The phase 1/2 CheckMate-040 and the phase 3 CheckMate-9DW trials consistently demonstrated meaningful activity of nivolumab plus ipilimumab (Nivo/Ipi) in previously treated and treatment-naïve patients with advanced HCC. However, patients with ≥50% liver involvement, Vp4 portal vein tumor thrombosis (PVTT), or bile duct invasion were excluded from these trials. We aimed to assess the real-world efficacy and safety of Nivo/Ipi in this high-risk population. This international, multicenter, retrospective study was conducted in patients with advanced HCC who received Nivo/Ipi at six hospitals in Korea, Hong Kong, Singapore, and Taiwan between 2016 and 2024. Patients with Child-Pugh B/C or ECOG >2 were excluded. Of the 206 patients assessed for eligibility, 145 were included in the final analysis: 44 classified as high risk (Vp4 PVTT, n = 10; ≥50% liver involvement, n = 34; bile duct invasion, n = 7) and 101 as non-high risk. Baseline characteristics were comparable, aside from differences in liver function and high-risk features. Nivo/Ipi was administered as third-line or later-line therapy in 76.6% of patients. The high-risk group exhibited a significantly lower objective response rate (ORR) (12.8% vs. 34.3%) and shorter median progression-free survival (PFS) (1.2 vs. 2.9 months) and overall survival (OS) (3.6 vs. 16.5 months). Among the high-risk features, ≥50% liver involvement was strongly associated with inferior ORR, PFS, and OS, whereas Vp4 PVTT and bile duct invasion alone were not significantly associated with outcomes. A higher intrahepatic tumor burden was also inversely associated with treatment response and survival. Adverse events were more frequent in high-risk patients, particularly hyperbilirubinemia (36.4% vs. 13.9%; grade ≥3: 11.4% vs. 1.0%). On multivariable analysis, ≥50% liver involvement and prior immune-checkpoint inhibitor exposure independently predicted shorter PFS and OS. Extensive liver involvement emerged as the key predictor of poor prognosis, whereas Vp4 PVTT and bile duct invasion were not associated with significantly worse outcomes.
The adoption of technical variant grafts has expanded the donor pool for pediatric liver transplantation, but it also poses a risk of portal vein thrombosis (PVT). This study evaluated risk and prognostic factors of PVT in children undergoing liver transplantation with technical variant grafts. A total of 3137 pediatric patients from 19 centers were included: 470 received split/reduced deceased donor grafts and 2667 received living donor grafts. Multivariable logistic regression was used to identify risk factors, whereas time-dependent Cox models were used to assess the impact on survival. PVT occurred in 102 patients (3.3%) and was associated with increased mortality (adjusted hazard ratio, 2.86; 95% confidence interval [CI], 1.13-7.25; P = 0.027) and graft loss (adjusted hazard ratio, 9.97; 95% CI, 4.90-20.3; P < 0.001). Risk factors included younger age, lower weight, higher Pediatric End-Stage Liver Disease score, longer cold ischemia and operation times, higher graft-to-recipient weight ratio, increased red blood cell transfusions, and biliary atresia. After adjusting for center, lower weight (odds ratio, 0.84 per kg; 95% CI, 0.71-1.00; P = 0.047) and biliary atresia (odds ratio, 2.34; 95% CI, 1.10-5.00; P = 0.027) remained predictors. Five-year patient (88.4% versus 93.1%) and graft survival (82.7% versus 96.3%) were significantly inferior in patients with PVT. Low-weight children with biliary atresia constituted a high-risk group, highlighting the necessity for early detection and management.
暂无摘要（点击查看详情）
Immunosuppression withdrawal (ISW) after liver transplantation (LT) is feasible in selected individuals but the risk of chronic graft damage is unknown. We aimed to describe the clinical characteristics and long-term outcomes of patients with successful ISW after LT. Retrospective cohort study involving 31 LT centres in 15 countries. Adult and paediatric patients with complete ISW for ≥12 months following LT were eligible. We evaluated long-term outcomes, including evidence of histological graft injury, rejection, and mortality. In all, 287 patients (223 adults and 64 children) were included, representing 0.46% of the reference LT population. The median time from LT to ISW was 9.4 years, followed by 7.8 years of post-withdrawal follow-up. The most common reasons for ISW were participation in a clinical trial (53%), patient decision (25.1%), and immunosuppression-related side effects (16.7%). ISW was associated with metabolic improvement including reductions in diabetes (34.1% to 19.7%) and hypertension (58.7% to 31.4%). Paired liver biopsies before and after ISW were available in 108 patients (37.6%) and among them 43.5% achieved operational tolerance. Worsening fibrosis (≥1 Ishak's stage) and new-onset inflammation occurred in 30.5% and 22.2% of patients, respectively. Five-year overall survival after ISW was 93%, and no patient experienced immunologically mediated graft loss. Neither worsening fibrosis nor inflammation had an impact on mortality (HR=1.77 [95%CI 0.63-4.96] and HR=1.46 [95%CI 0.39-5.49], respectively). ISW after LT may improve metabolic comorbidities. Mild histological graft changes may occur, but do not appear to affect long-term outcomes. Future studies should focus on safely expand ISW to a broader subset of LT patients.
HIV and hepatitis B virus (HBV) co-infection remains a major global health challenge and is characterized by profound immune dysregulation, including chronic immune activation, impaired antiviral immunity, and immune-mediated liver injury. With the widespread use of effective antiretroviral therapy, people living with HIV now experience prolonged survival, shifting clinical and research priorities toward long-term immunological consequences and chronic comorbidities such as HBV. Although a rapidly expanding body of literature has explored HIV/HBV co-infection, a comprehensive immunology-oriented overview of global research trends, collaborative structures, and evolving immune-related research themes is still lacking. Publications related to HIV/HBV co-infection published between 2014 and 2024 were retrieved from the Web of Science Core Collection and Scopus databases. After data cleaning and deduplication, 1,649 eligible records were included. Bibliometric analyses were performed using CiteSpace and VOSviewer to evaluate temporal publication trends, international and institutional collaboration networks, journal distributions, keyword co-occurrence patterns, citation bursts, and emerging research frontiers, with a particular focus on immune-related research themes and host-virus immune interactions. The annual number of publications increased steadily over the study period, with a marked rise in citation activity after 2017, reflecting sustained and growing scientific interest in the immunopathogenesis of HIV/HBV co-infection. High-income countries, particularly the United States and Western Europe, dominated research output and held central positions in global collaboration networks, whereas high-burden regions, such as sub-Saharan Africa, increasingly contributed through international partnerships. Keyword co-occurrence and citation-burst analyses revealed a clear immunological thematic evolution: early studies focused on antiviral therapy and virological suppression, followed by increased attention to epidemiology and clinical guidelines, and more recently a pronounced shift toward immune-related outcomes. Emerging research hotspots increasingly emphasized CD4+ T-cell dysfunction, persistent immune activation, immune exhaustion, chronic inflammation, and immune-mediated liver injury, highlighting the growing recognition of immune dysregulation as a central driver of disease progression, fibrosis, and long-term prognosis in HIV/HBV co-infected populations. Further analyses of the journal demonstrated the integration of immunology with virology, hepatology, and infectious disease research. Global research on HIV/HBV co-infection has evolved from predominantly treatment- and virology-focused studies toward immunology-driven, outcome-oriented, and translational research addressing long-term immune dysfunction and prognosis. Despite expanding international collaboration, substantial disparities persist between regions with high disease burden and those leading immunological research. These findings underscore the need for strengthened locally led, immunology-focused research, long-term cohort studies, and integrated immune-monitoring strategies to improve clinical outcomes for people living with HIV/HBV co-infection.
Artificial intelligence (AI) is reshaping clinical practice and redefining the competencies future physicians will need. International bodies, such as the Association of American Medical Colleges, have called for structured AI training in medical curricula. Despite growing international consensus, no systematic nationwide evaluation had been conducted in Spain prior to this study. This study aimed to characterize the presence, type, and curricular features of AI-related training across all Spanish universities offering an official medical degree and to assess differences by institutional ownership and geographic region. This cross-sectional study was conducted from July to September 2025. Universities were the unit of analysis. A census of all institutions offering an officially recognized medical degree was obtained from the Register of Universities, Centers and Degrees; all 52 eligible institutions were included. Publicly available curricula and course guides for the 2025-2026 academic year were reviewed by 2 independent researchers and validated by an external evaluator. Courses were classified as (1) a specific AI course (AI as primary topic, accounting for >50% of syllabus), (2) an AI-similar course (a digital health or biomedical informatics course referencing AI as secondary content), or (3) not AI-related training. Course-level variables included ownership (public or private), region, status (compulsory or elective), European Credit Transfer and Accumulation System (ECTS) credits, academic year, and department. All analyses were descriptive. Potential sources of bias were addressed through predefined classification criteria, duplicate independent extraction, and external dataset verification. Of 52 universities, 36 (69.2%) were public and 16 (30.8%) were private. A total of 10 (19.2%) institutions offered at least one specific AI course; 6 (11.5%) included an AI-similar course. Overall, 16 (30.8%) universities had incorporated AI in some form; 36 (69.2%) institutions had not incorporated AI. Rates were similar for public (7/36, 19.4%) and private institutions (3/16, 18.8%). Identified courses ranged from 3 to 6 ECTS credits, representing an average of 1.17% of the 360-credit degree; most were elective. Only the University of Jaén offered a compulsory course with AI content. Marked regional disparities were observed: Andalusia led with 5 of 9 (55.6%) universities offering a specific AI course, while 10 autonomous communities had no universities with any AI-related training. This study delivers the first census-based, reproducible, national assessment of AI integration in Spanish undergraduate medical education. Unlike prior work focused on individual programs or nonstandardized definitions, we applied a consistent taxonomic framework reusable for longitudinal monitoring and international benchmarking. Findings reveal a heterogeneous, predominantly elective, and low-weight curricular landscape with striking interregional inequities. These results inform curriculum reform, accreditation standards, and faculty development priorities and support the establishment of minimum national competency standards and systematic monitoring to ensure equitable AI literacy among future physicians in Spain.
This study aims to provide a comprehensive bibliometric analysis of global research trends surrounding TGR5 in cholestatic liver diseases from 2006 to 2025, with the objective of elucidating publication outputs, geographic and institutional contributions, collaborative networks, journal co-citation analysis and reference co-citation mapping, key research themes, and emerging frontiers. Bibliographic data were retrieved from the Web of Science Core Collection (WoSCC) and supplemented by validation against Scopus and PubMed to mitigate database selection bias.Analyses were performed using CiteSpace (version 6.2.R2), VOSviewer (version 1.6.20), and the bibliometrix R package. Performance analysis was employed to evaluate productivity and impact across countries, institutions, and authors. Advanced science mapping techniques, including Thematic Map analysis, network topology metrics, and citation burst detection, were conducted to provide deeper computational and systems-level biological insights. A total of 418 publications were included. Annual publications showed a steady upward trend, with the United States leading in productivity (n = 138), total citations (n = 14,638), and H-index (59), followed by China with high output but relatively lower citation impact. European countries, notably Italy and Germany, demonstrated strong collaborative networks and influence relative to output volume. Keyword and thematic analyses revealed a shift from molecular mechanisms to clinical applications and, more recently, to gut microbiota and metabolic interactions. Major research clusters encompassed bile acid receptors, gut-liver axis mechanisms, and metabolic disorders. Quantitative network analysis revealed a modularity of 0.8238 and mean silhouette of 0.96, indicating well-defined cluster structures. Although prominent research groups were identified, international collaboration remained limited. The study illustrates the dynamic and evolving nature of TGR5 research, marked by a transition from basic science to translational and systems-level approaches. As the first comprehensive bibliometric and systems-level mapping analysis of TGR5 research in cholestatic liver diseases, this study uniquely integrates computational network analysis with microbiome-host interaction frameworks.While research productivity continues to grow, future efforts would benefit from enhanced international collaboration, microbiome engineering, systems medicine, biomarker discovery, and AI-integrated hepatology research. These findings provide valuable insights for researchers and policymakers aiming to navigate and advance this promising field.
Inflammatory bowel disease (IBD) remains understudied in Pakistan. This retrospective observational study assessed the management of IBD patients at Shifa International Hospital, Islamabad, from January 2019 to June 2024. Adherence to UK NICE 2019 guidelines (NG129 for CD, NG130 for UC) was evaluated. Data from 167 adult IBD patients (from initial 238 identified; 141 ulcerative colitis, 26 Crohn's disease) were extracted from electronic medical records after excluding inactive cases (n = 60), paediatric patients (n = 7), pregnant women (n = 3), and unconfirmed diagnoses (n = 1). Demographics, medications, comorbidities, surgeries, and diagnostic findings were analysed. Steroids were administered to 54.5% of patients (52.7% UC, 1.8% CD), aminosalicylates to 53.9% (50.3% UC, 3.6% CD), and immunosuppressants to 43.7% (40.2% UC, 3.5% CD). Discharge medications included steroids (46.1%), aminosalicylates (49.1%), and immunosuppressants (31.1%). Only 3/9 UC and 5/9 CD guideline recommendations were followed. Biologic use (anti-TNF) was low (8.9%), and 18% underwent surgery (total proctocolectomy most common). Diabetes (31%) and hypertension (28%) were prevalent comorbidities. Abdominal pain (52%) and diarrhea (46%) were frequent complaints. Colonoscopy (43%) and biopsies (20.4%) were key diagnostic tools. Histopathology revealed mild inflammation (29.4%) and moderate-severe inflammation (17.4%). IBD management showed significant deviation from international guidelines, particularly regarding biologic utilization (8.9%) and surgical rates (18%). These findings highlight urgent need for resource-stratified treatment protocols and enhanced clinical training to bridge the gap between evidence-based recommendations and real-world practice in resource limited settings.
The rising burden of alcohol-associated liver disease (ALD) calls for effective interventions. Alcohol cessation remains the only intervention known to reduce long-term ALD morbidity and mortality. Integrating treatment for alcohol use disorder with medical and hepatology care shows significant promise. This study aims to conduct a randomized, controlled, type 1 hybrid implementation-effectiveness trial in patients with ALD to evaluate an evidence-based smartphone app for alcohol use disorder (Connections). The primary aim is to (1) compare the effectiveness of the Connections app plus usual care to the effectiveness of usual care alone on days of alcohol abstinence for patients with ALD and (2) assess the implementation of the Connections app in the ALD population using a multilevel model of system change to determine facilitators and barriers to the successful adoption of the app at the patient, provider, and clinic levels. Study procedures were approved by the Institutional Review Board on March 13, 2024. Patients are recruited from General Hepatology and Multidisciplinary Clinics in Wisconsin and Michigan. Participants are randomized to an intervention (Connections + treatment as usual) or no intervention (treatment as usual). During the 6-month enrollment period, participants complete monthly e-surveys measuring alcohol consumption and quarterly e-surveys measuring patient health indicators and behaviors. Patients earn up to US $240 for participation. This study was funded in September 2023. Recruitment began in June 2024 and is ongoing. As of February 26, 2026, 144 participants have been enrolled in the study. Of these, 65 (45.1%) have completed all the study activities. We aim to recruit 298 participants through 2027, with analysis and results publication estimated in 2028. Implementation insights highlight the importance of flexibility and strong provider relationships. Challenges include reliance on technology, which limits access for patients with low digital literacy, and the risk of loss to follow-up. This trial is the first fully powered implementation-effectiveness study of a mobile health app for alcohol cessation in ALD, testing a new care model that integrates multidisciplinary expertise. DERR1-10.2196/94231.
Advances in chemotherapy have increased survival in biliary tract cancer patients, and reports of the effectiveness of neoadjuvant therapy are emerging. Accordingly, developing optimal drainage strategies under chemotherapy is important. We aimed to clarify suitable drainage methods and assess the prognostic value of the time to first reintervention (TTFR) following chemotherapy induction. We retrospectively analyzed 81 patients with malignant hilar biliary obstruction (MHBO) who underwent biliary stenting followed by chemotherapy between April 2012 and October 2023. TTFR following chemotherapy induction and drainage- and survival-related factors were evaluated. The median follow-up, survival, and TTFR were 425, 479, and 167 days, respectively. TTFR was correlated with overall survival (r = 0.60, p < 0.01). Univariable analyses identified prechemotherapy cholangitis and stenting above the sphincter of Oddi (SO) as factors associated with shorter TTFR, whereas multivariable analysis revealed stenting above the SO as the only independent factor (hazard ratio [HR] 0.44, p = 0.01). Among 52 non-endoscopic sphincterotomy (EST) patients, prechemotherapy cholangitis (HR 2.05, p = 0.04), stenting above the SO (HR 0.47, p = 0.04), and multiple drainage segments (HR 0.42, p = 0.04) influenced TTFR in univariable analyses. No significant factor was detected among 28 patients undergoing EST. The TTFR was comparable between above- and across-SO placement groups up to 2 months, but superior in the above-SO group at 6 months (69%-73% vs. 27%-42%). TTFR following chemotherapy induction is a prognostic factor in MHBO patients. Stenting above the SO may prolong TTFR, particularly in those without prior EST or expected to continue chemotherapy beyond 2 months. Trial Registration: N/A.
Acute pancreatitis (AP) is a major cause of gastrointestinal hospitalizations worldwide. Although typically self-limiting, up to one-third of cases develop complications associated with increased morbidity and mortality. Despite recent advances that have improved outcomes, clinical heterogeneity necessitates updated, evidence-based guidance. In addition, there remains a need to improve the implementation of evidence-based recommendations across Ibero-Latin American countries by bringing together diverse scientific societies and regional experts to enhance applicability and the dissemination of best practices. This guideline offers comprehensive recommendations for both mild and complicated AP diagnosis and management. Questions on AP management were addressed by expert teams comprising one coordinator and four pancreatology specialists from the Iberian Peninsula and Latin America. For each question, a systematic review was conducted using PubMed, Embase, and the Cochrane Library, focusing on randomized controlled trials and systematic reviews published between January 1979 and March 2024 in English, Spanish, or Portuguese. In the absence of high-quality evidence, the search was expanded to include observational studies. Recommendations were formulated using the GRADE system and submitted to an expert panel for consensus; unresolved questions were revised and resubmitted until consensus was reached. Twenty evidence-based recommendations were developed, addressing key aspects of AP management, including definitions, diagnostic criteria, etiological assessment, initial management, management of local complications, splanchnic vein thrombosis, abdominal compartment syndrome, indications for intensive care admission, antibiotic use, early endoscopic retrograde cholangiopancreatography, timing of cholecystectomy, strategies for detecting choledocholithiasis, and the management of pancreatic function insufficiency. Each recommendation included a statement, the level of evidence, the strength of the recommendation, and a summary of the supporting evidence. The iLATAM guidelines are the first Ibero-Latin American clinical practice guidelines for AP. They provide evidence-based recommendations integrating medical, endoscopic, and surgical approaches, with the aim of promoting consistent, high-quality care across diverse healthcare settings. In alignment with international standards for transparency and methodological rigor, the methodological protocol for this guideline was registered in PROSPERO (International Prospective Register of Systematic Reviews) on July 23, 2022 (Registration ID: CRD42022345788).
It has long been a focus of research to differentiate among the various causes of neonatal cholestasis, particularly biliary atresia (BA) from non-BA. The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome's role in the pathophysiology of BA is becoming increasingly clear. However, animal models served as the foundation for most of this research. As it is important to diagnose BA as early as possible for a favorable prognosis, the current investigation aimed to investigate the function of NLRP3 rs10754558 and NLRP3 gene expression level in distinguishing BA from non-BA. The study included 21 patients with BA, 24 patients with neonatal cholestasis due to causes other than BA, and 20 healthy infants as the control group. A clinical evaluation and standard laboratory testing were conducted on each participant. NLRP3 rs10754558 and NLRP3 gene expression level were measured using TaqMan allelic discrimination assay and quantitative real-time polymerase chain reaction (PCR), respectively. A significant difference in NLRP3 rs10754558 was observed between the BA and non-BA groups in the general genotype model (p = 0.048) and the overdominant model (p = 0.012). However, there was no discernible variation in the levels of NLRP3 gene expression between the two groups. In non-BA patients, there was a negative association between the international normalized ratio (INR) and expression of the NLRP3 gene. No correlation was found between NLRP3 expression and liver inflammation and fibrosis, nor between NLRP3 rs10754558 and NLRP3 expression. In conclusion, NLRP3 rs10754558 may contribute to non-BA neonatal cholestasis in ways other than by influencing gene expression levels. However, in non-BA patients, NLRP3 expression levels may improve coagulation.
Among the most impactful therapeutic advances in the management of diabetes over the past two decades has been the development of incretin-based therapies, specifically glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and in combination with glucose-dependent insulinotropic polypeptide (GIP) RAs. Since the introduction of exenatide in 2005, a growing number of these drugs has transformed the management of type 2 diabetes (T2D). Their pleiotropic effects include weight loss, reduced insulin resistance, improved glucose regulation, and reductions in known risk markers for diabetic kidney disease and cardiovascular disease. To date, these important noninsulin glucose-lowering therapies have only received regulatory approval for use in T2D, obesity, sleep apnea, and metabolic dysfunction-associated steatohepatitis with moderate-advanced fibrosis, supported by randomized controlled trials (RCTs) and real-world data that demonstrate efficacy and safety. Regulatory approval for use of weekly GLP-1 and GLP-1/GIP RAs in type 1 diabetes (T1D) has not yet been achieved, in part because of the limited number of inconsistent, small-scale, RCTs and real-world studies for glycemic impacts of these agents in T1D. Larger RCTs are ongoing or planned in participants with T1D. Potential safety risks include hypoglycemia and hyperglycemia-related ketosis in T1D after initiation of GLP-1/GIP RA drugs. While RCTs are ongoing to further investigate GLP-1 and GLP-1/GIP RA agents as adjunct therapy for people with T1D, access to these drugs is already possible, based on their use to treat overweight and obesity. However, without regulatory approval for the T1D indication, access and opportunities for people with T1D to engage with important education regarding the safety of GLP-1 and GLP-1/GIP RA therapy may be limited. This precludes support from diabetes health care professionals to optimize diabetes management of these agents alongside expected insulin dose changes. The purpose of this consensus report is to review the current literature and provide guidelines for diabetes clinicians and people with T1D to facilitate the safe use of GLP-1/GIP RAs in the management of T1D. This consensus statement has been endorsed by the following professional associations: Advanced Technologies & Treatments for Diabetes (ATTD), International Diabetes Federation-Europe, American Association of Clinical Endocrinologists (AACE), Breakthrough T1D, International Society for Pediatric and Adolescent Diabetes (ISPAD), Association of Diabetes Care and Education Specialists (ADCES).
Cholangiocarcinoma (CCA) is a rare cancer, with limited understanding of genetic and prognostic determinants. We aimed to explore genetic risk factors, assess their prognostic implications and evaluate associated systemic and intratumoral features. We screened the UK Biobank to identify single-nucleotide polymorphisms (SNPs) potentially associated with intrahepatic CCA (International Classification of Diseases, 10th Revision (ICD-10) code: C22.1). Candidate SNPs were genotyped in a real-life cohort of 221 patients undergoing liver resection for intrahepatic or perihilar CCA at Charité - Universitätsmedizin Berlin. Intratumoral gene expression and pathway co-expression were examined. Serum proteomic profiles were evaluated in patients with intrahepatic CCA and the overall population. In exploratory analyses, the telomerase reverse transcriptase (TERT) rs10069690 T allele was associated with a reduced risk of intrahepatic CCA (T allele vs C/C homozygotes: adjusted OR 0.824 (95% CI 0.713 to 0.951), p=0.008). However, T allele carriers undergoing liver resection for CCA had independently shorter overall survival (OS) compared with C/C homozygotes (median OS 21 (17-25) months vs 31 (24-38) months, p=0.034, HR 1.427 (1.023-1.991)). In serum proteomic analyses of the general population, presence of the T allele was associated with differences in immune-related pathways, including signatures consistent with increased lymphocyte differentiation and reduced NK-cell-mediated cytotoxicity. In intrahepatic CCA tumours, higher TERT mRNA expression was positively correlated with gene expression patterns consistent with increased cell cycle activity and regulatory T cell signatures, and negatively associated with pathways of cell differentiation, adhesion and immune effector function. These exploratory, hypothesis-generating findings suggest that the TERT rs10069690 variant may be associated with intrahepatic CCA risk and clinical outcomes, as well as with immune-related and proliferative pathways. The observed context-dependent associations warrant independent validation and further functional investigation.
Alpha-fetoprotein (AFP) is widely used in hepatocellular carcinoma (HCC) surveillance, but its performance may vary with etiology and tumor stage. We assessed etiology-specific AFP and des-gamma-carboxyprothrombin (DCP) positivity at HCC diagnosis, focusing on early-stage disease. We retrospectively enrolled consecutive adults with newly diagnosed, treatment-naïve HCC at two tertiary centers in Japan (2007-2023). AFP (cutoff ≥ 10 ng/mL) and DCP (≥ 40 mAU/mL) at diagnosis were analyzed overall and by etiology (Hepatitis B virus (HBV), Hepatitis C virus (HCV), sustained virological response [SVR], and non-B/non-C [NBNC]). Early stage was defined as Barcelona Clinic Liver Cancer (BCLC) 0/A and Union for International Cancer Control tumor-node-metastasis (UICC) T1a. Among 1396 patients, 760 (54.4%) had BCLC 0/A and 278 (19.9%) had T1a tumors. AFP positivity differed by etiology in BCLC 0/A disease (HBV 50.0%, HCV 64.6%, SVR-related 39.0%, NBNC 39.7%; p < 0.001), and in T1a tumors (48.1%, 60.3%, 39.0%, and 34.5%, respectively; p = 0.002). DCP (n = 1364) positivity in BCLC 0/A showed less variability (40.6%, 47.8%, 40.8%, and 58.4%, respectively; p = 0.005). Either-marker positivity in BCLC 0/A increased (64.1%, 80.0%, 59.2%, and 70.6%, respectively); the incremental yield from DCP alone among AFP-negative cases was 21.1% in SVR-related and 30.5% in NBNC early-stage HCC. AFP positivity at diagnosis was substantially lower in early-stage SVR-related and NBNC HCC than in HCV-related HCC. Adding DCP provides complementary detection, supporting an etiology-aware dual-marker strategy at diagnosis.
Existing studies suggest that up to half of individuals with primary biliary cholangitis (PBC) remain undiagnosed, contributing to lack of clarity on true prevalence of PBC. We aim to evaluate the prevalence of PBC among a national cohort of US veterans. National Veterans Affairs data from January 1, 2010, to April 30, 2025, were evaluated to identify adults with PBC using a combination of International Classification of Diseases (ICD)-9/10 diagnostic codes (57.16, K74.3) and/or presence of positive antimitochondrial antibody. Prevalence of PBC (per 100,000 persons) and proportion of patients with cirrhosis at time of PBC diagnosis was evaluated by age, sex, and race/ethnicity. Among over 5.13 million veterans who had ≥1 annual health-care encounter, the prevalence of PBC ranged from 19.5 to 76.2 per 100,000 persons when using different combinations of ICD-9/10 codes and antimitochondrial antibody diagnostic criteria. Among most scenarios, PBC prevalence was highest among women, older individuals (age ≥60 years), and Hispanic, or Asian/Pacific Islanders. The proportion of patients with cirrhosis at time of PBC diagnosis ranged from 10.7% to 26.4%, with generally higher rates of cirrhosis in men vs women. Among a national cohort US veterans, the prevalence of PBC ranged from 19.5 to 76.2 per 100,000 persons when evaluating various diagnostic criteria. It is concerning that up to a quarter of patients may have already had cirrhosis at time of PBC diagnosis, emphasizing the importance of greater awareness of timely diagnosis and treatment of PBC.
Background Hepatic encephalopathy (HE) is a debilitating and potentially fatal complication of advanced liver disease. While most patients with HE improve with medical therapy, a significant subset requires mechanical ventilation, an escalation of care associated with higher mortality, prolonged hospitalization, and greater financial burden. Despite this clinical and economic burden, factors associated with mechanical ventilation and the outcomes of intubated HE patients remain poorly defined at a national level. We aimed to characterize both the risk factors for mechanical ventilation and the associated clinical outcomes among hospitalized patients with HE using a large, representative cohort. Methods We performed a retrospective cohort study using the National Inpatient Sample (NIS) from 2016 to 2020. Adult patients (≥18 years) hospitalized with HE were included and identified using International Classification of Diseases, 10th Revision (ICD-10) codes for cirrhosis with HE. Elective admissions and transfers from acute-care hospitals were excluded. Baseline characteristics and clinical outcomes were compared between patients requiring mechanical ventilation and those not intubated. Multivariable logistic regression was used to identify factors associated with mechanical ventilation. Results From 2016 to 2020, 572,600 HE hospitalizations were identified, with 9.1% (52,295) requiring mechanical ventilation. Ventilated patients were younger (57.9 vs. 60.3 years, p<0.001), more often male (61% vs. 58%) and Black (11% vs. 8.6%), and had higher rates of sepsis (50% vs. 12%), acute kidney injury (AKI) (64% vs. 35%), and gastrointestinal (GI) bleeding (28% vs. 16%) (p<0.001 for all). Mechanical ventilation was associated with higher mortality (43% vs. 4.7%; adjusted OR, 8.32; 95% CI, 7.84-8.83), longer length of stay (11.5 vs. 6.0 days; adjusted RR, 1.43; 95% CI, 1.40-1.47), and increased costs ($48,511 vs. $15,731; adjusted RR, 2.23; 95% CI, 2.18-2.28), all p<0.001. On multivariable analysis, the strongest factors associated with mechanical ventilation included sepsis (OR, 5.42; 95% CI, 5.17-5.67), AKI (OR, 2.35; 95% CI, 2.24-2.46), and GI bleeding (OR, 1.84; 95% CI, 1.75-1.94). Conclusion Nearly 1 in 10 hospitalized patients with HE required mechanical ventilation, which was associated with substantially higher in-hospital mortality and increased hospitalization costs. Sepsis, renal failure, and GI bleeding were the strongest factors associated with intubation. These findings suggest that mechanical ventilation likely reflects underlying disease severity rather than serving as an independent driver of mortality. These clinical features are associated with mechanical ventilation and may aid risk stratification in hospitalized patients with HE.
This randomized controlled trial (RCT) aimed to evaluate the efficacy and safety of a rotational thromboelastometry (ROTEM)-guided transfusion strategy in children with decompensated cirrhosis presenting with severe coagulopathy and/or thrombocytopenia undergoing invasive procedures. This was an open-label, RCT which included (i) children 6 months to 18 years of age with decompensated liver cirrhosis, (ii) international normalized ratio (INR) between 2.5 and 3.5 (for procedures other than liver biopsy) and 2-2.5 (for liver biopsy), and/or (iii) platelet count between 20 and 50 × 109/L listed for invasive procedures. An interactive web response system was used to randomize the patient. Blood component transfusions in both arms were administered according to a predefined criterion. A total of 363 invasive procedures in decompensated chronic liver disease patients were screened for inclusion into the study. Of these, 76 were randomized (38 in each group with comparable baseline parameters). The proportion of patients receiving any blood component transfusion was significantly lower in the ROTEM arm (76.3% vs. 100%, p = 0.001). However, the volume of total and individual blood components transfused was comparable between groups. There was no difference in procedure-related bleed and transfusion-related complications between the two arms. In our study, the total costs incurred were higher in the ROTEM group (p < 0.001). In this cohort of children with decompensated cirrhosis and severe coagulopathy, ROTEM-guided transfusion reduced overall transfusion exposure but did not decrease blood product volume and was not cost-effective under the applied thresholds. ClinicalTrials.gov identifier: NCT05734001 (Clinicaltrials.gov); CTRI/2023/02/049779 (Clinical trials registry of India).
Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in the Middle East and North Africa (MENA) region, yet published estimates of prevalence and outcomes remain uncertain because the underlying denominators are inconsistently defined. This perspective argues that MENA MASLD epidemiology is systematically biased by three interacting mechanisms: distorted sampling frames, referral pathway selection, and structural undercapture of rural and displaced populations. Much of the current evidence is derived from convenience cohorts concentrated in urban, tertiary care settings where diagnostic availability and follow-up are greater than in the general population, leading to directional rather than random error. In parallel, risk stratification pathways that rely on two-step testing can funnel case detection toward specialty rich settings, overrepresenting advanced disease while missing earlier stages managed outside hepatology services. MASLD nomenclature change and incomplete alignment of coding and clinical documentation may further introduce artefactual inflection points that complicate trend interpretation. We highlight how underdiagnosis and under-recording in primary care propagate bias across downstream estimates and how validation of administrative algorithms and text-based ascertainment can quantify hidden disease reservoirs within routine data systems. Building on regional priority settings, we propose denominator-focused actions: probability-based sampling embedded in noncommunicable disease surveys; purposeful inclusion of rural and displaced groups; linkable data across primary care, laboratories, hospitals, and mortality registries; and harmonized coding and terminology. By decision-grade denominators, we refer to population denominators that are sufficiently representative, transparent, and linkable to support national surveillance, resource allocation, and trial-readiness decisions.
Two-dimensional shear-wave elastography (2D-SWE) is a practical method for assessing liver fibrosis. However, an optimal cut-off value to rule out significant fibrosis (≥F2) in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to determine the evidence-based rule-out cut-off through diagnostic meta-analysis. A systematic review was of MEDLINE, EMBASE, and Cochrane CENTRAL was performed through December 2025 for studies evaluating 2D-SWE with liver biopsy as the reference standard. Pooled sensitivity, specificity, and summary area under the receiver operating characteristic curve (sAUC) were estimated. The rule-out cut-off was defined as the highest threshold achieving pooled sensitivity ≥80%. External validation was performed using an independent clinical cohort. Twenty-two studies involving 3,171 adults with biopsy-proven MASLD were analyzed. The sAUC was 0.84 (95% confidence interval (CI), 0.81-0.87), with pooled sensitivity 79.6% and specificity 76.0%. The rule-out cut-off of 6.6 kPa (95% CI, 5.4-8.2) achieved sensitivity 80.0% and specificity 70.7%. At this threshold, negative predictive value exceeded 95% at prevalences of 5% and 10%. Diagnostic performance was generally preserved across subgroups, but was modestly attenuated in populations with greater metabolic burden and in studies using Supersonic ultrasound platforms. External validation (n=163) demonstrated consistent sensitivity (0.86) and specificity (0.68). 2D-SWE demonstrated good diagnostic accuracy for significant fibrosis in MASLD. A liver stiffness of 6.6 kPa can reliably rule out significant fibrosis. As 2D-SWE can be integrated into conventional ultrasound systems, it may facilitate broader implementation of fibrosis screening beyond specialized centers. [Clinical trial number: PROSPERO (International Prospective Register of Systematic Reviews), CRD42024616042].