BACKGROUND AND AIM:The combined use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) may provide synergistic benefits for liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM). We evaluated the comparative effectiveness of GLP-1RA plus SGLT2i versus GLP-1RA monotherapy on liver fibrosis progression. METHODS:We conducted a retrospective cohort study using data from the Mass General Brigham healthcare network (2010-2024). Adults with MASLD and T2DM initiating GLP-1RA therapy were included if their baseline FIB-4 scores indicated low-risk (<1.3) or intermediate-risk (1.3-2.67) categories. Combination therapy was defined as concurrent SGLT2i use for ≥50% of the GLP-1RA treatment period. The primary outcome was fibrosis progression, defined as advancement to a high-risk FIB-4 category. The secondary outcome was hepatic complications (cirrhosis, hepatocellular carcinoma, liver transplantation, or decompensation). Propensity score matching (1:2) was performed to minimize confounding. RESULTS:After matching, 879 combination therapy users were compared with 1690 monotherapy users. Combination therapy was associated with a significantly lower risk of fibrosis progression (3.10 vs. 4.01/100 person-years; HR 0.76, 95% CI 0.61-0.95) and a numerically lower incidence of hepatic complications (1.05 vs. 1.34/100 person-years; HR 0.76, 95% CI 0.53-1.09). Subgroup analyses showed consistent protective associations, with a significant benefit observed among patients with a BMI ≤35. Sensitivity analyses confirmed reduced fibrosis progression in both the ≥90-day and ≥180-day landmark analyses. CONCLUSIONS:GLP-1RA plus SGLT2i therapy was associated with reduced fibrosis progression compared with GLP-1RA monotherapy in MASLD and T2DM.

BACKGROUND:The long-term renal safety of tenofovir-based therapy in patients with chronic hepatitis B virus (HBV) infection remains uncertain, particularly regarding end-stage kidney disease requiring renal replacement therapy (RRT). We investigated the comparative risk of renal dysfunction between tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF). METHODS:We identified treatment-naïve adult patients with chronic HBV infection who initiated TAF or TDF between 2017 and 2020 from the Korean National Health Insurance Service. After 1:1 propensity score (PS) matching, we compared the incidence of RRT and chronic kidney disease (CKD) between the two groups. RESULTS:Among 46,663 eligible patients (TAF, n = 16,885; TDF, n = 29,778), the median follow-up was 2.61 years. The incidence of RRT were 0.56 and 0.96 per 1,000 person-years in the TAF and TDF groups, respectively (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.47-1.16). In the PS-matched cohort (n = 31,218), the adjusted HR for RRT was 0.67 (95% CI, 0.40-1.10) in TAF compared to TDF. Male sex, older age, hypertension, cirrhosis and current smoking were associated with the increased risk of RRT. CONCLUSION:In this nationwide claims-based cohort, TAF and TDF showed comparable renal safety with respect to RRT and the development of CKD. Male sex, older age, hypertension, and liver cirrhosis were associated with increased renal risk and warrant close monitoring.

Background/Aims:Hepatocellular carcinoma (HCC) in younger patients is uncommon, and its clinical behavior and prognosis remain unclear. We aimed to evaluate the characteristics, treatment patterns, and outcomes of young-onset HCC using large-scale datasets. Methods:This study analyzed two cohorts: the Asan Medical Center (AMC) HCC registry (2009-2023) and the nationwide Korean Liver Cancer Association (KLCA) registry. Young-onset HCC was defined as age ≤40 years. The primary comparison was between young (≤40 years) and non-young (>40 years) patients, with additional analyses using three age groups (≤40, 41-65, >65 years). Propensity score matching (PSM) was used to adjust for baseline differences. Overall survival (OS), recurrence-free survival (RFS), treatment patterns, and treatment intensity were evaluated. In the KLCA cohort, survival analyses were restricted to patients diagnosed between 2015 and 2021. Results:A total of 21,699 AMC patients and 21,172 KLCA patients were included. Young-onset HCC accounted for 955 (4.4%) and 627 (3.0%) of cases, respectively. Before matching, younger patients had larger tumors, higher alpha-fetoprotein levels, and more advanced disease. After PSM, OS was comparable between groups in the AMC cohort (median 3.8 vs. 4.0 years; p=0.890) and in the KLCA cohort (median 3.7 vs. 2.9 years; p=0.053). Stage-stratified analyses showed no significant differences in OS. RFS was also similar between groups in the AMC cohort. Initial treatment distribution and longitudinal treatment intensity were comparable between groups, whereas patients aged >65 years were less likely to receive curative treatments. Conclusions:Young-onset HCC shows more aggressive tumor features but similar outcomes after adjustment. Age alone may not be an independent determinant of prognosis.

The role of liver biopsy in hepatocellular carcinoma (HCC) is being re-evaluated in the era of precision oncology and biomarker-driven systemic therapy. Although histopathological examination remains the diagnostic gold standard, HCC is unique among solid tumors in that accurate non-invasive imaging criteria allow diagnosis without routine biopsy in selected clinical settings. However, increasing biological heterogeneity, expanding therapeutic options, and the growing need for molecular stratification have renewed interest in tissue-based evaluation. Recent international guidelines have gradually broadened the indications for liver biopsy, particularly in selected diagnostic scenarios, prior to systemic therapy, and for molecular profiling. Beyond diagnostic confirmation, liver biopsy provides important information for histological subtyping, prognostic stratification, and biomarker discovery. Advances in immunohistochemistry, next-generation sequencing, and artificial intelligence-assisted pathology have further enhanced the clinical value of tumor tissue. In parallel, contemporary cohort studies indicate that liver biopsy is associated with low complication rates when modern techniques and standardized peri-procedural management are applied. Despite these advances, the integration of liver biopsy into routine clinical practice remains limited. To contextualize this gap, the Korean Liver Cancer Association conducted a nationwide survey of HCC specialists. The survey showed that liver biopsy is infrequently performed in current practice due to perceived procedural risks and limited immediate impact on therapeutic decision-making. Taken together, accumulating evidence supports a reappraisal of the clinical role of liver biopsy in HCC. Optimizing procedural safety, standardizing indications, and integrating tissue-based molecular insights into therapeutic decision-making may help bridge the gap between emerging evidence and real-world practice.

Background/Aims:Cancer-related pain remains undertreated despite established guidelines. In hepatocellular carcinoma (HCC), underlying chronic liver disease may amplify concerns regarding analgesic safety. We aimed to evaluate pain prevalence, analgesic use, pain-related perceptions, and educational needs among patients with HCC. Methods:We conducted a cross-sectional survey of 200 adult patients with HCC receiving systemic therapy at a tertiary referral center. A 30-item questionnaire assessed pain presence and intensity using a numeric rating scale (NRS), analgesic use patterns, liver-related safety concerns, opioid-related stigma, and educational needs. Clinical characteristics, including tumor burden and liver function, were analyzed in relation to pain and perception domains. Results:Fifty-five patients (27.5%) reported current pain (mean NRS, 3.6 ± 2.5; mean worst pain 5.2 ± 2.8). Among them, 31 (56.3%) were using analgesics; however, 51.6% reported using them only when pain became unbearable. Misconceptions regarding analgesic safety were prevalent: 70.0% believed long-term analgesic use damages the liver, 56.0% believed analgesics are unsafe with impaired liver function, 46.5% associated opioids with addiction, and 30.0% hesitated due to the term "narcotic". These beliefs were not associated with Child-Pugh class or serum albumin level. Extrahepatic metastasis was associated with higher liver-related concern scores and a trend toward increased pain prevalence. Patients with elementary school education or less had poorer pain scale knowledge and no prior counseling. Conclusions:Pain undertreatment and safety-related misconceptions are common in HCC and appear independent of objective liver function. Structured, proactive education-particularly for patients with untreated pain and low educational attainment-may improve pain control in this population.

Tenofovir alafenamide (TAF) exhibits antiviral efficacy comparable to tenofovir disoproxil fumarate (TDF). Nonetheless, concerns persist regarding TAF's impact on the lipid profile and potential atherosclerotic cardiovascular disease (ASCVD) risk. This study evaluated long-term ASCVD risk in patients with chronic hepatitis B (CHB) treated with TAF or TDF using Korean National Health Insurance Service claims data. We retrospectively analyzed treatment-naïve patients with CHB who received TAF or TDF between 2017 and 2022. Cumulative ASCVD incidence was estimated using the Kaplan-Meier method and compared using the log-rank test. Propensity score (PS) matching and Cox regression were used to minimize confounding and identify ASCVD risk factors, respectively. Among 44,714 patients with CHB, 16,120 (36.1%) received TAF, whereas 28,594 (63.9%) received TDF. Over a median follow-up period of 3.0 years, ASCVD occurred in 817 patients (630 TDF-treated and 187 TAF-treated), with an annual incidence of 6.18/1000 patient-years (PYs). TAF was associated with lower ASCVD risk than TDF (4.60 vs. 6.88/1000 PYs; p < 0.001), a trend maintained after PS matching (4.67 vs. 6.67/1000 PYs; hazard ratio 0.70; p < 0.001) among 15,169 matched pairs. Older age, male sex, hypertension, current smoking, and aspartate aminotransferase ≥ 40 U/L were risk factors for ASCVD development. Despite concerns about lipid metabolism, TAF did not increase ASCVD risk compared with TDF, offering reassurance for clinicians selecting antiviral therapies for patients with CHB.

BACKGROUND:Over recent decades, treatment for human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection has significantly advanced. HIV is known to accelerate liver disease progression and increase liver-related mortality in patients with HCV infection. AIM:To reassess the effectiveness of HCV treatments by comparing outcomes between HIV/HCV co-infected and HCV mono-infected patients. METHODS:We retrospectively included patients with HCV mono-infection or HIV/HCV co-infection at 12 tertiary referral centers from January 2009 to December 2020. The primary endpoint was overall survival (OS). Secondary endpoints included achievement of a sustained virologic response (SVR), time-to-occurrence of hepatocellular carcinoma (HCC), and the changes in fibrosis-4 (FIB-4) index. RESULTS:A total of 904 patients were included: 792 with HCV mono-infection and 112 with HIV/HCV co-infection, of whom 97 (86.6%) had received prior HIV treatment. HCV treatment was administered to 741 (93.6%) mono-infected and 86 (76.8%) co-infected patients. Among treated patients, SVR was achieved in 93.4% of mono-infected and 81.4% of the co-infected group [P = 0.114 after inverse probability of treatment weighting (IPTW) adjustment]. OS and HCC occurrence showed no significant differences between groups, regardless of the HCV treatment method, after IPTW [hazard ratio (HR) = 0.37, 95% confidence interval (95%CI): 0.05-3.07, P = 0.360 for OS; HR = 0.19, 95%CI: 0.02-1.48, P = 0.113 for HCC occurrence]. The FIB-4 index significantly improved 1 year after achieving SVR with direct-acting antivirals in both groups. CONCLUSION:With optimal HIV/HCV treatment regimens, HCC occurrence and mortality risks in co-infected patients have become comparable to those in patients with HCV mono-infection.

BACKGROUND AND AIMS:Hepatitis B surface antigen (HBsAg) loss, a functional cure in chronic hepatitis (CHB), is rare. Temporal changes in HBsAg loss rates were evaluated in relation to COVID-19 vaccination rollout in South Korea. METHODS:An interrupted time series (ITS) analysis was performed using electronic health records of 59,946 adults with CHB (2002-2025). Monthly HBsAg loss incidence rates were estimated using a competing risk framework. National COVID-19 vaccination coverage was used as a surrogate for population-level exposure. A three-phase segmental regression model assessed changes before vaccination, during a predefined vaccination effect period (18 months following ≥ 80% of two-dose coverage), and after this period. Hepatocellular carcinoma (HCC) incidence was analysed as a negative control. RESULTS:Over 382,509 person-years, 2483 HBsAg loss events occurred. Pre-vaccination rates were stable (0.11-0.80 per 100 person-years). Following the COVID-19 vaccination rollout, the incidence increased to 0.96 in 2021, peaking at 1.27 in 2022, before declining to 0.93 in 2024. In the ITS model, no baseline trend was observed (p = 0.606). At the intervention point (November 2021), HBsAg loss rates increased significantly (incidence rate ratio; 1.56; 95% CI 1.26-1.93; p < 0.001). No significant slope change was observed during the vaccination period, while a negative slope change was observed post-vaccination (coefficient -0.039 per month; p = 0.003). Findings were consistent across sensitivity and subgroup analyses. HCC incidence showed no significant changes. CONCLUSION:COVID-19 vaccination was temporally associated with transiently higher HBsAg loss rates in CHB, followed by attenuation, suggesting a potential population-level immunomodulatory effect on HBV dynamics.

Background: Combined hepatocellular–cholangiocarcinoma (cHCC-CCA) is an uncommon primary liver cancer with distinct histology but overlapping clinical features with hepatocellular carcinoma (HCC). This study compared postoperative outcomes between cHCC-CCA and HCC in patients with very-early or early-stage tumors. Methods: We retrospectively analyzed 137 patients with cHCC-CCA and 3637 with HCC, all of which were pathologically confirmed at Barcelona Clinic Liver Cancer stage 0–A and treated with curative-intent resection at a high-volume tertiary center between 2010 and 2018. Tumors were reclassified according to the 2019 World Health Organization criteria. To minimize baseline imbalances, 1:4 propensity score matching was performed, yielding 137 patients with cHCC-CCA and 532 matched patients with HCC. Overall survival (OS) and recurrence-free survival (RFS) were compared using Cox regression and subgroup analyses. Results: In the matched cohort, baseline characteristics – including tumor stage – were well balanced; nevertheless, 5-year RFS and OS were significantly lower in cHCC-CCA [RFS, 46.8% vs. 56.8%; hazard ratio (HR), 1.41; 95% confidence interval (CI), 1.10–1.81; P = 0.007; and OS, 70.8% vs. 86.1%; HR, 2.02; 95% CI, 1.47–2.78; P < 0.001]. Subgroup analyses consistently demonstrated inferior outcomes for cHCC-CCA across clinical strata. Notably, OS was comparable between groups among patients without recurrence; however, in those with recurrence, cHCC-CCA was associated with significantly worse OS and a higher incidence of extrahepatic relapse (24.1% vs. 7.7%; P < 0.001), most frequently in the lungs and lymph nodes. Conclusion: cHCC-CCA is associated with significantly poorer postoperative outcomes than HCC, particularly in the setting of recurrence. Intensified surveillance and strategies to reduce extrahepatic recurrence may be warranted in this population.

Background: Hepatocellular carcinoma (HCC) is a major health concern, highlighting the need for effective surveillance. Republic of Korea's (South Korea's) National Cancer Screening Program (NCSP) uses ultrasound and serum alpha fetoprotein (AFP) tests for high-risk populations, but its performance remains unevaluated. The AFP result is only used when a mass under 1 cm is detected on ultrasound, raising concerns about its appropriateness. Methods: We analyzed data from 820,380 participants in Korea's NCSP for HCC between 2018 and 2020, comparing the ultrasound-alone protocol, current criteria, and the modified criteria newly proposed in this study. The current criteria define surveillance positivity as positive ultrasound findings or equivocal findings with elevated AFP, while the modified criteria consider either positive ultrasound findings or elevated AFP. Sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve for detecting HCC with various AFP cutoffs were evaluated. Results: Ultrasound alone had a sensitivity of 44.26% and a specificity of 97.38%. The current criteria achieved a sensitivity of 44.82-46.51% and a specificity of 97.18-97.38% for detecting HCC with various AFP cutoffs ranging from 5 to 100 ng/mL. The AUROC for the modified criteria was 0.8728, significantly higher than that of the current criteria (0.7209, P < 0.001). An AFP cutoff of 7 ng/mL was identified as the optimal threshold based on Youden's index. An AFP cutoff of 7 ng/mL slightly reduced specificity from 97.28% to 92.24%, whereas sensitivity markedly increased from 46.22% to 76.72%. Additionally, an AFP cutoff of 20 ng/mL yielded an increased sensitivity of 63.25% with maintaining specificity of 96.71%. Conclusion: The modified NCSP criteria we proposed, which incorporate AFP more proactively, identified an optimal cutoff for the Korean NCSP by balancing both sensitivity and specificity. This approach may contribute to improving the effectiveness HCC surveillance in the future.