Translational gastroenterology and hepatology最新文献

Background: The diagnosis of autoimmune pancreatitis (AIP) can be challenging due to nonspecific symptoms, low sensitivity of serologic markers, and some overlap in presentation with pancreatic ductal adenocarcinoma (PDAC). We aimed to quantify delays in the diagnosis of AIP and identify factors associated with diagnostic delay.

Methods: This was a single-center retrospective study between 2013 and 2023 of adult patients diagnosed with type 1 AIP based on HISORt criteria. Patients were compared to a randomly selected group of controls with PDAC. Data on clinical presentation, lab results, imaging, procedures, and initial treatment regimen were collected. Timing to diagnosis and predictive factors were identified and compared between groups.

Results: Overall, 41 patients with AIP were identified and compared to 41 patients with PDAC. AIP patients had delays in diagnosis from symptom onset compared to controls (79.1±141.2 vs. 5.2±5.43 weeks, P<0.001). Within the AIP group, female sex (136.6±202.2 vs. 42.3±63.5 weeks, P=0.004) and fatty infiltration of the pancreas on imaging (194.1±163.9 vs. 33.7±60.3 weeks, P<0.001) were associated with delays in diagnosis, respectively. Presenting with jaundice (27.1±33.0 vs. 93.7±156.3 weeks, P=0.01) and obtaining endoscopic ultrasound-guided or surgical biopsies (49.7±79.9 vs. 221.6±262.9 weeks, P=0.04) were associated with a shorter time from symptom onset to diagnosis, respectively. Patients were more promptly diagnosed in the last 5 years of the study compared to the first 5 years (13 vs. 28 weeks, P=0.02).

Conclusions: AIP remains a challenging diagnosis, with extensive delays in diagnosis averaging 1.5 years from symptom onset. Our findings may improve patient identification and reduce diagnostic delay in AIP patients.

Ulcerative colitis (UC) is a chronic inflammatory condition characterized by persistent inflammation of the colonic mucosa. Ulcerative proctitis (UP), a localized subtype limited to the rectum, accounts for approximately 37% of UC cases. Although often considered less severe than more extensive forms of UC, UP poses unique diagnostic and therapeutic challenges due to its distinct clinical course and the limited availability of targeted research. UP significantly impairs patients' quality of life, yet randomized controlled trials (RCTs) frequently exclude this population, leading to a paucity of high-quality data to guide management. Diagnostic criteria for UP require endoscopic and histopathological confirmation of inflammation confined to within 15 cm of the anal verge once other etiologies are excluded. First-line treatment typically includes topical 5-aminosalicylates (5-ASA) and corticosteroids, which have demonstrated efficacy in inducing remission. For refractory cases, advanced therapies, including biologics and small-molecule agents, offer promising options, though robust evidence specific to UP is limited. This review underscores the gaps in contemporary UP research, including variability in study designs, definitions, and outcome measures, which hinder meta-analyses and the development of standardized treatment guidelines. Furthermore, the role of therapeutic drug monitoring and the long-term benefits of mucosal healing remain unclear in UP. Personalized treatment strategies, informed by disease severity, patient preferences, and access to care are essential. Regular surveillance incorporating clinical and endoscopic assessments is critical to optimize disease control and mitigate complications. Future studies are necessary to define treatment targets, evaluate novel therapies, and establish evidence-based guidelines to improve outcomes for patients with UP.

Background: Post cholecystectomy pain is a common clinical problem. Investigation and management of patients with recurrent episodes of biliary pain and normal imaging is challenging. Low phospholipid associated cholelithiasis (LPAC) is a recently described syndrome that often presents with difficult to manage episodes of post cholecystectomy pain. Ursodeoxycholic acid (UDCA) treatment of LPAC is supported by animal studies and case series but has not been assessed in a randomised trial.

Methods: This protocol presents the design and rationale for an investigator-initiated, prospective, randomised, placebo-controlled, double-blind, Phase 3 crossover trial: Ursodeoxycholic acid in LPAC treating Recurrent Abdominal Pain (ULTRA Pain). The study population consists of 24 patients with difficult to manage post cholecystectomy pain diagnosed with LPAC with no or minimal changes on liver ultrasound imaging. Participants will be recruited through the gastroenterology clinic at Royal Melbourne Hospital and randomly assigned to receive UDCA 10 mg/kg daily for 1 year followed by a matched placebo, or vice versa, separated by an effective 6-week washout period. The primary endpoint is the number of patient reported episodes of biliary pain. Secondary outcomes include the number of episodes of biliary pain with associated transiently elevated liver function tests (LFTs), and episodes of biliary pain in those with the diagnosis of LPAC confirmed by ultrasound, the Recurrent Abdominal Pain Intensity and Disability (RAPID) score, and the score of several questionnaires measuring quality of life. An independent monitor has been appointed to oversee safety of participants. An intention-to-treat analysis will be performed in accordance with CONSORT guidelines. Regression methods appropriate to the type of primary or secondary outcome, such as linear regression for continuous outcome or Poisson or negative binomial regression if found to be skewed, or binary logistic regression for binary outcomes will be employed. Alpha or level of statistical significance will be set to p <0.05 and 95% confidence intervals will be reported throughout.

Discussion: This trial will provide level 1 evidence on the efficacy of UDCA in treating LPAC presenting with post cholecystectomy pain.

Trial registration: This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000450819).

Background: Colorectal carcinoma (CRC) is a prevalent malignancy worldwide. Due to suboptimal screening practices, CRC is frequently diagnosed at an advanced stage. The role of mitochondrial abnormalities in the advancement of CRC is significant, but the prognostic effect of mitochondrial genes remains unclear. Recent research emphasizes mitochondrial dysfunction's key role in oncogenesis and cancer progression. Mitochondria are vital for cellular metabolism, energy production, and regulating processes like apoptosis, redox homeostasis, and signal transduction. Their dysfunction causes metabolic reprogramming, heightened oxidative stress, and cell death resistance. Though mitochondrial abnormalities link to CRC's aggressive phenotypes, the prognostic value of a comprehensive set of mitochondrial genes remains unclear, leaving a critical knowledge gap. The primary objective of this study was to systematically investigate the prognostic potential of mitochondrial genes in CRC and to develop a novel, reliable risk-scoring model. We aimed to identify key mitochondrial genes associated with patient survival, construct a predictive signature, and validate its efficacy in independently prognosticating overall survival (OS).

Methods: This study used single-cell RNA sequencing (scRNA-seq) data of CRC tissues from The Cancer Genome Atlas (TCGA), and a comprehensive set of 1,650 mitochondrial genes from MitoCarta 3.0. A differential gene expression analysis, gene set enrichment analysis (GSEA), pathway analysis, and Cox proportional hazards regression analysis were conducted.

Results: The Cox regression analysis identified five mitochondrial genes (i.e., CPT2, ACSL6, MOCS1, TERT, and PTRH1). These five genes were used to establish a reliable risk-scoring system. Patients with elevated risk scores had more severe clinical manifestations and worse survival outcomes. These results were corroborated in an external validation set (GSE17536 cohort). A predictive model was developed based on these genes that had robust predictive capabilities with areas under the curve (AUCs) of 0.75, 0.77, and 0.78 in the prediction of the 1-, 3-, and 5-year OS of CRC patients, respectively. Additionally, the correlation between the risk score and immune microenvironment characteristics (e.g., immune infiltration patterns, stromal/immune scores) further substantiated the predictive power of the model.

Conclusions: This study established a novel prognostic model for CRC based on mitochondrial genes, thereby extending the understanding of the disease's progression. Subsequent studies should seek to validate these findings within a broader cohort of patients and explore the potential therapeutic roles of the identified mitochondrial genes in the management of CRC.

Background: With a 2- to 3-fold higher incidence in men, hepatocellular carcinoma (HCC) is the leading indication for liver transplantation (LT). Despite this sex disparity in HCC incidence, the influence of recipient sex on long-term LT outcomes, including HCC recurrence, is not well established. This study investigates the impact of recipient sex on the long-term outcomes following LT for HCC.

Methods: All consecutive patients undergoing LT for HCC between 2005 and 2018 were retrospectively analyzed. Data regarding patient demographics, tumor characteristics, and post-transplant outcomes were collected, and recipients were stratified by sex. Kaplan-Meier analysis was used to assess overall and recurrence-free survival (RFS). Multivariable Cox regression models were then used to determine independent predictors of HCC recurrence within each sex group.

Results: Of the 384 adult recipients (mean age was 58.7±8.4 years and mean follow-up of 86.5±51.5 months), 17.2% of patients were female. The main etiology of cirrhosis in the female and male groups was alcohol-related (19.7%, 36.5%), HCV (40.9%, 24.5%) and metabolic dysfunction-associated steatohepatitis (MASH) (10.6%, 12.3%). The Model for End-Stage Liver Disease (MELD) and Child-Pugh scores were similar in both groups. 87.9% and 76.4% of the patients were within the Milan criteria and 95.5% and 91.5% of the patients had an alpha-fetoprotein (AFP) score ≤2 at the time of LT, respectively. The 1-, 3-, 5-, 10- and 15-year survival rates were similar in the male and female groups (91.5%, 81.5%, 72.4%, 57.7% and 44.9% vs. 89.4%, 80.1%, 72.0%, 50.0% and 29.6%, P=0.43). Microvascular invasion was seen in 30.3% and 36.3% of the patients, respectively, P=0.36). Recurrence rates were comparable in female and male groups (19.7% vs. 20.1%, respectively, P=0.94). The 10-year RFS rate was 50.6% in the female group and 54.9% in the male group (P=0.61).

Conclusions: Recipient sex does not impact long-term survival or HCC recurrence after LT. However, sex-specific predictors of HCC recurrence were identified: AFP score >2 and prior hepatectomy in females, and these plus diabetes mellitus and older age in males. Furthermore, female recipients presented with a significantly lower incidence of alcohol-associated cirrhosis as the underlying cause of HCC.

Background: Currently, the relationship between immune cell phenotypes and susceptibility to autoimmune liver diseases (AILDs) remains underexplored. This study aims to investigate potential causal associations between immune cell phenotypes and AILDs using a bioinformatics approach.

Methods: We utilized a two-sample Mendelian randomization (MR) analysis to explore the potential causal relationship between immune cell phenotypes and susceptibility to AILDs, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The data of 731 immune cell phenotypes were sourced from a study cohort with 3,757 individuals, while all AILDs summary data were obtained from an open-access database containing the data of AIH, PBC and PSC from 485,234, 24,510 and 14,890 subjects, respectively.

Results: For AIH, its incidence was negatively influenced by three phenotypes of natural killer (NK) cells [HLA-DR+ NK absolute count (AC), HLA-DR⁺ NK %NK, and HLA-DR⁺ NK %CD3^- lymphocyte] and two phenotypes of monocytes (CD14⁺ CD16⁺ monocyte AC, CD16 on CD14^- CD16+ monocyte), as well as positively affected by HLA-DR on plasmacytoid dendritic cell (DC) and HLA-DR on CD33^- HLA-DR⁺ myeloid cell. For PBC, its susceptibility was positively impacted by three phenotypes of B cells, i.e., CD27 on CD24⁺ CD27⁺ B cell, CD27 on IgD⁺ CD38^- unswitched memory (unsw mem) B cell, and CD27 on memory B cell. For PSC, its risk was negatively correlated with CD28 on CD45RA^- CD4 not regulatory T (Treg) cell and FSC-A on CD4⁺ NK cell.

Conclusions: This study suggests a potential causal relationship between immune cells and AILDs, providing preliminary insights into their immunological basis and informing the potential therapeutic targets for further functional studies in treating AILDs.

Background and objective: Erosive esophagitis (EE) is the second most common phenotype of gastroesophageal reflux disease (GERD). While proton pump inhibitors (PPIs) are considered the mainstay treatment for healing and maintaining remission of EE, a significant proportion of patients, particularly those with advanced grades, fail to respond adequately. This review provides an updated overview of the current pharmacological treatment options for EE.

Methods: An extensive electronic literature search was performed using PubMed database to identify relevant articles. The search included prospective clinical trials, observational trials, case-control studies, systematic reviews with or without meta-analysis, and narrative reviews describing pharmacological therapy for adult patients with EE. Articles were limited to English language publications. Search terms encompassed various treatment modalities including PPIs, potassium-competitive acid blockers (P-CABs), histamine 2 receptor antagonists (H2RAs), sucralfate, prokinetics, rebamipide and alginates.

Key content and findings: Research has shown varying effectiveness across different treatments for EE. While randomized controlled trials found alginates, sucralfate, and histamine-2 receptor antagonists to have limited healing efficacy, PPIs remain the most effective treatment, achieving healing rates of 75-95% after 8 weeks, though symptom resolution reaches about 60-85%. Among PPIs, esomeprazole shows slightly better healing outcomes compared to others. However, PPI effectiveness decreases in advanced EE cases [Los Angeles (LA) grades C/D], with healing rates dropping to 60-70%. More recently, P-CABs have demonstrated promising results, demonstrating healing rates non-inferior to PPIS but superior in patients with advanced EE or PPI-resistent EE. Given that most patients experience relapse upon discontinuation, maintaining PPI or PCAB therapy is crucial for preventing EE recurrence.

Conclusions: The future of EE management lies in a more personalized approach that takes into account disease severity, PPI response, and patient preferences. While PPIs remain the mainstay of treatment, P-CABs represent a promising new therapeutic option, particularly for severe and PPI-resistant cases. The addition of nighttime to bedtime H2RAs or use of double PPI dose may benefit refractory cases. Further studies are needed to directly compare PPIs and P-CABs in different EE grades and evaluate the value of adjunctive therapies.

Background: The new therapeutic modality incorporating a countermeasure against a westernized diet, i.e., a plant-based diet, showed far better outcomes than current standards in inflammatory bowel disease (IBD). Infliximab is widely used for induction and subsequent scheduled maintenance therapy in patients with IBD. However, the efficacy of infliximab diminishes over time. In the present study, we investigated the durability of scheduled infliximab maintenance therapy incorporating plant-based diet in IBD.

Methods: This was a prospective single-group trial at tertiary hospitals. Infliximab maintenance therapy was indicated in patients with severe disease or those who were unresponsive to conventional therapy. Infliximab (5 mg/kg body weight) was infused every 8 weeks on an inpatient basis, and plant-based diet, a lacto-ovo-vegetarian diet, was served three- or four-times during hospitalization. Patients were instructed to continue the diet after discharge. Durability was assessed using the Kaplan-Meier method.

Results: Twenty-four patients [16 with Crohn's disease (CD), eight with ulcerative colitis (UC)] were included: median age 27.5 years old, disease duration 53.5 months, and concomitant use of immunosuppressant 21%. Intensification of infliximab was employed in 46% of patients. There was no significant difference in durability rates between CD and UC. Durability rates were 87% at both 5 and 10 years. Plant-based diet score in the median follow-up period of 9.3 years, which indicates adherence to the plant-based diet, was significantly higher than the baseline score.

Conclusions: Infliximab maintenance therapy incorporating plant-based diet yielded a high durability rate of 87% at 5 years in patients with IBD.

Background: Recurrent bleeding from small bowel angiodysplasia (SBA) is common, and identifying risk factors for rebleeding can help identify high-risk patients who may benefit from further therapy. The pathophysiology of SBA is linked to an imbalance of angiogenic factors such as angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2), as well as higher serum levels of Ang-2. Additionally, murine models of steatohepatitis showed elevated serum and hepatic Ang-2 levels, which directly promote pathological angiogenesis. The present study aimed to evaluate risk factors for rebleeding in symptomatic patients with SBA.

Methods: Upon review of the medical records and application of the inclusion and exclusion criteria, 109 cases were determined to be affected by SBAs. Five patients were ineligible for the study because of a shorter than one-year follow-up period or early use of a specific treatment. Thus, in a retrospective observational study of 104 patients with gastrointestinal bleeding from SBA between 2012 and 2016 who were conservatively managed at the beginning of follow-up, we obtained clinical features and risk factors for rebleeding, and we analyzed potential predictors of rebleeding through univariate and multivariable analysis.

Results: We found that 57 of 104 patients (54.8%) experienced rebleeding during a follow-up of more than one year. The majority were females (71.2%), and we noted that hypertension (70.2%) and dyslipidemia (43.3%) were the most common comorbidities. Multiple regression analysis indicated that waist circumference (WC) (odds ratio for each 1 cm increment =1.04; 95% confidence interval: 1.01-1.08; P=0.02) was a significant risk factor for rebleeding.

Conclusions: In patients with symptomatic SBAs, an increase in WC positively correlated with the risk of rebleeding.