations between intakes of individual nutrients or whole food groups and non-alcoholic fatty liver disease among Korean adults.

BACKGROUND AND AIM: Dietary factors are closely associated with the risk of non-alcoholic fatty liver disease (NAFLD). Asian and Western diets differ in energy-nutrient composition, fatty-acid composition, and main nutritional sources; therefore, the implications would be limited if the Western-oriented study results were applied to Asian patients. We aimed to identify the nutrient and food group intakes of a typical Asian diet and assess their effects on NAFLD risk. METHODS: In total, 348 subjects were recruited from 5 participating hospitals. Information on sociodemographic characteristics and health-related behaviors were obtained through face-to-face interviews. NAFLD was diagnosed by ultrasound. Dietary intakes were assessed with a 24-h recall applying a multiple-pass approach and 4-day food records that included 1 or 2 weekend days. RESULTS: There were no significant differences in health-related behaviors between the cases and controls except for smoking behavior. The cases had elevated triacylglycerol, fasting glucose, and low-density lipoprotein cholesterol levels compared with the controls. In men, after adjusting for variables, low intakes of vitamin C (odds ratio [OR], 4.23), vitamin K (OR, 3.93), folate (OR, 3.37), omega-3 fatty acids (OR, 2.16), and nuts and seeds (OR, 3.66) were associated with a significantly higher risk for developing NAFLD. In women, vitamin K (OR, 2.54) and vegetable (OR, 4.11) intakes showed a significant beneficial effect for lowering NAFLD risk. CONCLUSIONS: Adequate intakes of vitamin C, vitamin K, folate, omega-3 fatty acids, nuts and seeds, and vegetables may help in preventing NAFLD in Korean adults.

Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND: Liver X receptor (LXR) is an oxysterol-activated nuclear receptor involved in the control of major metabolic pathways for cholesterol homeostasis and lipogenesis. Although the role of LXR in hepatic steatosis is well known, its correlation with intrahepatic inflammation and fibrosis has not been thoroughly studied. We investigated the association between LXRα, hepatic inflammation, and fibrosis, as well as its correlation with other intrahepatic lipid transporters in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We evaluated clinical characteristics including sex, age, body mass index, and laboratory findings from 40 NAFLD and 16 control patients. Immunohistochemical staining was carried out on liver biopsy samples from all patients. RESULTS: The positive rate of LXRα expression was 30 % in the control group, 50 % in the NAFLD group, and 97 % in NASH groups. LXRα expression was positively correlated with not only the amount of intrahepatic fat, but also with intrahepatic inflammation and hepatic fibrosis. LXRα expression showed positive correlation with intrahepatic expression of ABCG5/8, CD36, and SREBP-1c. The expression of ABCA1, ABCG5/8, SREBP-1c, and CD36 was higher in NAFLD than in controls and there was no further increase in the NASH group. NPC1L1 was abundant in human liver. Expression of NPC1L1 was negatively correlated with intrahepatic inflammation and LXRα intensity. CONCLUSION: LXR expression correlated with the degree of hepatic fat deposition, as well as with hepatic inflammation and fibrosis in NAFLD patients. Our research suggests that LXR is an attractive target for treatment and regulation of hepatic inflammation and fibrosis.

Melatonin attenuates dextran sodium sulfate induced colitis with sleep deprivation: possible mechanism by microarray analysis.

BACKGROUND: Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract. It can be aggravated by stress, like sleep deprivation, and improved by anti-inflammatory agents, like melatonin. We aimed to investigate the effects of sleep deprivation and melatonin on inflammation. We also investigated genes regulated by sleep deprivation and melatonin. METHODS: In the 2% DSS induced colitis mice model, sleep deprivation was induced using modified multiple platform water bath. Melatonin was injected after induction of colitis and colitis with sleep deprivation. Also mRNA was isolated from the colon of mice and analyzed via microarray and real-time PCR. RESULTS: Sleep deprivation induced reduction of body weight, and it was difficult for half of the mice to survive. Sleep deprivation aggravated, and melatonin attenuated the severity of colitis. In microarrays and real-time PCR of mice colon tissues, mRNA of adiponectin and aquaporin 8 were downregulated by sleep deprivation and upregulated by melatonin. However, mRNA of E2F transcription factor (E2F2) and histocompatibility class II antigen A, beta 1 (H2-Ab1) were upregulated by sleep deprivation and downregulated by melatonin. CONCLUSION: Melatonin improves and sleep deprivation aggravates inflammation of colitis in mice. Adiponectin, aquaporin 8, E2F2 and H2-Ab1 may be involved in the inflammatory change aggravated by sleep deprivation and attenuated by melatonin.