Risk Factor For Cholangiocarcinoma Research Articles

Biliary tract cancer

BackgroundBiliary tract cancers comprise a heterogeneous collection of malignancies usually described as cholangiocarcinoma of the intra- or extrahepatic bile duct, including perihilar cholangiocarcinoma and gallbladder cancer. MethodsA review of pertinent parts of the ESSO core curriculum for the UEMS diploma targets (Fellowships exam, EBSQ), based on updated and available guidelines for diagnosis, surgical treatment and oncological management of cholangiocarcinoma. ResultsFollowing the outline from the ESSO core curriculum we present the epidemiology and risk factors for cholangiocarcinoma, as well as the rationale for the current diagnosis, staging, (neo-)adjuvant treatment, surgical management, and short- and long-term outcomes. The available guidelines and consensus reports (i.e. NCCN, BGS and ESMO guidelines) are referred to. Recognition of biliary tract cancers as separate entities of the intrahepatic biliary ducts, the perihilar and distal bile duct as well as the gallbladder is important for proper management, as they each provide distinct clinical, molecular and treatment profiles to consider. ConclusionCore competencies in knowledge to the diagnosis, management and outcomes of biliary tract cancers are presented.

Endoscopic sphincterotomy or papillary balloon dilatation as a risk factor for cholangiocarcinoma: a meta-analysis

Endoscopic sphincterotomy or papillary balloon dilatation as a risk factor for cholangiocarcinoma: a meta-analysis

Renin-angiotensin system inhibitors improve the survival of cholangiocarcinoma: a propensity score-matched cohort study

BackgroundHypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear.MethodsThis is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis.ResultsResults of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32–0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20–0.79), respectively. Calcium channel blockers, diuretics, and β-blockers didn’t show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2–34.4); OS, 24.8 months (16.5–42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1–24.1); OS, 14.6 months (10.6–28.4)). The 1 year, 2 years, and 3 years’ survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%).ConclusionsRASis usage improves the survival of patients with CCA and hypertension concurrently.

Reduction of carcinogens in fermented fish (pla-ra and pla-som) by heating.

The risk factors for cholangiocarcinoma (CCA) are opisthorchiasis and the intake of a combination of nitroso compounds through the consumption of traditionally fermented fish, which is very popular in areas where liver flukes are endemic. The incidence of CCA remains high because this cultural habit of rural people has been altered. Therefore, decreasing nitrate and nitrite concentrations in fermented fish are an alternative approach to reducing the risk of CCA. Thus, this study aimed to reduce nitrate and nitrite concentrations in fermented foods by heating and investigated its effect on CCA development in a hamster model. We used Association of Official Analytical Chemists method 973.31 to measure the nitrate and nitrite concentrations in both fermented fish (pla-ra [PR]) and pickled fish (pla-som [PS]) before and after boiling for 5 and 30 min, respectively. The same samples were fed to Opisthorchis viverrini (OV)-infected or -uninfected hamsters for 3 months. Thereafter, the hamsters' liver and blood were collected for analysis. The levels of nitrates and nitrites in PS and PR significantly decreased following boiling for 5 and 30 min. The OV-PR and OV-PS groups showed dramatically increased numbers of inflammatory cells, fibrosis surrounding the bile duct, and focal fibrotic areas. However, after boiling the fermented dishes for 5 and 30 min, the extent of inflammatory cell infiltration and intensity of fibrosis in these groups were decreased. Our findings suggest that boiling reduces nitrate and nitrite toxicity in fermented dishes, as evidenced by reduced hepatic inflammation. However, regardless of heating, kidney tissues are adversely affected when fermented meals are consumed daily.

Diagnosis of Indolent Clonorchis sinensis and Opisthorchis viverrini Infections as Risk Factors for Cholangiocarcinoma: An Unmet Medical Need.

Cholangiocarcinoma is a highly aggressive cancer of the biliary tract epithelium. This form of cancer is prevalent in Asia, and recent reports show that its incidence is relatively rare but increasing in the United States. Although risk factors for cholangiocarcinoma have yet to be elucidated, a growing body of literature suggests chronic infection of genetically susceptible individuals with the food-borne zoonotic trematodes Clonorchis sinensis (C sinensis) and Opisthorchis viverrini (O viverrini) may play a role. Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for almost 30 years. During this period, the trematodes' feeding activities and their excretory-secretory products may damage the bile duct epithelium and promote local inflammation. These pathological processes could then provoke epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to the initiation and progression of cholangiocarcinoma in genetically susceptible people. The International Agency for Research on Cancer has determined that there is sufficient evidence in humans for the carcinogenicity of chronic infections with C sinensis and O viverrini. Timely serodiagnosis of indolent C sinensis and O viverrini infections is important as these parasites may be a risk factor for cholangiocarcinoma in veterans who served in Vietnam. About 774,000 living Americans served in Vietnam and there is an urgent need to develop sensitive and specific serologic assays to detect both acute and indolent infections. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival.

Clonorchis sinensis infection contributes to hepatocellular carcinoma progression in rat.

Clonorchis sinensis (C. sinensis) infection is a risk factor for cholangiocarcinoma. Whether it also contributes to the development of hepatocellular carcinoma (HCC) is still unclear. This study explored the potential relationship between C. sinensis infection and HCC. A total of 110 Sprague-Dawley rats were divided into four treatment groups, the negative control group (NC) received intragastric (i.g.) administration of saline, while the clonorchiasis group (CS) received i.g. administration of 150 C. sinensis metacercariae. The diethylnitrosamine-induced group (DEN) received intraperitoneal (i.p.) administration of DEN. The clonorchiasis DEN-induced group (CSDEN) received i.g. administration of 150 C. sinensis metacercariae followed by i.p. administration of DEN. Hematoxylin and eosin staining, immunohistochemistry, and Masson's trichrome staining were performed for histopathological analysis of the isolated tissues. RNA-seq technology and RT-PCR were employed for gene expression. In the DEN group, 15 rats survived, of which 9 developed liver cirrhosis and 7 developed HCC. In the CSDEN group, all of the 17 surviving rats developed cirrhosis, and 15 showed development of HCC. The incidence of liver cirrhosis and HCC was significantly higher in the CSDEN group than in the DEN group. KEGG pathway analysis of the differentially expressed genes suggested significant upregulation in inflammation-associated pathways. Immunohistochemistry and RT-PCR results showed significant upregulation of hepatic progenitor cell markers (CK19, SOX9, EpCAM) in the CS group compared to the NC group, as well as in the CSDEN group compared to the DEN group. Our study suggests that C. sinensis infection increases risk of HCC in a rat model by stimulating proliferation of hepatic progenitor cells.

Cholangiocarcinoma and pleural mesothelioma: asbestos exposure as a shared risk factor? A comparison of age-standardized incidence rates in Italy

Background and aim. Cholangiocarcinoma (CC) is the second most common primary liver malignancy. Anatomically, CC is divided into intrahepatic (ICC) and extrahepatic (ECC) forms. A possible causal association between ICC and exposure to asbestos has been hypothesized. To support this, we compared age-standardized incidence rates (ASR) of CC and malignant pleural mesothelioma (MPM) in Italy considering that asbestos is thought one of the major risk factors for MPM. Materials and Methods. We extracted ASR of ICC, ECC and MPM reported by 36 Italian cancer registries and listed in the last report on Cancer Incidence in Five Continents of the IARC. Data referred to 2008-2012 and covered 29 million population. We used linear regression analysis to evaluate the possible association between ASR of ICC, ECC and MPM. Analyses were stratified by sex. Results. From 2008 to 2012 ASR per 100,000/years in men ranged: 0.4-2.2 for ICC, 0.5-1.8 for ECC, and 0.0-0.7 for MPM. In women, ASR per 100,000/years ranged: 0.2-1.0 for ICC, 0.1-1.3 for ECC, and 0.0-0.6 for MPM. At regression analysis ICC did not report an association with MPM in men (beta coefficient -0.044, 95%CI -0.980–0.892) and women (beta coefficient -0.093, 95%CI -0.670–0.485). No association was detected for ECC as well. Conclusions. This crude analysis does not appear to support the hypothesis that CC could be associated to exposure to asbestos. This could be related to the large amount of known and suspected risk factors for CC that include common liver diseases due to genes, viruses and personal habits. Analyses adjusted for aggregated data might help disentangle this issue. Keywords: Asbestos, Cholangiocarcinoma, age-standardized incidence rates.

Examination on the risk factors of cholangiocarcinoma: A Mendelian randomization study.

Background: Several risk factors have been identified for CCA, however, whether such associations were causal remains unknown. Methods: Mendelian randomization (MR) has been applied to examine the causal relationship between 26 putative risk factors and CCA. The genetic variants for each risk factor were extracted from their corresponding genome-wide association study (GWAS) if they reached the genome-wide significance (p-value < 5 × 10−8). The genetic associations with CCA were obtained from the publicly available GWAS with the largest sample size. Mainly, inverse-variance weighted (IVW) has been adopted to estimate the causal effect on CCA. Both multivariable and mediation MR analyses were carried out to detect independent factors. Results: Three putative risk factors can causally elevate the risk of CCA after FDR correction, including liver fat content (LFC), non-alcoholic fatty liver disease (NAFLD), and cholelithiasis. The odds of CCA would increase per 1-SD increase in the liver fat content (LFC) (OR = 2.12 [1.66, 2.71]) and logOR of NAFLD. The genetic liability to cholelithiasis would increase the risk of CCA as well (OR = 2.17 [1.47, 3.20]). They were still significant in other methods. The multivariable MR analysis indicated that genetically-elevated LFC should increase the risk of CCA independently of cholelithiasis (OR = 1.88 [1.39, 2.55]). In the mediation MR analysis, the indirect effect was not significant when treating cholelithiasis as the mediator (indirect OR = 0.95 [0.85, 1.07]). Conclusion: This MR study identified that gallstone and liver fat accumulation are two independent risk factors of CCA, suggesting two modifiable ways of preventing CCA.

Opisthorchis Felineus Infection is a Risk Factor for Cholangiocarcinoma in Western Siberia: A Hospital-based Case-control Study.

Cholangiocarcinoma (CCA), a fatal bile duct cancer, has a high incidence in Western Siberia, Russian Federation. In addition, Opisthorchis felineus, a bile duct-dwelling trematode liver fluke is highly endemic. Closely related species have been shown to be cancerogenic agents in Asia. We therefore examined the association between O felineus infection and CCA in Western Siberia. We conducted a hospital-based, individually matched case-control study between January 2017 and August 2020 in Tomsk Oblast and Khanty-Mansiysk Autonomous Okrug, Yugra, Russian Federation. Histologically confirmed CCA patients (cases) were compared with matched age, sex, and place of residence hospital controls. The examination of study participants included the diagnosis of current and past O felineus infection, abdominal ultrasonographical assessment, physical examination, and interview on exposures to potential risk factors. We identified 40 patients with CCA and 160 controls. Exposures to O felineus infection was strongly associated with CCA (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4-10.8; P = .008). Also, cases reported more often that they were currently or in the past were infected by O felineus compared with controls (OR, 4.03; 95% CI, 1.7-9.5; P = .001). Furthermore, cases reported river fish consumption and fishing habits significantly more often than controls (OR, 5.5; 95% CI, 1.5-19.8; P = .009 and OR, 3.3; 95% CI, 1.4-7.7; P = .005). The study results revealed a strong significantly increased risk for CCA development in O felineus-infected individuals. Elaboration of the guidelines on screening programs for early CCA diagnosis, prevention, and treatment is socially important in endemic regions.

Disparities in palliative care utilization in cholangiocarcinoma patients: A National Cancer Database (NCDB) study.

e24077 Background: Cholangiocarcinoma is an adenocarcinoma of the intra- and extrahepatic bile duct epithelial cells. Although cases of cholangiocarcinoma in the US are rare, there is a low 5-year survival rate for these patients. The preferred treatment option for all subtypes is surgical resection. Alternative options include palliative care (PC) treatments such as chemotherapy, radiotherapy and locoregional treatments. There are many obstacles in accurately diagnosing cholangiocarcinoma, including obtaining adequate tumor samples for histology and determining what is malignant vs. benign in patients with primary sclerosing cholangitis (an important risk factor of cholangiocarcinoma). Such delays in diagnosis can lead to delays in treatment, which in turn results in a poor prognosis and worse outcome for patients. To the authors’ knowledge, there is no current study assessing PC disparities in patients with cholangiocarcinoma. Methods: A total of 46,751 patients who had a diagnosis with cholangiocarcinoma were identified utilizing the National Cancer Database (NCDB) ICD-O-3 histology code 8160. The 5-year survival of PC use was analyzed via a Kaplan-Meier curve. Demographic factors (race, biological sex, income, facility type, insurance, geographic location, and Charlson-Deyo co-morbidity score) were studied in relation to the receipt of PC. Results: Approximately 15.16% of our cohort received PC (7,089/46,751). There was a statistically significant difference in the staging of those patients that received palliative care, with 52% of our cohort being stage IV (p &lt; 0.001). The sex of patients who received PC was equally distributed between men and women (51.0% to 49.0%). The majority of PC recipients were white (83.6%) individuals making under $63,000 (69.6%) with a reported Charlson-Deyo score of 0 (64.9%). Many patients who received PC had Medicare (57.6%) and were treated at either an academic/research program (45.4%) or at a comprehensive community cancer program (33.6%). Facility locations were predominantly located in the Mid-South Atlantic and East North Central regions, compared to the Pacific regions (56.3% vs 8.4%), and patients who received PC lived mainly in urban areas (98.2%). The median survival for PC patients was shorter compared to patients that did not receive PC (5.32 months vs 9.23 months). Conclusions: This is one of the most comprehensive studies that identifies the demographic disparities of patients who received PC for cholangiocarcinoma. The typical PC patient is a white individual with Medicare, living in an urban area in the Mid-South Atlantic and East North Central region making under $63,000. By highlighting the disparities that exist, our study can aid clinicians in addressing PC under-utilization in specific demographics to help provide more comprehensive care.

Biliary Tract Malignancies Related to Gallbladder Polyps, Primary Sclerosing Cholangitis, and Choledochal Cysts.

Biliary Tract Malignancies Related to Gallbladder Polyps, Primary Sclerosing Cholangitis, and Choledochal Cysts.

Effectiveness of Village Health Volunteer Parallel Program for Proactive Action to Reduce Risk Factors for Cholangiocarcinoma in Two High-Risk Countries in the Greater Mekong Subregion

Thailand and Laos were classified as risk areas for cholangiocarcinoma (CCA) in a 2017 assessment in the Greater Mekong Subregion. In 2019, the potential of village health volunteers (VHVs) in both risk areas was developed. The VHVs trained in 2014 (VHV-A) were mentors transferring knowledge of CCA prevention to the trainees (known as VHV-B) in a parallel manner. After that, VHV-Bs in each area educated people to change their behavior. Both parties worked in the same direction to reduce risk factors. In 2020, data were collected after the program was organized in the same populations. The people were aged 30-69 years, whose names were in the civil registration, and had lived in that area for at least five years. Afterward, no less than 172 participants from each location were randomly selected. The research tools used were intervention and questionnaires. Descriptive and inferential statistics were employed for data analysis. After the experiment, all the experimental group’s risk factors were significantly different from those of the control group. This study’s outcome was an effective program for proactive action in reducing risk factors in the risk areas. Therefore, it should be applied to reduce risk factors for CCA in other regions.

A tumorigenic cell line derived from a hamster cholangiocarcinoma associated with Opisthorchis felineus liver fluke infection

AimsThe food-born trematode Opisthorchis felineus colonizes bile ducts of the liver of fish-eating mammals including humans. There is growing evidence that this liver fluke is a risk factor for cholangiocarcinoma (CCA). Cancer cell lines are necessary for drug screening and for identifying protein markers of CCA. The aim was to establish a cell line derived from cholangiocarcinoma associated with opisthorchiasis felinea. Main methodsAllotransplantation, immunohistochemistry, karyotype analysis, cell culture techniques, immunocytochemistry and real-time PCR. Key findingsHere we repot the establishment of first CCA cell line, CCA-OF, from a primary tumor of an experimental CCA in Syrian hamsters treated with low doses of dimethyl nitrosamine and associated with O. felineus infection. The cell line was found to be allotransplantable. Expression of epithelial and mesenchymal markers (cytokeratin 7, glycosyltransferase exostosin 1, Ca2+-dependent phospholipid-binding protein annexin A1 and vimentin) was demonstrated by immunostaining of the primary tumors, CCA-OF cells, and allotransplants. CCA-OF cells were found to express presumed CCA biomarkers previously detected in both human and experimental tumors associated with the liver fluke infection. The cells were diploid-like (2n = 42–46) with complex chromosomal rearrangements and have morphological features of epithelial-like cells. The usefulness of the CCA-OF cell model for antitumor activity testing was demonstrated by an analysis of effects of resveratrol treatment. It was shown that resveratrol treatment inhibited the proliferation and the migration ability of CCA-OF cells. SignificanceThus, the allotransplantable CCA-OF cell line can be used in studies on helminth-associated cholangiocarcinogenesis and for the testing of antitumor drugs.

Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma.

Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer. SIGNIFICANCE: MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.See related commentary by Chagani and Kwong, p. 1014.This article is highlighted in the In This Issue feature, p. 995.

The MBOAT7 rs641738 variant is associated with an improved outcome in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that causes liver cirrhosis, leading to liver failure. Additionally, PSC is a risk factor for cholangiocarcinoma. Its mechanism is unknown, and liver transplantation remains the sole curative option. The membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 and rs626283 variant alleles have been associated with both an accelerated progression of the disease and a higher risk for developing a more severe phenotype in many chronic hepatic diseases. Thus, we analysed their effect on long-term outcomes and laboratory parameters in PSC patients. We determined MBOAT7 genotypes and estimated the actuarial survival rate free of liver transplantation, using the Kaplan-Meier estimator. The differences between the estimates were analysed using the log-rank test. Patient blood was drawn and analysed for different serum parameters including cholestatic markers. Additionally, MBOAT7 RNA expression in human hepatic cell lines MZCHA1 (a biliary adenocarcinoma cell line), HepG2 (a hepatocellular carcinoma cell line), LX-2 (hepatic stellate cell line) and H-69 (cholangiocyte cell line) was analysed. Transplant-free survival was significantly prolonged in carriers of two rs641738 variant alleles, which was referred to as the TT genotype (mean 19.6 years; 95% confidence interval [CI]: 16.3-22.9 years) compared to the CC (mean 15.4 years, 95% CI 12.8-18.0 years) and heterozygous genotypes (mean 13.2 years, 95% CI 11.4-15.0 years) (P=0.017). This effect was restricted to male patients. We confirmed the high expression of MBOAT7 in hepatic stellate cells and found that MBOAT7 is less expressed in biliary epithelial cell lines, compared to parenchymal hepatic cells. Unlike other chronic liver diseases, carrying two MBOAT7 variant alleles does not seem to affect PSC patients negatively, but seems to have a positive effect on transplant-free survival. This study could help improve individual prognosis in PSC patients and give some new perspective on the involvement of the immune system in PSC.

12 Non-Alcoholic Fatty Liver Disease and Risk for Intrahepatic and Extrahepatic Cholangiocarcinoma: Meta-Analysis of Case Control Studies

INTRODUCTION: The incidence of cholangiocarcinoma is increasing worldwide. Over 8000 cases of both intrahepatic (ICC) and extrahepatic cholangiocarcinoma (ECC) are diagnosed every year in the US. Several recent studies have evaluated the role of non-fatty alcoholic liver disease (NAFLD) as a risk factor for cholangiocarcinoma. We performed a meta-analysis of case-control studies to evaluate the role of NAFLD as a risk factor for intrahepatic and extrahepatic cholangiocarcinoma. METHODS: We performed a systematic search of Medline, EMBASE and the Cochrane Library for studies without language restriction for case-control studies evaluating the risk of intra-hepatic and extra-hepatic cholangiocarcinoma in adult patients with NAFLD. We also hand searched grey literature from major gastrointestinal meetings. Standardized forms were used to extract data regarding number of cases of NAFLD and cholangiocarcinoma. Data was extracted by two reviewers independently. Summary odds ratio was calculated using Comprehensive Meta-analysis software. Heterogeneity, quality of studies and publication bias were also assessed. Random effects model was used for calculating the effect size. RESULTS: Ten studies met the inclusion criteria. 9 studies reported data on ICC and 5 studies reported data on ECC. Studies were performed in China, Taiwan, Japan, US, Europe and Korea. The period of patient enrollment ranged from 1992 to 2017. The majority of the studies used hospital based controls. The quality of the studies was assessed using Newcastle-Ottawa Scale. NAFLD was associated with a higher risk of ICC (OR 1.78: 95% CI 1.3–2.5, P = 0.001, I2 = 81). On subgroup analysis based on region of study, the increased risk was seen only in the studies reported from the Asian countries (5 studies, OR 1.93; 95% CI, 1.22–3.05, P = 0.005) but not from the Western countries (4 studies, OR 1.58; 95% CI 0.83–3.0, P = 0.17). On pooling all studies, risk of ECC was not increased in patients with NAFLD (OR 1.38; 95% CI 0.67–2.83, P = 0.55, I2 = 95%). However on subgroup analysis, increased risk of ECC was seen in the Western countries (2.42; 95% CI 2.01–2.91, P = 0.0001), but not the Asian countries. No significant publication bias was present. CONCLUSION: NAFLD is a risk factor for cholangiocarcinoma. Increased risk of ICC with NAFLD was seen in the Asian countries and ECC in the Western countries. Further studies are needed to confirm these findings.

1438 A Starry Sky Liver: Klebsiella Pneumoniae Septic Shock Caused by Infected Multiple Biliary Hamartomas

INTRODUCTION: Biliary hamartomas or von Meyenburg complexes are an exceedingly rare benign cystic disease of the liver. They are diagnosed radiographically due to a distinct appearance. We present an unusual case of a patient presenting with septic shock from multiple infected biliary hamartoma cysts. CASE DESCRIPTION/METHODS: A 52-y/o caucasian female presented to the emergency department with 20 pounds of unintentional weight loss over 3 months, painless jaundice, rigors and worsening altered mental status. Medical history included: Down's syndrome with progressive dementia, depression, and hypothyroidism. Physical exam notable for hypotension, fever, and tachycardia. Laboratory evaluation illustrated a leukocytosis of 10.9, total bilirubin of 7.6, direct bilirubin 6.1, alkaline phosphatase 926, ALT 44, AST 71, INR 2.3. An abdominal ultrasound revealed numerous hepatic cysts without cholelithiasis. MRCP confirmed innumerable uniform hepatic cysts without connection to the biliary tree consistent with multiple biliary hamartomas. The hepatic cysts lacked mural nodules. She was treated for presumed septic shock from ascending cholangitis with empiric IV antibiotics and vasopressors. With continued supportive care, her liver enzymes and coagulopathy normalized. Blood cultures grew Klebsiella pneumoniae. Her septic shock resulted from cholangitis due to infected biliary hamartomas. She discharged after 7 days in healthy condition. DISCUSSION: Multiple biliary hamartomas (MBH) are rare, benign lesions of the liver. They occur roughly 0.6-2.8% of the general population. Multiple biliary hamartomas are thought to arise from ductal plate malformations involving the small interlobular bile ducts. The cysts are typically uniform in size and most are asymptomatic found incidentally on imaging. MBH are associated with autosomal polycystic kidney disease, hepatic fibrosis, and polycystic liver disease. Gold standard for diagnosis of MBH is MRCP. It depicts striking stereotypical multiple T2 hyper-intense cystic lesions distributed homogeneously within the liver without communication to the bile ducts. Differential diagnosis for this imaging appearance includes metastasis, simple liver cysts, liver cancer, biliary adenomas, and Caroli's disease. Albeit unclear, MBH may be a risk factor for cholangiocarcinoma. This case highlights a peculiar case of biliary septic shock caused by infected liver biliary hamartomas.

Abstract 1526: Colitis promotes intrahepatic cholangiocarcinoma via gut microbiome dependent, CXCL1/CXCR2 mediated MDSC accumulation

Abstract Inflammatory bowel disease (IBD) is a known risk factor for cholangiocarcinoma. Gut microbiome dysregulation is closely associate with IBD, however, its role in IBD-promoted cholangiocarcinoma is unknown. Here, we established a preclinical mouse model recapitulating the tumor-promoting effect of IBD on cholangiocarcinoma. Increased translocation of gut bacteria to liver is observed in IBD. Oral antibiotic-mediated bacterial depleting shows that neomycin- but not vancomycin-sensitive bacteria mediate the IBD-accelerated tumor progression without affecting IBD disease status. Gut microbiome regulates anti-tumor immunity. A robust increase of hepatic CXCR2+ granulocytic myeloid-derived suppressor cells (G-MDSC) was observed, which is caused by IBD and can be blocked by oral neomycin treatment, but not dependent on tumor-bearing condition, gender or mouse strain. Depleting the increased hepatic G-MDSC abolished the IBD-enhanced tumor progression. The liver accumulation of CXCR2+ G-MDSC was regulated by CXCL1 expression of hepatocytes, which was controlled by gut microbiome-mediated LPS/TLR4 axis. The increase of liver granulocytes can also be found in patients with active IBD. Our study provides novel knowledge that bacterial dysregulation in IBD fosters a tumor-promoting environment in liver and contributes to cholangiocarcinoma disease progression. Citation Format: Qianfei Zhang, Chi Ma, Umberto Rosato, Bernd Heinrich, Qiong Fu, Laurence Diggs, Tim Greten. Colitis promotes intrahepatic cholangiocarcinoma via gut microbiome dependent, CXCL1/CXCR2 mediated MDSC accumulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1526.

Combined detection of serum carbohydrate antigen 19-9, carcinoembryonic antigen and indirect bilirubin in the diagnosis of cholangiocarcinoma

Objective To compare the sensitivity of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and indirect bilirubin (IBIL) detected separately and jointly for cholangiocarcinoma. Methods The clinical data of 376 patients with biliary diseases were retrospectively analyzed, including 57 patients in the cholangiocarcinoma group and 319 patients in the benign biliary lesions group. Independent risk factors for cholangiocarcinoma were screened by univariate analysis and logistic regression analysis. The sensitivity and specificity were calculated by separate and joint detection, and the difference was analyzed. Results The logistic regression analysis revealed that CA19-9 (P=0.046), CEA (P=0.000) and IBIL (P=0.000) were independent risk factors for cholangiocarcinoma. The sensitivity of CA19-9 + IBIL + CEA was 89.5% in the cholangiocarcinoma group, AUC was 0.813, and its sensitivity and AUC were the highest in both individual and combined tests. Conclusion For the early diagnosis of cholangiocarcinoma, combined detection of CA19-9, CEA and IBIL is superior to the detection of individual indicators, which significantly increases the detection rate of cholangiocarcinoma, and reduces the rate of missed diagnosis. Key words: Cholangiocarcinoma; Carbohydrate antigen 19-9; Carcinoembryonic antigen; Indirect bilirubin

Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis.

This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338-2351).