Biliary Tract Inflammation Research Articles

Occupational and Environmental Cholangiocarcinoma-Related Toxic Exposures

Cholangiocarcinoma (CCA) is a malignancy that originates from the epithelial cells of the biliary system. Despite advancements in medical diagnostic techniques, CCAs remain a challenge to detect due to their silent clinical progression, making it difficult to diagnose these diseases. There are several well-established risk factors for CCA, including biliary tract infection and inflammation. However, there is also growing evidence that community and occupational exposures play a significant role in the development of bile duct cancers. This review examines the geographical distribution of these risk factors and the importance of surveillance in individuals exposed to these toxins who are more prone to developing CCA.

Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases

BackgroundAutoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear. MethodsUtilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR). ResultsCausal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27+ B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28+ CD8+ T cells exhaustion and increased levels of CD28- CD8+ T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC. ConclusionsOur research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.

Associations of fatty acids with the risk of biliary tract calculus and inflammation: a Mendelian randomization study

BackgroundThe presence of gallstones in both the gallbladder and bile ducts is referred to as cholelithiasis. The prevalence of cholecystolithiasis and bile duct stones differs. Observational and Mendelian randomization (MR) studies have elucidated the significant contributing role of numerous fatty acids (FAs) in the development of cholelithiasis. Despite numerous studies about cholelithiasis, evidence on the relationship between serum FA levels and cholecystolithiasis, as well as bile duct stones with or without inflammation, remains insufficient.MethodsA two-sample MR study was designed to clarify the impact of serum FA levels on various bile duct inflammatory diseases. The summary statistics of single nucleotide polymorphisms (SNPs) associated with fatty acids were obtained from the UK Biobank (UKB) and included data from 114,999 participants. The researchers obtained GWAS summary statistics for cholecystolithiasis and bile duct stones in 463,010 and 361,194 European participants, including cases with and without inflammation. No sample overlap between the exposure and outcome was verified through the “mr-lap” package. The SNPs were screened to identify instrumental variables (IVs). Cochran’s Q test was applied for heterogeneity assessment. Inverse variance weighting (IVW) (fixed effects or random effects), MR-Egger regression and weighted median methods were used for MR. Multivariable MR was applied to determine the direct effect of each exposure on the outcome. A false discovery rate (FDR) was applied to adjust for multiple testing correction based on the Benjamini-Hochberg method. Finally, the FinnGen Consortium was used to validate some results.ResultsThe overall concentration of polyunsaturated fatty acids (PUFAs) in the serum was negatively associated with the risk of calculus of the gallbladder with acute cholecystitis (IVW, OR = 0.996, P = 0.038, CI 0.992–0.999; weighted median, OR = 0.995, P = 0.025, CI 0.991–0.999). The percentage of PUFAs to total monounsaturated fatty acids(MUFAs) (IVW, OR = 0.998, P = 0.045, CI 0.997–0.999) and the percentage of PUFAs to total FAs (IVW, OR = 0.997, P = 0.025, CI 0.995–0.999) had a protective role against cholecystitis. The percentage of PUFAs to total FAs had a protective role against calculus of the gallbladder without cholecystitis (IVW, OR = 0.995, P = 0.026, CI 0.990–0.999; MR Egger, OR = 0.99, P = 0.03, CI 0.982–0.998; weighted median, OR = 0.991, P = 5.41e-06, CI 0.988–0.995). Conversely, the percentage of MUFAs to total FAs increased the risk for cholecystitis (IVW, OR = 1.001, P = 0.034, CI 1.0001–1.002). However, there were no causal effects of the above exposures on the outcomes through multivariable MR and multiple testing correction. Finally, the causal effects of the above exposures on cholecystitis were validated in the FinnGen Consortium, which suggested that the percentage of PUFAs to total FAs (IVW, OR = 0.744, P = 0.021, CI 0.579–0.957) had a protective role against cholecystitis.ConclusionThese Mendelian randomization findings suggested that more attention should be focused on people who have low serum PUFA levels, which may have a potential role in the occurrence of calculus of the gallbladder or cholecystitis rather than calculus of the bile duct without cholangitis or cholecystitis.

Microbial exposure during early life regulates development of bile duct inflammation

Objectives The early life microbiome has been linked to inflammatory diseases in adulthood and a role for the microbiome in bile duct inflammation is supported by both human and murine studies. We utilized the NOD.c3c4 mouse model that develops a spontaneous immune-driven biliary disease with a known contribution of the microbiome to evaluate the temporal effects of the early life microbiome. Materials and methods Germ-free (GF) NOD.c3c4 mice were conventionalized into a specific pathogen free environment at birth (conventionally raised, CONV-R) or at weaning (germ-free raised, GF-R) and compared with age and gender-matched GF and conventional (CONV) NOD.c3c4 mice. At 9 weeks of age, liver pathology was assessed by conventional histology and flow cytometry immunophenotyping. Results Neonatal exposure to microbes (CONV-R) increased biliary inflammation to similar levels as regular conventional NOD.c3c4 mice, while delayed exposure to microbes (GF-R) restrained the biliary inflammation. Neutrophil infiltration was increased in all conventionalized mice compared to GF. An immunophenotype in the liver similar to CONV was restored in both CONV-R and GF-R compared to GF mice displaying a proportional increase of B cells and reduction of T cells in the liver. Conclusions Microbial exposure during early life has a temporal impact on biliary tract inflammation in the NOD.c3c4 mouse model suggesting that age-sensitive interaction with commensal microbes have long-lasting effects on biliary immunity that can be of importance for human cholangiopathies.

The Use of Inflammatory Markers for Treatment Response Monitoring in Acute Cholangitis: A Retrospective Cohort Study

IntroductionIn acute cholangitis (AC), monitoring treatment response to antimicrobial therapy allows for making timely decisions on early biliary decompression. The aims of this study were to compare the discriminating powers of traditional blood inflammatory markers and propose new inflammatory markers that have a better ability to distinguish between patients with and without biliary tract infection. MethodsThis was a retrospective cohort study. Patients who underwent endoscopic retrograde cholangio-pancreaticography for AC and those without biliary tract inflammation were randomly selected in the 4:3 ratio of their hospital admissions from our hospital endoscopic retrograde cholangio-pancreaticography database. The exclusion criterion was the absence of C-reactive protein (CRP) measurements. ResultsThe discriminating powers of the neutrophil count, lymphocytes, albumin, neutrophil-to-lymphocyte ratio, and CRP were superior to that of white blood cell (P1 < 0.005; P2 = 0.004; P3 < 0.0005; P4 < 0.0005; P5 < 0.0005). In monitoring treatment response in AC, lymphocyte count, albumin, neutrophil-to-lymphocyte ratio, and CRP were better than neutrophil count (P6 = 0.037, P7 < 0.005, P8, 9 < 0.0005). The area under the receiver operating characteristic curve (AUC) of CRP was higher than the AUC for lymphocytes, 96% (95% confidence interval [CI]: 94-98%) versus 81% (95% CI: 76-86%) (P < 0.0005), and larger than the AUC for albumin, 88% (95% CI: 84-92%) (P < 0.0005), indicating a greater discriminating power of CRP. However, the discriminating power of CRP-to-lymphocyte ratio (CLR) was more than that for CRP (P = 0.006) but equal to CRP-to-(lymphocytes∗albumin) ratio (CLAR) (P = 0.249). The AUCs of CLR and CLAR were both 98% (95% CI: 96-99%). ConclusionsCLR and CLAR have superior discriminating powers than traditional inflammatory markers used for monitoring treatment response in AC.

The association of immune-related genes and the potential role of IL10 with biliary atresia.

Biliary atresia (BA) is a severe immune-related disease that is characterized by biliary obstruction and cholestasis. The etiology of BA is unclear, our aim was to explore the relationship between biliary tract inflammation and immune-related genes. We selected 14 SNPs in 13 immune-related genes and investigated their associations with BA by using a large case‒control cohort with a total of 503 cases and 1473 controls from southern China. SNP rs1518111 in interleukin10 (IL10) was identified as associated with BA (P = 5.79E-03; OR: 0.80; 95% CI: 0.68-0.94). The epistatic effects of the following pairwise interactions among these SNPs were associated with BA: signal transducer and activator of transcription 4 (STAT4) and chemokine (C-X-C motif) ligand 3 (CXCL3); STAT4 and damage-regulated autophagy modulator1 (DRAM1); CXCL3 and RAD51 paralog B (RAD51B); and interferon gamma (IFNG) and interleukin26 (IL26). Furthermore, we explored the potential role of IL-10 in the pathogenesis of the neonatal mouse model of BA. IL-10 effectively prevented biliary epithelial cell injury and biliary obstruction in murine BA as well as inhibit the activation of BA-related immune cells. In conclusion, this study provided strong evidence implicating IL10 as a susceptibility gene for BA in the southern Chinese population. This study provided strong evidence implicating IL10 as a susceptibility gene for BA in the southern Chinese population. This study could infer that IL-10 may play a protective role in BA mouse model. We found that four SNPs (rs7574865, rs352038, rs4622329, and rs4902562) have genetic interactions.

Forkhead box M1 recruits FoxP3+ Treg cells to induce immune escape in hilar cholangiocarcinoma.

ObjectiveHilar cholangiocarcinoma (HCCA) is a malignancy related to chronic biliary tract inflammation. Tumor immune escape is a necessary process of tumorigenesis. Forkhead box M1 (FoxM1) could affect the progression of various carcinomas. This study attempted to elaborate on the mechanism of FoxM1 in HCCA immune escape.MethodsHCCA cell lines were collected to measure the expression of FoxM1 and FoxP3. CD8+ T cells were extracted to establish the co‐culture system with HCCA cells and Treg cells. pcDNA3.1‐FoxM1 or si‐FoxP3 was transfected into HCCA cells in the co‐culture system. HCCA cell viability, mobility, and invasiveness as well as levels of transforming growth factor (TGF)‐β and interleukin (IL)‐6 were evaluated. The binding relation between FoxM1 and FoxP3 promoter was verified. HCCA cells with pcDNA3.1‐FoxM1 were subcutaneously injected into mice to establish the xenograft mouse models.ResultsFoxM1 and FoxP3 were overexpressed in HCCA cells. The co‐culture of CD8+ T and HCCA cells inhibited HCCA cell activity and Treg cells limited CD8+ T killing. FoxM1 overexpression strengthened the inhibiting role of Treg cells in CD8+ T killing, upregulated TGF‐β and IL‐6 levels, and encouraged HCCA immune escape. FoxM1 bound to the FoxP3 promoter region to promote FoxP3 transcription. Silencing of FoxP3 neutralized the promoting role of FoxM1 overexpression in Treg cell immunosuppression and HCCA cell immune escape. FoxM1 aggravated tumor development, upregulated FoxP3 expression, increased Treg cells, and reduced CD8+ T cells.ConclusionFoxM1 bound to the FoxP3 promoter region to promote FoxP3 transcription and recruited FoxP3+ Treg cells, thereby inducing HCCA immune escape.

Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes.

AN UNUSUAL CAUSE OF PLEURAL EMPYEMA

SESSION TITLE: Fellows Disorders of the Pleura Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Empyema usually results as a complication of pneumonia, however trans-diaphragmatic spread of infection into pleural space from a liver abscess is very rare. CASE PRESENTATION: A 54-year-old female presented with 5 days of worsening dyspnea on exertion, decreased appetite and a right sided pleuritic chest pain. Her past medical history was significant for colorectal cancer with liver metastasis, for which she underwent right hepatectomy 3 weeks before presentation. On admission, she was diaphoretic along with hypotension, tachycardia, tachypnea and hypoxia. Blood work revealed neutrophil predominant leukocytosis of 25,000/µl. Computed tomography (CT) of chest showed moderate right sided pleural effusion without loculation. A 6 x7x 8 cm subcapsular fluid collection was also noted in the right posterolateral hepatic lobe, which was the site of her recent hepatic resection. Given these findings, there was a high suspicion for transdiaphragmatic spread of infection causing empyema. A diagnostic right thoracentesis showed an exudative effusion with a ph of 6.78, glucose 2, lactate dehydrogenase of 2213 and grams stain showing gram positive cocci. For optimal source control a 14 Fr chest tube and a percutaneous hepatic drain were placed, along with administration of alteplase and dornase. Fluid culture from both sites speciated as Staphylococcus epidermidis and empiric antibiotics were narrowed down to linezolid. Repeat CT chest imaging showed worsening loculated empyema, and patient underwent video assisted thoracoscopic surgery for adhesion lysis and evacuation. Intraoperatively, bile was found in the pleural space and the hepatic drain was seen coursing through the pleural cavity, which was subsequently removed. Post procedure patient showed marked clinical improvement. DISCUSSION: Empyema caused by transdiaphragmatic spread of infection from a pyogenic liver abscess (PLA) is very rare. Right hepatic resection leading to empyema has a reported incidence of 1%. Such patients also tend to have more biliary leakage and intrabdominal abscesses as studied by Goumard C et al. [1]. PLA themselves usually arises from intra-abdominal or biliary tract infection and are often polymicrobial. When monomicrobial, Klebsiella pneumoniae is the most common primary pathogen while Staphylococcus epidermidis, like in our patient, has been infrequently reported. Risk factors for development of complicated parapneumonic effusion requiring surgical or chest tube drainage include isolation of mixed gram positive and negative species (HR 10.62, p value 0.044, CI 1.069–105.411). Presence of bilateral pleural effusions and biliary tract inflammation are also significant risk factors for development of pleural empyema.[2]. CONCLUSIONS: Liver abscess leading to empyema through trans-diaphragmatic spread is an infrequent cause of empyema, and should be considered in patients who have undergone recent liver surgery. Reference #1: 1.Goumard, C., et al., Pleural Empyema Following Liver Resection: A Rare But Serious Complication. World J Surg, 2016. 40(12): p. 2999-3008. Reference #2: 2.Yi, E., et al., Evaluation of clinical risk factors for developing pleural empyema secondary to liver abscess. BMC Gastroenterol, 2019. 19(1): p. 215. DISCLOSURES: No relevant relationships by Ilya Berim, source=Web Response No relevant relationships by Sidra Raoof, source=Web Response

S1396 Intraluminal Cystic Artery Pseudoaneurysm Manifesting With Hemobilia

INTRODUCTION: Cystic artery pseudoaneurysm (CAP) is a rare cause of hemobilia and may arise as sequelae of inflammatory processes such as acute cholecystitis or surgical/procedural interventions. Its pathogenesis is posited to be due to vascular wall erosion from surrounding inflammation or, in the case of iatrogenic injury, direct vascular injury. We present a rare case of CAP arising after percutaneous cholecystostomy placement and a subsequent fall. CASE DESCRIPTION/METHODS: An 80-year-old woman with atrial fibrillation and recurrent pulmonary embolism was admitted to the hospital with acute cholecystitis. She was treated with IV antibiotics and percutaneous cholecystostomy. 5 days after cholecystostomy, the patient suffered from a fall and complained of RUQ abdominal pain and hematemesis the next day. Vitals were normal and her her abdomen was soft with RUQ tenderness. Cholecystostomy drainage bag had almost 400 mL of bloody output. Hemobilia was suspected due to the combination of bloody cholecystostomy output and hematemesis. CT abdomen demonstrated heterogeneously dense fluid (50 to 70 Hounsfield units) within the gallbladder lumen, concerning for hemorrhagic blood products, and a new cystic artery pseudoaneurysm measuring 6 mm [Figure 1]. The patient developed obstructive jaundice one day later with total bilirubin 3.8 mg/dL, direct bilirubin 3.1 mg/dL, alkaline phosphatase 635 U/L, GGT 740 U/L, AST 354 U/L, ALT 114 U/L highly suggestive of hemobilia (Quincke’s triad of obstructive jaundice, abdominal pain and GI bleeding). Repeat CT abdomen showed the cystic artery pseudoaneurysm now 1.3 centimeters [Figure 2]. Cholecystectomy with resection of the pseudoaneurysm was performed without complication. DISCUSSION: Diagnosis of cystic artery pseudoaneurysm should be considered in patients with antecedent biliary tract intervention or inflammation presenting with hemobilia. Contrast enhanced computed tomography may visualize a nodular lesion associated with the cystic artery with the same degree of enhancement as the aorta. Conventional angiography may be utilized in cases where transcatheter arterial embolism is planned and offers visualization of the pseudoaneurysm in real time. Management of cystic artery pseudoaneurysm is contingent on a patient’s clinical condition. In stable patients, cholecystectomy with surgical ligation reflects definitive management. Arterial embolization with delayed cholecystectomy may be preferred in cases of hemodynamic instability or contraindications to surgical management.Figure 1.: CT abdomen (day 9) re-demonstrating pericholecystic inflammatory changes consistent with known cholecystitis, interval development of hemorrhagic blood within gallbladder lumen, and cystic artery pseudoaneurysm measuring 6 mm (red arrow).Figure 2.: CT abdomen (day 11) axial view (A) and sagittal view (B) demonstrating interval increase in blood products within the gallbladder lumen and increased size of cystic artery pseudoaneurysm to 1.3 centimeters (red arrows).

Evaluation of clinical risk factors for developing pleural empyema secondary to liver abscess

BackgroundThe aim of this study was to investigate the clinical manifestation and predictive risk factors of pleural empyema developing during treatment of the pyogenic liver abscess.MethodsMedical records of patients with the liver abscess in our institution were reviewed retrospectively. Enrolled patients were classified into four groups; Group 1: patients without pleural effusion, Group 2: patients with pleural effusion and who were treated noninvasively, Group 3: patient with pleural effusion and who were treated with thoracentesis, and Group 4: patients with pleural effusion that developed into empyema. Patient characteristics, clinical manifestation, and possible risk factors in development of empyema were analyzed.ResultsA total of 234 patients was enrolled in this study. The incidence rate of empyema was 4.27% (10 patients). The mean interval for developing pleural effusion was 5.6 ± 6.35 days. In multivariate analysis, risk factors for developing pleural effusion included the location of the liver abscess near the right diaphragm (segment 7 and 8, OR = 2.30, p = 0.048), and larger diameter of the liver abscess (OR = 1.02, p = 0.042). Among patients who developed pleural effusions, presences of mixed microorganisms from culture of liver aspirates (OR = 10.62, p = 0.044), bilateral pleural effusion (OR = 46.72, p = 0.012) and combined biliary tract inflammation (OR = 21.05, p = 0.040) were significantly associated with the need for invasive intervention including surgery on effusion.ConclusionThe location of the liver abscess as well as pleural effusion, elevated inflammatory markers, and combined biliary tract inflammation may be important markers of developing pleural complication in patients with pyogenic liver abscess.

1410 A Rare Case of Extrahepatic Cholestasis Secondary to Acquired Immunodeficiency Syndrome (AIDS)—Related Kaposi Sarcoma

INTRODUCTION: Kaposi sarcoma is an aggressive cancer seen in immunocompromised patients caused by Human Herpesvirus-8 (HHV-8) infection. Cutaneous and pulmonary complications are the most frequent, biliary tract involvement is rarely reported, typically asymptomatic but may present as cholangitis or progress to liver failure. CASE DESCRIPTION/METHODS: 35-year-old male with HIV and CD4 count of 35 cells/uL, not on antiretroviral therapy for the past year, presented with fever, fatigue, diffuse lymphadenopathies, unintentional weight loss, generalized abdominal pain and scleral icterus for the last 2 weeks. Physical exam showed icterus, small hyperpigmented lesions throughout his trunk, a violaceous nodular enlargement of the hard palate, generalized lymphadenopathy, diffusely tender abdomen and hepatomegaly. Laboratory studies were significant for total bilirubin 23 mg/dL, direct bilirubin 16 mg/dL, ALP 288 U/L, GGT 193 U/L, AST 66 U/L, ALT 40 U/L, INR 1.3. CT of the abdomen showed hepatomegaly and an infiltrative process in the portal hepatis to the celiac area with obstruction of the biliary tract with intrahepatic biliary dilation. Endoscopic retrograde cholangiopancreatography demonstrated 3 cm stricture in the common hepatic duct, a biopsy was taken, and 2 stents were placed. Endoscopic ultrasound with biopsies taken from a stomach nodule and porta hepatis were performed as well. Pathology from porta hepatis mass showed blood clot however, HHV-8 stain from the common hepatic duct and stomach nodule biopsies was positive for Kaposi sarcoma. Doxorubicin and antiretroviral therapy were started, and patient was discharged in view of symptomatic improvement. Liver function tests normalized 8 weeks after presentation. DISCUSSION: Kaposi sarcoma involving the biliary tract has been associated with cholangitis and jaundice and may also be caused from extensive disease of the porta hepatis with compression of the extrahepatic biliary tree. Current first-line treatment for advanced Kaposi sarcoma is lipososomal anthracyclines (doxorubicin, daunorubicin). HHV-8 infection cannot be eradicated, but long-term remission is possible. Treatment is indicated in patients with progressive hepatic and biliary disease. Kaposi sarcoma has also been associated with AIDS (acquired immunodeficiency syndrome) cholangiopathy, a form of biliary tract inflammation with stricture formation in severely immunosuppressed HIV patients and management consists of endoscopic sphincterotomy for papillary stenosis and stenting.

The association between biliary tract inflammation and risk of digestive system cancers

The relationship between biliary tract inflammation (BTI) and digestive system cancers is unclear. This study aimed to evaluate the association between BTI and the risks of digestive system cancers.Using the Taiwan National Health Insurance claims data, information on a cohort of patients diagnosed with BTI (n = 4398) between 2000 and 2009 was collected. A comparison cohort of sex-, age-, and index year-matched persons without BTI (n = 17,592) was selected from the same database. The disease was defined by the ICD-9-CM. Both cohorts were followed until the end of 2010 and incidences of digestive system cancers were calculated.The results revealed an increase in adjusted hazard ratio (aHR) of biliary tract cancer (24.45; 95% confidence interval [CI]: 9.20–65.02), primary liver cancer (1.53; 95% CI: 1.07–2.18), and pancreatic cancer (3.10; 95% CI: 1.20–8.03) in patients with both gallbladder and BTI. The aHR of stomach cancer was also found to be increased (2.73; 95% CI: 1.28–5.81) in patients with gallbladder inflammation only. There were no differences in esophageal cancer (aHR: 0.82; 95% CI: 0.23–2.87) and colorectal cancer (aHR: 0.92; 95% CI: 0.59–1.45). The aHR for digestive system cancers increased by 3.66 times (95% CI: 2.50–5.35) and 12.20 times (95% CI: 8.66–17.17) in BTI visits frequency averaged 2 to 4 visits per year and frequency averaged ≥5 visits per year, respectively.Patients with BTI have significantly higher risk of digestive system cancers, particularly biliary tract, pancreatic, and primary liver cancers, compared with those who are without it.

New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers.

Unsuspected gallbladder carcinoma discovered during or after cholecystectomy: focus on appropriate radical re-resection according to the T-stage

The long-term survival of patients with unsuspected gallbladder carcinoma (UGC) and the role of radical re-resection for this disease remain unclear. A retrospective study was carried out on 38 UGC patients. The time-to-event data were demonstrated by Kaplan-Meier curves. Comparing survival curves of two groups using the log-rank test. The overall incidence of UGC in patients underwent cholecystectomy in our hospital was 0.18% (25 of 14,073). Distribution according to actual pT-stage (the UICC) was: pT1a: n=3; pT1b: n=11; pT2: n=4; pT3: n=12; pT4: n=8. The preoperative diagnosis included a high rate of acute biliary tract inflammation (24 of 38, 63.2%). Compared with other gallbladder carcinoma patients, UGC group had significantly higher proportion of early stages (pT1) (36.8%, 14 of 38 cases) (p<0.01), and better prognosis. The comparison of radical re-resection versus simple cholecystectomy showed a significant benefit in overall survival for the pT3 group (22.0±5.48 vs. 5.0±0.9months; p=0.02). There are median survival differences between the two subgroups of patients with pT1b tumors whether received re-resection or not. Median survival was 62.0months and 24.0±8.5months, respectively, though the differences are not statistically significant (p=0.131). Radical re-resection is strongly recommended for patients with pT1b-stage cancer. The reoperation should be performed as soon as possible, preferably within 10days after the initial operation.

Mechanisms of oxysterol-induced disease: insights from the biliary system.

Oxysterols are oxidized species of cholesterol that are derived from exogenous (e.g. dietary) and endogenous (in vivo) sources. Oxysterols play critical roles in normal physiologic functions as well as in pathophysiologic processes in a variety of organ systems. This review provides an overview of oxysterol biology from the vantage point of the biliary system. Several oxysterols have been identified in human bile in the context of biliary tract infection and inflammation. This finding has led to investigations regarding the potential pathophysiologic significance of biliary oxysterols in diseases affecting the biliary system, with an emphasis on cholangiocarcinoma. Emerging evidence implicates specific oxysterols in the development and progression of this malignancy. This review will summarize the literature on oxysterols in the biliary system and discuss how the accumulated evidence contributes to a hypothesis describing the molecular basis of cholangiocarcinogenesis.

Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma

Well established risk factors for intrahepatic cholangiocarcinoma such as biliary tract inflammation and liver flukes are not present in most Western countries patients. Although cirrhosis and other causes of chronic liver disease have been implicated, their contribution as risk factors for cholangiocarcinoma is unclear and our aims were to analyze these emerging potential risk factors by systematic examination of case-control series from geographically diverse regions. We performed a literature review and meta-analysis of case-control studies on intrahepatic cholangiocarcinoma and cirrhosis and related risk factors. Tests of heterogeneity, publication bias and sensitivity analyses were performed and an overall odds ratio and 95% confidence intervals calculated. Eleven studies from both high and low prevalence regions were identified. All studies except those evaluating cirrhosis, diabetes, and obesity exhibited significant heterogeneity. Cirrhosis was associated with a combined OR of 22.92 (95% CI=18.24-28.79). Meta-analysis estimated the overall odds ratio (with 95% confidence intervals) for defined risk factors such as hepatitis B: 5.10 (2.91-8.95), hepatitis C: 4.84 (2.41-9.71), obesity: 1.56 (1.26-1.94), diabetes mellitus type II: 1.89 (1.74-2.07), smoking: 1.31 (0.95-1.82), and alcohol use: 2.81 (1.52-5.21). Sensitivity analysis did not alter the odds ratio for any risk factors except smoking and there was no evidence of publication bias. Cirrhosis, chronic hepatitis B and C, alcohol use, diabetes, and obesity are major risk factors for intrahepatic cholangiocarcinoma. These data suggest a common pathogenesis of primary intrahepatic epithelial cancers.

Preneoplastic conditions underlying bile duct cancer.

Malignancies arising from the biliary tract can arise from the epithelial lining of the biliary tract and surrounding tissues. Conditions that predispose to malignancy as well as preneoplastic changes in biliary tract epithelia have been identified. In this overview, we discuss preneoplastic conditions of the biliary tract and emphasize their clinical relevance. Chronic biliary tract inflammation predisposes to cancer in the biliary tract. Biliary tract carcinogenesis involves a multistep process as a consequence of chronic biliary epithelial injury or inflammation. Reminiscent of other gastrointestinal epithelial malignancies such as gastric, colon, and pancreatic cancer, biliary tract cancers may evolve via multistep progression from epithelial hyperplasia and dysplasia to malignant transformation. The potential role of initiating cells is also becoming recognized. In spite of improved risk factor recognition, and advances in diagnostic tools, the early diagnosis of pre-malignant or malignant biliary tract conditions is extremely challenging, and there is a paucity of evidence on which to base their management. As a result, the role of pre-emptive surgery remains largely undefined.

AIDS Cholangiopathy in an Asymptomatic, Previously Undiagnosed Late-Stage HIV-Positive Patient from Kenya

AIDS-associated cholangiopathy is a form of biliary tract inflammation with stricture formation seen in AIDS patients who are severely immunosuppressed. It is no longer common in countries in which HAART therapy is widely employed but is still seen in underdeveloped countries. The majority of patients are symptomatic at the time of presentation. Herein, we describe a seventy-four-year-old woman who presented with unilateral leg swelling after a prolonged airplane flight. She was otherwise entirely asymptomatic. Routine laboratory testing was notable for a hypochromic microcytic anemia, slight leukopenia, and mild hypoalbuminemia. Liver enzymes were all elevated. Deep venous thrombosis was confirmed, and a CT scan of the chest disclosed no pulmonary emboli. However, the visualized portion of the abdomen showed dilatation of the common bile and pancreatic ducts. This was confirmed on ultrasonography and MRCP, and no obstructive lesions were noted. An ERCP revealed a dilated common bile duct without filling defects or strictures. A balloon occlusion cholangiogram showed strictures and beading of the intrahepatic ducts. Shortly thereafter, serology for HIV returned positive along with a depressed CD4 cell count, and the patient was diagnosed with AIDS-associated cholangiography.

Increased risk of colorectal cancer among patients with biliary tract inflammation: A 5‐year follow‐up study

The purpose of the study was to investigate the risk of colorectal cancer among patients with biliary tract inflammation (BTI) compared to non-BTI patients during a 5-year follow-up period. The study group comprised 1,613 patients with BTI, among which 32 cases (1.98%) developed colorectal cancer. The comparison group included 8,065 randomly selected subjects (5 for every patient with BTI), 74 of whom contracted colorectal cancer (0.92%). Stratified Cox proportional hazard regressions were calculated to estimate the adjusted hazard of colorectal cancer between the study group and comparison group. The adjusted hazard ratio for colorectal cancer for patients with BTI was 6.54 times (95% CI = 3.07-13.92) as high as for those without BTI within a 1-year follow-up period, 3.20 times (95% CI = 1.93-5.30) as high within a 3-year follow-up period, and 2.21 times (95% CI = 1.45-3.37) as high within a 5-year follow-up period. We also found that the adjusted hazard ratio for colorectal cancer for those with bile duct inflammation was 3.30 times (95% CI = 1.87-5.84) as high as for those without BTI within the 5-year follow-up period. However, no increased hazard of colorectal cancer was observed for patients with gallbladder inflammation. We concluded that patients with BTI had a significantly higher risk of colorectal cancer compared to patients without BTI.