Background/Aims:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity. Gastrointestinal adverse events are common; however, the association with gastroesophageal reflux disease (GERD) has not been validated across diverse populations. We aimed to assess GERD signals associated with GLP-1 RAs using disproportionality analysis across three national adverse event reporting systems. Methods:We analyzed FAERS, JADER, and Canada Vigilance. GLP-1 RAs were compared against dipeptidyl peptidase-4 inhibitors as active comparators. GERD was identified using MedDRA preferred terms. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by drug, age, and sex. Results:Among 260,417 GLP-1 RA reports, significant GERD signals were detected across all databases: FAERS (ROR, 2.83; 95% CI, 2.39 to 3.35; 9,245 vs 139), JADER (4.76; 95% CI, 2.45 to 9.27; 19 vs 16), and Canada Vigilance (2.91; 95% CI, 1.97 to 4.31; 206 vs 29). All signals met both ROR and proportional reporting ratio detection criteria. Drug-specific analyses revealed the strongest signals for semaglutide across all databases (3.44 to 6.93), followed by liraglutide (2.36 to 5.90), tirzepatide (2.76 to 5.77), and dulaglutide (2.35 to 3.32). Exenatide showed an inverse association in FAERS (ROR, 0.60; 95% CI, 0.46 to 0.77). Age-stratified analysis demonstrated increasing signal strength with age (≥65 years: ROR, 3.01; p-trend=0.028). Sensitivity analysis confirmed consistent signal directions. Conclusions:This first multi-database pharmacovigilance analysis confirms consistent GERD signals for GLP-1 RAs across Western and Asian populations, demonstrating approximately 2- to 5-fold higher reporting. Clinicians need to monitor for reflux symptoms during GLP-1 RA therapy, particularly in elderly patients.
Background/Aims:The safety and efficacy of endoscopic ultrasound-guided biliary drainage (EUS-BD) in patients with large-volume ascites (LVA) remain unclear. We aimed to evaluate the safety of EUS-BD in patients with distal malignant biliary obstruction complicated by LVA. Methods:This multicenter retrospective study included patients with distal malignant biliary obstruction who underwent EUS-BD. Pre-procedural computed tomography images were reviewed to identify patients with LVA, which was defined as ascites extending to the perihepatic region. The primary outcome was the safety of EUS-BD. Results:Among 1,524 patients with distal malignant biliary obstruction, 156 (10.2%) had LVA. EUS-BD was performed in 43 patients in whom endoscopic retrograde cholangiopancreatography failed or was infeasible. The technical and clinical success rates for EUS-BD were 97.7% and 81.4%, respectively. Adverse events (AEs), severe AEs, and intra-abdominal AEs (bile leak and peritonitis) occurred in 34.9%, 9.3%, and 18.6% of the patients, respectively. In the multivariate analysis, peritoneal dissemination was identified as an independent risk factor for overall AEs (odds ratio, 4.57; 95% confidence interval, 1.01 to 20.65; p=0.04). In the subgroup analysis, the perihepatic ascites thickness on axial computed tomography images was significantly greater in patients with intra-abdominal AEs than in those without AEs (p<0.01). The receiver operating characteristic curve analysis showed that the perihepatic ascites thickness predicted intra-abdominal AEs (area under the curve, 0.82; optimal cutoff, 15.5 mm). Fourteen patients (32.6%) died during the index hospitalization without discharge, with a median post-procedural survival of 1.8 months. Conclusions:EUS-BD may be associated with a high risk of AEs in patients with LVA, warranting a careful selection of patients.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a challenging multi-system global health problem, affecting approximately one-third of the world's population. Lifestyle modifications remain the cornerstone of MASLD management, which poses challenges in this population. The recent US Food and Drug Administration approval of resmetirom and semaglutide for the treatment of metabolic dysfunction-associated steatohepatitis with fibrosis signifies a substantial transformation in the therapeutic landscape. Other new therapeutic options are emerging, with encouraging phase 3 data from several agents spanning diverse mechanisms of action. This review summarizes the contemporary non-pharmacological and pharmacological approaches to MASLD.
Background/Aims:Steatotic liver disease (SLD) is an emerging comorbidity among people living with human immunodeficiency virus (PLWH), but its subtype-specific burden remains unclear. We aimed to evaluate the prevalence of SLD and its associations with mortality, cardiovascular diseases, and liver cirrhosis (LC). Methods:This retrospective cohort study included 4,597 Korean PLWH using data from the National Health Insurance Service (2013-2022). SLD was defined using the fatty liver index (≥30) and categorized into metabolic dysfunction-associated SLD (MASLD), alcohol-associated liver disease (ALD), and metabolic dysfunction-associated ALD (MetALD). Outcomes were all-cause mortality, cardiovascular diseases, and LC, analyzed using multivariable Cox proportional hazards and Fine-Gray competing risk models. Results:The prevalence of SLD was 45.7%, predominantly MASLD (86.5%), followed by Met-ALD (9.7%) and ALD (3.8%). SLD prevalence in PLWH was not higher than that in matched controls. Over a median 6-year follow-up, SLD was associated with increased mortality (adjusted hazard ratio, 1.53; 95% confidence interval [CI], 1.03 to 2.29). ALD was linked to higher stroke risk (adjusted subdistribution hazard ratio [aSHR], 3.10; 95% CI, 1.04 to 9.20), and MetALD to higher LC risk (aSHR, 5.72; 95% CI, 1.48 to 22.10). Conclusions:As SLD is significantly associated with mortality in PLWH, integrated management focusing on liver health, metabolic dysfunction, and alcohol use is essential to reduce adverse outcomes.
Colorectal cancer (CRC) remains a major global health burden and ranks third among the most commonly diagnosed malignancies and the second leading cause of cancer-related mortality worldwide. Its development arises through successive molecular and cellular alterations driven by cumulative genetic mutations, environmental exposure, and immune dysregulation. Among immune regulators, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) plays dual roles in CRC progression. On one hand, CTLA-4 preserves immune homeostasis by restraining excessive T-cell activation through competitive binding with CD80/CD86. This regulatory function is mediated by attenuated T-cell receptor signaling, dominance over CD28-mediated co-stimulation, and sustained activity of regulatory T cells to maintain peripheral tolerance. On the other hand, this inhibitory mechanism facilitates tumor immune evasion and contributes to cancer progression by limiting effector T-cell proliferation, reducing cytotoxic activity, and promoting immune exhaustion within the tumor microenvironment. Therapeutically, antibodies such as ipilimumab and tremelimumab leverage these roles by blocking CTLA-4 to restore antitumor immunity. However, the downstream signaling cascades following CTLA-4 activation and the detailed molecular basis of tremelimumab-mediated modulation are not yet fully understood. More detailed understanding of these dual-role mechanisms through integrative molecular, cellular, and structural analyses may help refine immune checkpoint blockade strategies and improve therapeutic outcomes in CRC patients.
Background/Aims:Growth impairment remains a major concern in pediatric Crohn's disease (pCD) patients, yet long-term growth trajectories and sex-specific treatment responses have not been adequately characterized. Methods:This study investigated 2-year growth trajectories and determinants of catch-up growth from a nationwide registry in Korea. Growth outcomes were analyzed in 533 children with pCD using multivariable linear regression and generalized additive models (GAM). Results:At diagnosis, 16.1% and 4.1% of patients had weight-for-age and height-for-age z-scores less than -2, respectively. Weight recovery was more readily achieved than linear growth during follow-up (median z-score change: 0.61, p<0.001 vs -0.01, p=0.582). Females presented with lower baseline weight z-scores than males (-1.00 vs -0.63; p=0.001) but displayed superior weight recovery (0.81 vs 0.51; p<0.001) and significant height recovery (0.09 vs -0.08 in males; p<0.001). In the multivariable analysis, the baseline weight z-score, platelet count, albumin, and disease activity predicted weight recovery (R²=26.3%), while the baseline height z-score was the strongest predictor of height recovery. The GAM analysis suggested that infliximab use was associated with enhanced height recovery (β=0.104, p=0.045), with benefits observed primarily in females aged <14 years (β=0.339, p=0.044). Conclusions:This Asian cohort study with the largest population to date demonstrates that weight recovery precedes linear growth, with females showing superior catch-up. Notably, our findings highlight a selective association between infliximab treatment and height recovery in females younger than 14 years, suggesting sex- and age-specific differences in the treatment response that warrant further investigation. (Clinical trial registration: Korea Clinical Research Information Service KCT0008723).
Background/Aims:We investigated the associations of testosterone levels with metabolic dysfunction-associated steatotic liver disease (MASLD) and vascular complications in a large Korean male cohort. Despite the high global prevalence of MASLD and significant morbidity from cardiovascular disease, the interplay among testosterone levels, MASLD, and vascular outcomes remains unclear, particularly in Asian populations. Methods:This cross-sectional study analyzed 1,167 men from the Korean Health Screening-Based MASLD Registry. MASLD was defined as imaging-confirmed steatosis with metabolic dysfunction. Log2-transformed testosterone levels were analyzed using logistic regression adjusted for metabolic risk factors to evaluate associations with MASLD, advanced fibrosis (Fibrosis-4 index [FIB-4] ≥1.3), carotid plaques, and cerebrovascular accidents (CVAs). Results:Among the 1,167 men (mean age 57.0 years), 730 (62.6%) had MASLD. These patients had lower testosterone levels than non-MASLD men did (223.5 ng/dL vs 347.5 ng/dL; p<0.001) and showed adverse metabolic features. Higher testosterone levels were independently associated with reduced risk of MASLD (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.85 to 0.94; p<0.001). Among the MASLD patients, higher testosterone levels were linked to a significantly lower prevalence of carotid plaques (OR, 0.77; 95% CI, 0.73 to 0.81) and CVAs (OR, 0.75; 95% CI, 0.67 to 0.82). The associations remained robust across sensitivity analyses with adjustments for obesity, diabetes, and dyslipidemia. No significant association was observed with advanced fibrosis (FIB-4 ≥1.3). Conclusions:Low testosterone levels are independently associated with MASLD and its vascular complications but not with advanced fibrosis. Serum testosterone levels may serve as a practical biomarker for metabolic and vascular risk stratification in MASLD patients, warranting validation in prospective and interventional studies. (ClinicalTrials.gov identifier NCT06843421).
Background/Aims:Cirrhosis is a leading cause of morbidity and mortality, and acute decompensation represents a pivotal event in its natural history. While long-term exposure to air pollution has been associated with liver disease progression, evidence on short-term effects remains limited. We investigated whether daily fluctuations in fine particulate matter (PM2.5) trigger acute decompensation in patients with cirrhosis. Methods:We conducted a nationwide, time-stratified case-crossover study using the Korean National Health Insurance Service database. Adults with cirrhosis from 2006 to 2021 were included. Emergency department (ED) visits for decompensation, including ascites, variceal bleeding, hepatic encephalopathy, jaundice, or hepatorenal syndrome, served as case days. Control days were matched (same month and weekday). Daily PM2.5 concentrations were assigned to residential districts using a 1-km grid. Conditional logistic regression was used to estimate odds ratios (ORs), adjusting for temperature, humidity, holidays, and weekday/weekend. Results:We analyzed 29,167 patients with cirrhosis (mean age, 59.9 years; 73.1% male) who presented to the ED with hepatic decompensation. Each interquartile range increase in PM2.5 was associated with a higher risk of decompensation (adjusted OR, 1.02; 95% confidence interval, 1.00 to 1.04). Participants in the highest exposure quintile had 5% higher odds of decompensation than those in the lowest quintile. Lagged exposure analyses indicated attenuation of associations with longer averaging windows. Subgroup analyses revealed no significant interactions. Conclusions:Short-term elevations in ambient PM2.5 levels were associated with an increased risk of acute hepatic decompensation requiring ED visits. Notably, daily air quality fluctuations may contribute to clinically significant events in this vulnerable population.
Ascites is a common complication of advanced liver disease, and accurate etiologic differentiation remains essential for clinical management. The serum-ascites albumin gradient (SAAG) is widely used to distinguish portal hypertensive from non-portal hypertensive ascites; however, its diagnostic performance across different clinical contexts has not been consistently established. We conducted a systematic review and meta-analysis of 47 studies involving 5,070 patients to evaluate the diagnostic accuracy of SAAG. Using a bivariate random-effects model, the pooled sensitivity and specificity were 0.889 (95% confidence interval [CI], 0.847 to 0.920) and 0.818 (95% CI, 0.752-0.870), respectively, with an area under the hierarchical summary receiver operating characteristic (HSROC) curve of 0.881. In subgroup analyses, SAAG showed excellent performance in identifying portal hypertension (area under the HSROC curve=0.936) and high specificity for malignant ascites, whereas its utility for predicting variceal bleeding was limited. Despite substantial heterogeneity and evidence of publication bias, the overall findings were consistent. These results support the continued use of SAAG as a practical and reliable first-line diagnostic tool in patients with ascites, particularly for confirming portal hypertension and excluding malignancy, while highlighting its limitations in other clinical settings.
Background/Aims:Pyogenic liver abscess (PLA) is a severe infectious disease with significant morbidity and mortality risk. We investigated the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the incidence of PLA and related complications. Methods:We analyzed data from 2,951,003 adults aged 40 to 64 years who underwent health examinations between 2009 and 2010 using the Korean National Health Insurance Service database. Hepatic steatosis was defined as a fatty liver index ≥30, and MASLD was identified based on established criteria. Changes in MASLD status over a 4-year follow-up period were evaluated for their impact on PLA risk. Results:Over a median follow-up of more than 14 years, the incidence rate of PLA was 27.2 per 100,000 person-years versus 13.3 per 100,000 person-years in the MASLD and non-steatotic liver disease (non-SLD) groups, respectively. Compared to non-SLD, MASLD was significantly associated with an increased risk of PLA (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.45 to 1.61) and its complications (HR, 1.72; 95% CI, 1.27 to 2.33). In the 4-year follow-up analysis, compared to individuals without any SLD at both baseline and follow-up, individuals with persistent MASLD had a higher risk of PLA (HR, 1.61; 95% CI, 1.49 to 1.74), followed by those whose MASLD regressed to non-SLD (HR, 1.38; 95% CI, 1.23 to 1.53) and those who developed MASLD during follow-up (HR, 1.27; 95% CI, 1.13 to 1.43). Other metabolic SLD categories also showed a higher risk of PLA than the non-SLD group. Conclusions:MASLD is significantly associated with an increased risk of PLA and related complications, with the highest risk observed in individuals with persistent MASLD.
Background/Aims:Current Korean guidelines recommend five different strategies for first-line eradication. No study has compared the cost-effectiveness of these five strategies in Korea. Methods:A decision tree model was developed to assess the costs and eradication outcomes of the five first-line eradication strategies. Empirical regimens included 14-day clarithromycin-based triple therapy (CTT), 10-day sequential therapy (ST), 10-day concomitant therapy (CT), and bismuth quadruple therapy (BQT). Tailored therapy (TT) was defined as resistance-guided treatment, in which patients with clarithromycin-resistant infections received 7-day BQT and those without resistance received 7-day CTT. Eradication rates were derived from the Korean nationwide Helicobacter pylori registry. Results:Among the empirical regimens, 14-day CTT showed the lowest eradication rate and highest cost. In contrast, ST, CT, and BQT demonstrated lower costs and higher eradication rates than 14-day CTT. TT achieved an overall eradication rate of 88.9% at a total cost of USD 221.91, which was higher than that of any empirical regimen. Compared with BQT, TT was associated with higher costs and lower eradication rates. Compared with ST, CT, and CTT, TT incurred higher costs but achieved higher eradication rates, with incremental cost-effectiveness ratios ranging from USD 3.82 to USD 21.34 per 1% increase in eradication rate. Conclusions:BQT demonstrated the most favorable cost-effectiveness among the first-line regimens recommended by the Korean guidelines. Although TT proved to be more cost-effective than CTT, it did not demonstrate superior cost-effectiveness compared with BQT.
Background/Aims:Traction-assisted endoscopic submucosal dissection (T-ESD), hybrid ESD (H-ESD), pocket-creation method ESD (P-ESD), and underwater ESD (U-ESD) were introduced to overcome the limitations of conventional ESD (C-ESD). We conducted a systematic review and network meta-analysis to compare the clinical outcomes of different colorectal ESD techniques. Methods:Randomized controlled trials (RCTs) comparing various ESD techniques (C-ESD, T-ESD, H-ESD, P-ESD, U-ESD) were included. Procedure time, dissection speed, en bloc resection, complete resection, perforation, and delayed bleeding were compared using network meta-analysis. Results:Sixteen RCTs involving 1,536 patients were included. T-ESD had a shorter procedure time (mean difference [MD], -25.17; 95% confidence interval [CI], -34.09 to -16.24). Dissection speed was faster with T-ESD (MD, 6.19; 95% CI, 2.12 to 10.26; surface under the cumulative ranking curve [SUCRA], 74.6) and H-ESD had a high SUCRA (73.0) for dissection speed. Based on the SUCRA rankings, T-ESD (81.4) and P-ESD (55.8) ranked higher for en bloc resection, while U-ESD (74.5) and T-ESD (65.2) ranked higher for complete resection. H-ESD consistently ranked lower than C-ESD for en bloc resection (6.5), complete resection (23.3), and delayed bleeding (23.6) according to SUCRA values. Regarding safety outcomes, T-ESD showed the most favorable SUCRA ranking for perforation (73.6), and U-ESD showed the most favorable SUCRA ranking for delayed bleeding (74.9). Conclusions:T-ESD ranked higher according to SUCRA values across multiple efficacy and safety outcomes. U-ESD ranked favorably for complete resection and delayed bleeding based on SUCRA values. H-ESD had a higher SUCRA value for dissection speed but ranked lower for en bloc resection, complete resection, and delayed bleeding.
Background/Aims:Colorectal cancer (CRC) shows clear sex-related differences influenced by hormonal and molecular factors, with estrogen generally exerting a protective effect through estrogen receptor beta (ERβ). The nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of oxidative stress and immune responses, may interact with estrogen signaling; however, this relationship in CRC patients remains poorly understood. Methods:A total of 300 patients with histologically confirmed CRC, 37 patients with colorectal adenomas, and 35 control subjects were prospectively enrolled. Colonic tissue samples were subjected to immunohistochemical staining for ERα, ERβ, androgen receptor, and NRF2. The associations of ER expression with clinicopathological variables, tumor stage, and survival outcomes were evaluated using chi-square tests, Pearson correlation analysis, Cox proportional hazards regression models, and Kaplan-Meier survival analysis. Results:ERβ expression was significantly lower in patients with advanced-stage, metastatic, and poorly differentiated CRC, whereas higher ERβ expression was more frequent in those with right-sided and early-stage CRC and was associated with higher body mass indices and lower metastatic rates. High ERβ expression correlated with significantly improved overall and cancer-specific survival (p=0.005 and p=0.010, respectively). A strong positive correlation was observed between ERβ and NRF2 expression (r=0.717, p<0.001), suggesting a mechanistic link between estrogen signaling and antioxidative pathways. ERα expression was low and inconsistent, whereas androgen receptor expression correlated with a favorable survival trend but lacked independent prognostic value. Conclusions:High ERβ expression was associated with favorable tumor characteristics and improved survival in CRC, supporting a tumor-suppressive role potentially mediated through interaction with the NRF2 antioxidative pathway (ClinicalTrials.gov identifier: NCT05638542).
Hepatic encephalopathy (HE) is a frequent complication of cirrhosis. Lactulose is guideline-recommended first-line therapy, whereas rifaximin is typically used adjunctively or when lactulose is not tolerated. We compared real-world outcomes of rifaximin monotherapy versus lactulose monotherapy for secondary HE prophylaxis. Using the TriNetX research network, we identified adults with cirrhosis (K74.6) and HE (K76.82) prescribed rifaximin or lactulose monotherapy, excluding patients with liver transplant, end-stage renal disease, or combination therapy. The index date was the first qualifying prescription after cirrhosis and HE documentation. After 1:1 propensity score matching for demographics, comorbidities, liver disease severity, polyethylene glycol-3350 use, and Model for End-Stage Liver Disease components, 1,734 matched pairs were analyzed. Outcomes were assessed using Cox proportional hazards models. Compared with lactulose, rifaximin was associated with lower all-cause mortality (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.60 to 0.79), hospitalization (HR, 0.46; 95% CI, 0.41 to 0.51), and SBP (HR, 0.29; 95% CI, 0.15 to 0.53), with similar recurrent HE (HR, 1.05; 95% CI, 0.94 to 1.16). These observational findings are hypothesis-generating and warrant prospective comparative and cost-effectiveness studies.
Background/Aims:Proton pump inhibitors (PPIs) effectively reduce bleeding in patients after endoscopic submucosal dissection (ESD). Tegoprazan, a potassium-competitive acid blocker, provides stronger acid suppression than PPIs do; however, its efficacy in preventing post-ESD bleeding has rarely been studied. The aim of this study was to compare the effects of tegoprazan and pantoprazole on post-ESD bleeding. Methods:In this randomized, multicenter trial, patients undergoing ESD for gastric epithelial neoplasms were randomly assigned to two groups; each received tegoprazan (50 mg once daily for 28 days) or pantoprazole (40 mg intravenously for 48 hours and orally once daily for 26 days). Adverse events and serum gastrin levels were assessed as safety outcomes. Results:The per-protocol set comprised 238 patients (117 tegoprazan, 121 pantoprazole). Noninferiority (within an 8.3% margin) in the post-ESD bleeding rates within 4 weeks was confirmed (risk difference, -6.30%; 95% confidence interval [CI], -14.67% to 2.07%; p=0.0003), with rates of 9.40% (11/117) and 15.70% (19/121) for the tegoprazan and pantoprazole groups, respectively. The bleeding rates within 24 hours were 5.98% (7/117) and 10.74% (13/121), respectively (risk difference, -4.76%; 95% CI, -11.75% to 2.23%). No significant differences were observed in adverse events or serum gastrin levels between the groups. Conclusions:Tegoprazan was non-inferior to pantoprazole in its effectiveness in preventing post-ESD bleeding, with comparable safety profiles. Notably, administering oral tegoprazan can potentially shorten the length of hospital stay and reduce medical costs, supporting its potential clinical value. Tegoprazan is expected to replace high-dose intravenous PPI therapy for patients after ESD (CRIS registration: KCT0006850).
Background/Aims:Hepatocellular carcinoma (HCC) recurrence after curative resection is classified into early recurrence (≤24 months), reflecting aggressive tumor biology, and late recurrence (>24 months), representing de novo carcinogenesis. We investigated whether preoperative dual positivity for Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) independently predicts early recurrence and whether this association is temporally specific. Methods:This retrospective cohort study included 431 patients who underwent curative resection for HCC between 2010 and 2023 at a single tertiary center. Dual positivity was defined as AFP-L3 ≥15% and PIVKA-II ≥100 mAU/mL. The primary outcome was early recurrence-free survival. Late recurrence was assessed using landmark analysis in patients who were recurrencefree at 24 months (n=258). Multivariable Cox proportional hazards regression was performed adjusting for clinical and tumor characteristics. Results:During a median follow-up of 36.0 months, 100 patients (23.2%) developed early recurrence and 73 (16.9%) developed late recurrence. Dual positivity was independently associated with early recurrence (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.44 to 3.93; p<0.001) but not with late recurrence (HR, 0.92; 95% CI, 0.39 to 2.15; p=0.844). The 24-month cumulative incidence of recurrence was 39.2% for dual-positive patients compared with 19.2% in the low-risk group. This association remained consistent across sensitivity analyses using alternative biomarker cutoffs and across most clinical subgroups. Conclusions:Preoperative dual positivity for AFP-L3 and PIVKA-II was associated with early but not late recurrence after curative resection for HCC, suggesting temporal specificity of this biomarker combination. Prospective validation studies are warranted.
