Protective effect of higher free thyroxine levels within the reference range on biliary tract cancer risk: a multivariable mendelian randomization and mediation analysis.

Background: Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC. Methods: Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis. Results: The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC). Conclusion: The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process.

Inhibition of Opisthorchis felineus glutathione-dependent prostaglandin synthase by resveratrol correlates with attenuation of cholangiocyte neoplasia in a hamster model of opisthorchiasis.

Food-borne trematodiases represent major neglected parasitic diseases. Trematodes of the family Opisthorchiidae including Opisthorchis felineus, Opisthorchis viverrini and Clonorchis sinensis are ranked eight on the global list of the 24 most prevalent food-borne parasites. Chronic O. felineus infection symptoms include precancerous lesions with the potential for malignancy. In recent decades, liver flukes of the family Opisthorchiidae have been extensively scientifically explored, however despite this the molecular mechanisms of O. felineus pathogenicity and its carcinogenic potential have not been studied. Opisthorchis felineus glutathione-dependent prostaglandin synthase (GST σ) is the major component of the excretory-secretory product of this liver fluke. We hypothesised that the activity of this enzyme is involved in the infection pathogenesis, including the formation of precancerous lesions. To test this hypothesis and to gain insights into the mechanisms of precancerous lesion formation, we (i) investigated whether excretory parasitic GST σ retains its enzymatic activity, (ii) tested resveratrol (RSV) as a possible inhibitor of this enzyme, and (iii) assessed biliary neoplasia and oxidative DNA damage as well as the expression of neoplasia and fibrogenesis marker genes after prolonged administration of RSV in a hamster model. RSV was found to inhibit GST σ enzymatic activity in a dose-dependent manner (R = 0.85, P < 0.001; half-maximal effective dose (ED50) = 48.6 µM). Prolonged administration of RSV significantly suppressed high-grade biliary neoplasia (P = 0.008), attenuated upregulation of hyperplasia and fibrogenesis-related genes (Tgfb, α-SMA and CK7), and decreased the elevated oxidative DNA damage. Taking into account that RSV can influence a wide range of pathways, further research is needed to confirm the role of GST σ in O. felineus pathogenicity. Nevertheless, the chemopreventive effect of RSV targeting biliary neoplasia formation might be useful for improving the outcomes in infected populations and represents a compelling rationale for RSV testing in combination chemotherapy of opisthorchiasis.

Choledochal cysts: Similarities and differences between Asian and Western countries.

Choledochal cysts (CCs) are rare bile duct dilatations, intra-and/or extrahepatic, and have higher prevalence in the Asian population compared to Western populations. Most of the current literature on CC disease originates from Asia where these entities are most prevalent. They are thought to arise from an anomalous pancreaticobiliary junction, which are congenital anomalies between pancreatic and bile ducts. Some similarities in presentation between Eastern and Western patients exist such as female predominance, however, contemporary studies suggest that Asian patients may be more symptomatic on presentation. Even though CC disease presents with an increased malignant risk reported to be more than 10% after the second decade of life in Asian patients, this risk may be overstated in Western populations. Despite this difference in cancer risk, management guidelines for all patients with CC are based predominantly on observations reported from Asia where it is recommended that all CCs should be excised out of concern for the presence or development of biliary tract cancer.

Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra- and/or extrahepatic biliary ducts. While its features and disease course can be variable, most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly, PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.

Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink.

OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.

Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

BACKGROUND: A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. METHODS: Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. RESULTS: We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose-response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). CONCLUSIONS: The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC.

Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management.

Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be challenging because inflammation-related changes in PSC may produce dominant biliary tract strictures mimicking CCA. Biomarkers such as detection of methylated genes in biliary specimens represent noninvasive techniques that may discriminate malignant biliary ductal changes from PSC strictures. However, conventional cytology and advanced cytologic techniques such as fluorescence in situ hybridization for polysomy remain the practice standard for diagnosing CCA in PSC. Curative treatment options of malignancy arising in PSC are limited. For a subset of patients selected by using stringent criteria, liver transplantation after neoadjuvant chemoradiation is a potential curative therapy. However, most patients have advanced malignancy at the time of diagnosis. Advances directed at identifying high-risk patients, early cancer detection, and development of chemopreventive strategies will be essential to better manage the cancer risk in this premalignant disease. A better understanding of dysplasia definition and especially its natural history is also needed in this disease. Herein, we review recent developments in our understanding of the risk factors, pathogenic mechanisms of PSC associated with CCA, as well as advances in early detection and therapies.

Cancer stem cells as therapeutic targets of hepato-biliary-pancreatic cancers.

Heterogeneity is one of the essential hallmarks of malignancies. Within bulk cancer cells, a striking variability differs in biological characteristics including the proliferation rate, cell-cell interaction, metastatic tendency and even sensitivity to anticancer therapies. Such diversity makes the investigation and treatment of the cancers complicated. Increasing evidence suggests this plasticity of cancers is a result of self-renewing and differentiation of a small subpopulation of cancer cells with stem-like properties, called cancer stem cells (CSCs). More importantly, CSCs are believed to be responsible for the resistance to conventional therapies and metastatic abilities in clinical practice. This review summarizes the molecular pathogenesis of hepato-biliary-pancreatic CSCs on the basis of the recent studies, and promising strategy of novel therapy targeting the signal transduction pathways or potentially epigenetic addictions of CSCs.

A selective cyclooxygenase-2 inhibitor (Etodolac) prevents spontaneous biliary tumorigenesis in a hamster bilioenterostomy model.

BACKGROUND: Secondary biliary carcinomas are associated with persistent reflux cholangitis after bilioenterostomy. Cyclooxygenase-2 (COX-2) has been a target for cancer prevention. The aim of this study was to evaluate the chemopreventive efficacy of long-term treatment with a selective COX-2 inhibitor medication during the natural course after bilioenterostomy without chemical induction. METHODS: Syrian golden hamsters which underwent choledochojejunostomy were randomly divided into two groups: the control group (n = 31), which was fed a normal diet, and the etodolac group (n = 33), which was fed 0.01% etodolac (a selective COX-2 inhibitor) mixed in the meal. The hamsters were killed at the postoperative weeks 20-39, 40-59, 60-79, or 80-100. Biliary neoplasms, cholangitis, proliferating cell nuclear antigen labeling index (PCNA-LI) of the biliary epithelium, and prostaglandin E2 (PGE2) production were evaluated. RESULTS: The occurrence rates of biliary neoplasm were 43.8 and 15.2% in the control and etodolac groups, respectively (p < 0.05). The incidence of biliary neoplasm increased as time progressed in the control group, whereas it remained at a low level throughout the experimental period in the etodolac group. PGE2 products tended to be lower in the etodolac group, and PCNA-LI was significantly lower in the etodolac group (p < 0.01). These results suggest that the medication etodolac suppresses cell proliferation of the biliary epithelium, thereby preventing biliary carcinogenesis. CONCLUSIONS: Etodolac is expected to prevent secondary biliary carcinogenesis caused by persistent reflux cholangitis after bilioenterostomy.

Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study.

UNLABELLED: Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to ≥ 4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [CI]: 0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95% CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant. CONCLUSION: Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer.

Biliary tract carcinoma: clinical perspectives on molecular targeting strategies for therapeutic options.

Biliary tract carcinoma (BTC) is a lethal malignancy. This lethality is essentially attributed to both slow carcinogenesis occurring under complex pathological circumstances and to the asymptomatic growth of BTC infiltrating the surrounding structures by varying routes. The disease is therefore usually detected at an advanced stage with a high frequency of distant organ metastasis. To date, conventional chemotherapy and radiation therapy have been notably ineffective against BTC. For an improved treatment outcome of BTC and prolonged survival, there is now a real and urgent need to focus on developing novel and potent therapeutic strategies aimed at exploiting select molecular targets associated with tumor proliferation, invasion, and/or metastasis that would impact in a significant way on clinical outcome. The outcomes of recent studies, by the analysis of BTC cells, BTC animal models, and clinical specimens of BTC patients, have revealed, in detail, the molecular mechanism of carcinogenesis and tumor progression of BTC, and these studies have exploited select molecular targets that could significantly impact the clinical outcome. In the near future, the development of new molecular targeting drugs with potent efficacy against BTC, and the performance of randomized clinical trials of these drugs are urgent and essential for the treatment of patients with BTC.

Chemoprevention of chemically-induced biliary carcinogenesis in hamsters by vitamin K2.

BACKGROUND/AIMS: Pancreaticobiliary maljunction (PBM) is a high risk factor of biliary tract cancer. The chemopreventive effects of Vitamin K2 (menaquinone-4: MK4) in a hamster PBM model were investigated. METHODOLOGY: The extrahepatic bile duct at the distal end of the common duct was ligated and cholecystoduodenostomy was performed (Group I). The same surgery was performed and from 4 weeks after surgery, 10 mg/kg of N-nitrosobis (2-oxopropyl) amine was subcutaneously injected once a week with a one-week interval (Group II). In addition of Group II, MK4 was orally administered once a day, five times with every week (Group III). The hamsters were sacrificed 20 weeks after surgery and histopathological findings of gallbladder were investigated. RESULTS: Group I showed predominantly proper epithelium without cancer. In Group II, atypical epithelium (AE) was observed in 75% of animals and early cancer was observed in 25%. Group III showed less AE and no cancer. The PCNA labeling index in Group III was statistically significantly lower than in Group II. In addition, no statistically significant differences were noted among the groups in terms of the apoptosis labeling index. CONCLUSIONS: MK4 suppressed biliary carcinogenesis by the induction of cell cycle arrest in a hamster biliary carcinogenetic model.

Risk factors for biliary tract and ampullary carcinomas and prophylactic surgery for these factors.

Curative resection is the only treatment for biliary tract cancer that achieves long-term survival. However, patients with advanced biliary tract cancer have only a limited prognosis even after radical surgical resection. Thus, to improve the longterm results, the early detection of biliary tract cancer and subsequent cure seem to be essential. The purpose of this study was to review the literature concerning the risk factors for cancerous and precancerous lesions of the biliary tract, and prophylactic surgery for these factors. It has been reported that pancreaticobiliary maljunction (PBM) with bile duct dilatation is a risk factor for gallbladder cancer and bile duct cancer, while PBM without bile duct dilatation is a risk factor for gallbladder cancer. Thus, in the former group, a prophylactic excision of the common bile duct and gallbladder should be recommended, while in the later group, a prophylactic cholecystectomy without bile duct resection may be the appropriate surgical procedure. It has also been reported that primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma. Patients with PSC often develop advanced cholangiocarcinoma with a poor prognosis. In patients with PSC, therefore, strict follow-up should be recommended. Adenoma and dysplasia have been regarded as precancerous lesions of gallbladder cancer. A polypoid lesion of the gallbladder that is sessile, has a diameter greater than 10 mm, and /or grows rapidly, is highly likely to be cancerous and should be resected. Although gallstones seem to be closely associated with gallbladder cancer, there is no evidence of a direct causal relationship between gallstones and gallbladder cancer. Thus, a cholecystectomy is not advised for asymptomatic cholecystolithiasis. Controversy remains as to whether adenomyomatosis of the gallbladder and porcelain gallbladder are associated with gallbladder cancer. With respect to ampullary carcinoma, adenoma of the ampulla is considered to be a precancerous lesion. This article discusses the risk factors for cancerous and precancerous lesions of the biliary tract and prophylactic treatment for these factors.

Late postoperative complications in patients with pancreaticobiliary maljunction.

BACKGROUND/AIMS: Reports on the late postoperative complications in patients with pancreaticobiliary maljunction (PBM) are limited. METHODOLOGY: Eighteen PBM patients with biliary dilatation and 12 without biliary dilatation were surgically treated at our institute. These 30 PBM patients were retrospectively reviewed, with particular attention to late postoperative complications. RESULTS: Nineteen patients without biliary malignancies underwent resection of the extrahepatic bile duct (BD) and hepaticojejunostomy. Two patients without biliary dilatation or malignancy underwent cholecystectomy alone. Nine patients with malignancies underwent hepatectomy with extrahepatic BD resection in 7 patients, pancreatoduodenectomy (PD) in 1, and PD + hepatectomy in 1. The median follow-up duration was 110 months. All patients without malignancies are presently alive in good healthy condition and have not developed any malignancy postoperatively. Late postoperative complications were seen in 6 (20%). Four patients with biliary dilatation were surgically or endoscopically treated for intrahepatic lithiasis 3, 12, 42 and 54 months after initial operation. One of them had a pancreatic protein plug 216 months after surgery, and was treated with papilloplasty after open laparotomy. In one patient without biliary dilatation, pancreatic protein plug and intrahepatic lithiasis were found 60 and 72 months after surgery, respectively, and both were treated endoscopically. CONCLUSIONS: Intrahepatic lithiasis and pancreatic protein plug are frequent late postoperative complications. The intrapancreatic residual choledochus or dilated pancreatic duct seems to be related to pancreatic protein plug. However, intrahepatic lithiasis may occur regardless of the pattern of the biliary tract dilatation. Careful, long-term follow-up is important in patients with PBM.

Drug insight: statins and gastrointestinal cancer.

Statins are popular lipid-lowering drugs that have had a great impact on the primary and secondary prevention of cardiovascular diseases. Basic and clinical research have also revealed that statins have biologic activities that go beyond lipid lowering, and suggest that they might have other therapeutic benefits. Perhaps the most exciting of these additional biologic effects is the finding that statins can exert an anticancer effect on cultured cancer cells, and in animal models. Clinical studies of statins for the treatment and prevention of cancer have, however, produced conflicting results. This review critically evaluates the current body of literature on the role of statins in the treatment and prevention of gastrointestinal cancers, with particular focus on clinical and observational studies.

Tea drinking and the risk of biliary tract cancers and biliary stones: a population-based case-control study in Shanghai, China.

Biliary tract cancers, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Apart from gallstones, etiologic factors for biliary tract cancer are not clearly defined. Several epidemiologic studies have suggested that consumption of tea, especially green tea, is protective against a variety of cancers, including gastrointestinal malignancies. As part of a large population-based case-control study of biliary tract disease in Shanghai, China, we evaluated the effects of tea consumption on the risk of biliary tract cancers and biliary stones. The study included 627 incident cases with biliary tract cancer, 1,037 cases with biliary stones and 959 randomly selected controls. Study subjects were interviewed to ascertain data on demographic, medical and dietary factors, including tea consumption. Forty-one percent of the controls were ever tea drinkers, defined as those who consumed at least 1 cup of tea per day for at least 6 months. After adjustment for age, education and body mass index, among women, ever tea drinkers had significantly reduced risks of biliary stones (OR = 0.73, 95% CI = 0.54-0.98) and gallbladder cancer (OR = 0.56, 95% CI = 0.38-0.83). The inverse relationship between tea consumption and gallbladder cancer risk was independent of gallstone disease. Among men, tea drinkers were more likely to be cigarette smokers, and the risk estimates were generally below 1.0, but were not statistically significant. Further studies are needed to confirm these results in other populations and clarify the hormonal and other mechanisms that may be involved.

Preferable operative age of choledochal dilation types to prevent patients with pancreaticobiliary maljunction from developing biliary tract carcinogenesis.

BACKGROUND: Pancreaticobiliary maljunction (PBM), which frequently accompanies choledochal dilation, is a high risk factor for biliary tract (gallbladder, bile duct) carcinoma because of the continuous reflux of pancreatic juice into the biliary tract. The aim of this study was to clarify the preferable operative age in PBM patients for the prevention of biliary tract carcinogenesis, with reference to the dilation types of bile ducts. METHODS: There were 165 PBM patients in total studied, including 92 pediatric patients (< or =15 y) (cystic, 63; spindle-like, 29; nondilation, 0) and 73 adult patients (>15 y) (cystic, 45; spindle-like, 18; nondilation, 10) who underwent operative excision of extrahepatic bile ducts or cholecystectomy. We investigated incidence by age of biliary tract malignancies and the risk according to types of dilation. RESULTS: In the pediatric group, no carcinoma case could be found preoperatively or postoperatively (mean follow-up period, 11.7 y). In the adult group, bile duct carcinomas could be detected in 6 cases of a cystic type (6 of 45; 13.3%) (3 preoperative, 3 postoperative). Among the bile duct carcinoma cases, the youngest patient was a 21-year-old woman who had undergone excision of an extrahepatic bile duct 3 years previously. Gallbladder carcinomas were detected in 16 patients: 3 of 45 cystic (6.7%), 6 of 18 spindle-like (33.3%), and 8 of 10 nondilation (80.0%), in whom the youngest patient was a 41-year-old woman with a spindle-like type. CONCLUSIONS: To prevent biliary tract carcinogenesis in PBM patients, cystic-dilated choledochus should be excised in childhood before the development to a precancerous stage. In spindle-like and nondilation types, cholecystectomy is absolutely necessary in early adulthood before age 40.