Peripheral Intrahepatic Bile Duct Research Articles

Spatially segregated defects and IGF1-responsiveness of hilar and peripheral biliary organoids from a model of Alagille syndrome.

Alagille syndrome (ALGS) manifests with peripheral intrahepatic bile duct (IHBD) paucity, which can spontaneously resolve. In a model for ALGS, Jag1Ndr/Ndr mice, this occurs with distinct architectural mechanisms in hilar and peripheral IHBDs. Here, we investigated region-specific IHBD characteristics and addressed whether IGF1, a cholangiocyte mitogen that is downregulated in ALGS and in Jag1Ndr/Ndr mice, can improve biliary outcomes. Intrahepatic cholangiocyte organoids (ICOs) were derived from hilar and peripheral adult Jag1+/+ and Jag1Ndr/Ndr livers (hICOs and pICOs, respectively). ICOs were grown in Matrigel or microwell arrays, and characterized using bulk RNA sequencing, immunofluorescence, and high throughput analyses of nuclear sizes. ICOs were treated with IGF1, followed by analyses of growth, proliferation, and death. CellProfiler and Python scripts were custom written for image analyses. Key results were validated invivo by immunostaining. Cell growth assays and transcriptomics demonstrated that Jag1Ndr/Ndr ICOs were less proliferative than Jag1+/+ ICOs. IGF1 specifically rescued survival and growth of Jag1Ndr/Ndr pICOs. Jag1Ndr/Ndr hICOs were the least proliferative, with lower Notch signalling and an enrichment of hepatocyte signatures and IGF uptake/transport pathways. Invitro (Jag1Ndr/Ndr hICOs) and invivo (Jag1Ndr/Ndr hilar portal tracts) analyses revealed ectopic HNF4a+ hepatocytes. Hilar and peripheral Jag1Ndr/Ndr ICOs exhibit differences in Notch signalling status, proliferation, and cholangiocyte commitment which may result in cholangiocyte-to-hepatocyte transdifferentiation. While Jag1Ndr/Ndr pICOs can be rescued by IGF1, hICOs are unresponsive, perhaps due to their hepatocyte-like state and/or expression of IGF transport components. IGF1 represents a potential therapeutic for peripheral bile ducts.

Endoscopic retrieval of a sheared guidewire remnant with microbiopsy forceps from a peripheral intrahepatic bile duct.

Watch a video of this article.

Changing survival of intrahepatic cholangiocarcinoma based on Surveillance, Epidemiology, and End Results Database (2000–2018).

e16182 Background: Intrahepatic cholangiocarcinoma (iCCA) is a primary hepatic malignancy arising from peripheral intrahepatic bile ducts with poor survival and increasing incidence. Treatment regimen has changed in the last two decades, whereas new molecular targeted therapies have emerged. The present study aims to characterize changes in treatment outcomes of iCCA using a national representative database. Methods: Data were retrieved from the Surveillance, Epidemiology and End Results (SEER) 18 Research Plus Database. Overall survival (OS) was analyzed based on age, gender, race, histological grade, stage, and treatment. Predictors of OS were evaluated by Cox regression models. Statistical analysis was performed with Stata 15.1 (STATA Corp., College Station, TX, USA). Results: The overall observed OS from 2000 to 2018 at 12, 36, and 60 months were 42.6%, 16.4%, and 10.2%, respectively. The median survival time (MST) increased from 6 to 11 months from 2000-2004 time period to 2015-2018 (p < 0.0001). Such an improved trend was observed in all stage groups (p < 0.0001). Among patients diagnosed after 2015, the 12, 24, and 36 month OS were 45.9%, 26.4% and 17.4 %, respectively; the MST were 25, 13, and 6 months for patients with localized (12-month OS: 72.7%; 36-month OS: 37.5% ), regional (12-month OS: 51.4%; 36-month OS: 18.9%), and distant diseases(12-month OS: 28.2%; 36-month OS: 4.5%), respectively (p < 0.0001). On multivariable analysis, older age, female, grade, stage, whether surgery, chemotherapy or radiotherapy was performed were statistically significant predictors of OS (p < 0.001). Conclusions: Survival outcomes of iCCA improved in the last twenty years in all cancer stages. Age, gender, grade, stage, and whether interventions were performed were prognostic factors.

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.

Prognostic impact of hepatitis B or C on intrahepatic cholangiocarcinoma.

Background/AimsIntrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy, arising from the peripheral intrahepatic bile duct epithelium. Hepatitis B virus (HBV) or hepatitis C virus (HCV) may be involved in the development of ICC. We explored the prognostic value of hepatitis virus infection, as well as other prognostic factors affecting survival in patients with ICC.MethodsA retrospective chart review was performed for patients diagnosed with ICC between August 2005 and December 2018 at Konkuk University Medical Center. We identified a total of 131 patients with ICC. Overall survival rates of patients with and without hepatitis were determined. Univariate and multivariate analyses were used to estimate factors influencing survival outcomes.ResultsA total of 17.6% (23/131) of patients were positive for HBV or HCV. Hepatitis B positive ICC patients were significantly younger with higher albumin and higher α-fetoprotein than those without hepatitis viral infections. The median survival of hepatitis-positive and hepatitis-negative groups was 280 and 213 days, respectively. Survival rates were not significantly different between the two groups (p = 0.279). Multivariate analyses indicated that lower serum carbohydrate antigen 19-9 (CA 19-9) (p < 0.001), lower T stage (p = 0.042), the absence of lymph-node metastasis (p = 0.043), and receiving curative surgery (p = 0.033) were independent predictors of better outcomes.ConclusionsWhile hepatitis influenced a number of clinical features in ICC patients, it did not affect survival rate. Prognostic factors influencing survival outcomes with ICC were CA 19-9 level, T stage, the presence of lymph node metastasis, and curative surgery.

SOME FEATURES OF CHOLESTASIS IN CANCER PATIENTS IN THE COURSE O THE IMPAIRMENT OF LIVER FUNCTIONAL RESERVES

Purpose. To discuss the possible causes of discrepancies in results of laboratory and X-ray methods of diagnostics of surgical cholestasis without a concomitant dilatation of the bile ducts, as well as features of X-ray-surgical tactics in such cases. Material and methods. In 2015-2016, 271 percutaneous transhepatic cholangiostomies were performed, including 23 cases - on unexpanded bile ducts, 7 these cancer patients with the laboratory evidence of cholestasis. The criteria for the absence of dilatation of the intrahepatic bile ducts were considered as not only an obvious non-visualized biliary tree on ultrasound, but also the diameter of the peripheral intrahepatic bile ducts less than 2 mm, which must be significantly less than similar peripheral branches of the portal vein. Results.Outside bile-outflow was effective, but only in two cases it provided the relief due to cholestasis performance. In 3 cases, blood bilirubin levels decreased by more than half of the initial ones. 5 out of 7 patients after external drainage of unexpanded bile ducts had evident signs of the liver failure. Two patients with malignant lesions of the biliary tree and baseline bilirubinemia over 450 umol/L died because of progressive liver failure. Conclusion. Mechanical jaundice corresponds to the concept of surgical cholestasis, which is associated with surgical diseases stipulating the violation of the outflow of bile and requires biliary decompression. By reducing the functional reserves of liver surgical cholestasis may not be accompanied by the significant expansion of the bile duct, which can be considered as a predictor of hepatic failure, which nevertheless requires cholangiostomy.

Imaging of intrahepatic cholangiocarcinoma – up to date

Kurzfassung: With advance of imaging modalities and its scanning technique, small sized cholangiocellular carcinoma (CCC) are often seen in clinical practices. Small sized CCCs are sometimes well-enhanced on early phase of dynamic CT/MRI, so they may mimic HCC, especially in the screening of HCC in cirrhotic patients. Interestingly small hypervascular CCCs sometimes share cholangiolocellular carcinoma (CoCC) features in pathologic evaluation. CoCC is a rare primary liver cancer which is thought to arise from stem cells located in canal of Hering or bile ductule. Thus CoCC is now classified into stem cell feature subtype of combined hepatocellular and cholangiocellular carcinoma in the WHO classification 4th. The imaging findings of CoCC can be summarized in the following points. 1. Early enhancing nodule with perinodular enhancement, 2. Delayed tumoral enhancement, 3. Intermingled hepatic supporting structures such as portal veins and hepatic veins, 4. No or minimal dilatation of peripheral intrahepatic bile duct. However, because CoCC consists of various combination of CoCC, HCC-like and CCC-like components, the imaging findings are variable. Lernziele: In this session, I'd like to show the imaging and pathologic correlation of mass-forming type of CCC and pure type of CoCC with special attention to its unique growth pattern, vasculatures and tumor stroma.

Hepatitis B virus infection and intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a devastating malignant tumor arising from the peripheral intrahepatic bile duct epithelium. The incidence and mortality of ICC is markedly increasing over the past two decades worldwide, though the cause for this rise in incidence is unclear, thus intensifying the search for alternative etiological agents and pathogenetic mechanisms. Hepatolithiasis, primary sclerosing cholangitis, parasitic infection (Opisthorchis viverrini or Clonorchis sinensis), fibropolycystic liver disease, and chemical carcinogen exposure are thought to be the risk factors for ICC. Nevertheless, the majority of ICC patients do not have any of these risk factors, and none of the established risk factors can explain the recent increasing trend of ICC. Therefore, identifying other risk factors may lead to the prevention and early detection of ICC. Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in HBV-endemic areas. This review discusses the evidence implicating chronic HBV infection as a likely etiology of ICC and the pathogenetic mechanisms that might be involved.

A Case of Colloid Carcinoma Arising in Association with Intraductal Papillary Neoplasm of the Liver

Colloid carcinoma of the liver is very rare, and its clinicopathologic features have not been well characterized yet. We describe herein a case of colloid carcinoma of the liver. Imaging revealed a lobulated mass, measuring 12 cm in diameter at the right lobe of the liver with direct invasion of adjacent peripheral intrahepatic bile ducts. Right hemihepatectomy of the liver was performed according to the possibility of the tumor's malignant behavior. Histopathological examination of the specimen revealed large extracelluar stromal mucin pools containing floating cuboidal to columnar neoplastic cells without ovarian-like stroma. This case seemed to be colloid carcinoma arising in association with intraductal papillary neoplasm of the liver.

Endoscopic diagnosis of intraductal papillary mucinous neoplasm of the bile duct

Intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) is considered an uncommon tumor. The purpose of this study was to evaluate the diagnostic utility of endoscopic cholangiography (ERC) with subsequent peroral cholangioscopy (POCS) and/or intraductal ultrasonography (IDUS) for this tumor. From December 1991 to November 2006, a retrospective analysis was made of eight patients with IPMN-B. Their clinical features and the endoscopic diagnostic strategy for POCS and IDUS were reviewed. In all the patients, ERC failed to show papillary tumors, due to coexisting mucin or biliary sludge. POCS was carried out after ERC and it showed the presence and locations of papillary tumors in all patients, except for one with a tumor in the peripheral intrahepatic bile duct (B3). IDUS was performed in seven of the eight patients; in five of these patients, intraductal protruding tumors were clearly visualized, whereas flat tumors were not identified in the remaining two patients. In one of the eight patients, endoscopic nasobiliary drainage did not remove the huge amount of mucin. Hence, this patient required subsequent percutaneous biliary drainage. Six of the eight patients underwent surgical treatment; five patients underwent a hepatic resection with or without extrahepatic bile duct resection and one underwent a pancreaticoduodenectomy. Five of the six operated patients are still alive; one patient died of gastric cancer 90 months after the operation (mean follow-up period, 45.3 months). The two remaining patients, who were considered inoperable due to major medical comorbidities, died of liver failure and cholangitis 3 and 6 months, respectively, after stent placement. ERC failed to delineate intraductal papillary tumors, due to coexisting mucin. The presence and location of papillary tumors were correctly diagnosed by both POCS and IDUS, but POCS may be better than IDUS to diagnose the extent of the tumor.

Intrahepatic bile duct dilatation with a liver cyst and hemangioma: Report of a case

We report a case of intrahepatic bile duct dilatation with a liver cyst and hemangioma. A 58-year-old woman was referred for investigation of a cystic lesion and peripheral intrahepatic bile duct dilatation in the left lateral segment of the liver. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) showed dilatation of the intrahepatic bile ducts in the left lateral segment, near a 4.5-cm cystic lesion. Early enhancement into the delayed phase was seen in the dorsal part of the cystic lesion. Celiac angiogram showed a belt-shaped hypervascular area, but no encasement or irregularity of the artery. To exclude malignancy, we performed a left lobectomy. Microscopically, the cyst was lined with a single layer of flattened epithelial cells and a spongy tumor was diagnosed as cavernous hemangioma, which compressed the bile duct. The histopathological diagnosis was biliary stenosis associated with cavernous hemangioma of the liver. Invasive surgery may be avoided by awareness of this unusual benign pathology.

Autoimmune cholangitis mimicking periductal-infiltrating cholangiocarcinoma

We report here on the imaging findings of a case of autoimmune cholangitis that involved a segmental bile duct of the liver. Abdominal computed tomogram showed ill-defined low-attenuation lesion at the hilar portion of the right hepatic lobe, and this was associated with peripheral intrahepatic bile duct dilatation. Gadolinium enhanced liver magnetic resonance imaging (MRI) showed wall thickening with periductal enhancement along the segmental tributaries of the right intrahepatic bile duct. The pathologic findings revealed lymphoplasmacytic infiltration and severe fibrosis, indicating autoimmune cholangitis.

Imaging diagnosis of clonorchiasis

Among several diagnostic tools for clonorchiasis (Clonorchis sinensis infection), radiologic examinations are commonly used in clinical practices. During the 2 past decades, many reports regarding imaging findings of clonorchiasis were introduced. The basic imaging finding of clonorchiasis is diffuse dilatation of the peripheral intrahepatic bile ducts, without dilation of the large intrahepatic or extrahepatic bile ducts. By this finding, however, active clonorchiasis cannot be differentiated from cured infection. Some recent radiologic studies suggested specific findings of active clonorchiasis. Besides direct demonstration of worms, increased periductal echogenicity on sonography and periductal enhancement on dynamic contrast-enhanced CT or MR imaging possibly represent active clonorchiasis. Those images of the liver clonorchiasis are known to be correlated with worm burdens (EPG counts) in their frequency and also severity. The images of cholangiocarcinoma associated with clonorchiasis show both the tumor with obstruction images and diffuse dilatation of the peripheral intrahepatic bile ducts. Radiological images can be a good practical alternative diagnostic method of clonorchiasis.

Metastatic colon cancer from intrahepatic cholangiocarcinoma

A 62-year-old man had been followed because of an elevated serum level of carcinoembryonic antigen without the detection of any cancer lesions. However, there was a sudden increase in the serum level of carcinoembryonic antigen, and abdominal imagings showed a hepatic tumor with peripheral intrahepatic bile duct dilatation, and a submucosal tumor at the sigmoid colon with intact mucosa. Histopathological findings showed that the hepatic tumor had perineural invasion, suggesting an intrahepatic cholangiocarcinoma, and that the colon tumor infiltrated the submucosa, while its mucosa was intact. Both tumors showed similar pathological features and were positive for cytokeratin 20 and 7. These findings suggested intrahepatic cholangiocarcinoma with metastatic sigmoid colon cancer.

Multiple Cavitary Pulmonary Metastases from Cholangiocarcinoma

Because a cavitary pulmonary metastasis is rare, it may not be readily identified. However, various types of cancers can metastasize to the lung in the form of cavities. We report a case of a multiple cavitary metastases to the lung from a cholangiocarcinoma in a 60-year-old man. He complained of generalized weakness and a poor oral intake for 2 months. The plain chest radiography and the chest computed tomography showed multiple small thick-walled cavities and nodules the both lungs. A bronchoscopic examination revealed a focal irregularly elevated surface of the mucosa at the orifice of the superior segment of the right lower lobe and the biopsy demonstrated an infiltrative metastatic adenocarcinoma. The abdomen-pelvis computed tomography showed an ill-marginated and irregularly low-dense area in the right lobe of the liver and a diffuse dilatation of the peripheral intrahepatic bile ducts. The esophagogastroscopy and colonoscopy showed no abnormal findings. It was concluded that the cholangiocarcinoma of the liver metastasized to the lung in the form of cavities. Thereafter, the patient underwent six cycles of the systemic chemotherapy with gemcitabine and cisplatin, and the follow-up imaging studies showed a partial response.

Long-term survival of peripheral intrahepatic cholangiocarcinoma with metastasis to the para-aortic lymph nodes

A 64-YEAR-OLD WOMAN WAS ADMITTED with upper abdominal pain. On admission physical examination revealed only slight tenderness in the abdomen. The laboratory data showed slight elevations of leucine aminopeptidase (57 U/L) and γglutamyl transpeptidase concentrations (43 U/L), a normal serum level of carcinoembryonic antigen (1.3 ng/mL), and an elevated serum level of carbohydrate antigen 19-9 (229.2 U/L). Abdominal ultrasonography and computed tomography revealed a tumor measuring 15 mm and dilated intrahepatic bile ducts at the left lateral lobe of the liver but no swelling of regional or para-aortic lymph nodes. Percutaneous transhepatic cholangiography showed stenosis of an intrahepatic bile duct at the left lateral superior segment of the liver and dilation of the peripheral intrahepatic bile duct (Figure). At surgery para-aortic lymph nodes metastasis was proved by biopsy and intraoperative pathologic examination. Left hemihepatectomy with lymph nodes dissection was performed. The resected specimen revealed an infiltrating bile duct tumor that measured 20 × 20 mm at the left lateral superior segment. Histologic examination showed a moderately differentiated tubular adenocarcinoma with metastases to 7 of 12 para-aortic lymph nodes and 1 of 5 lymph nodes in the hepatoduodenal ligament. Immunohistochemical stains showed a strong positive plasma membrane–type pattern CD44 standard, CD44 variant 6, and E-cadherin, but telomerase activity (with a telomeric repeat amplification protocol) was not detectable. The patient has survived for 7 years without evident recurrence.

A clinicopatholgoical study on intrahepatic cholesterol gallstones

In order to clarify the pathogenesis and process of the formation of intrahepatic cholesterol gallstones, we examined the clinical features, cholangiograms and pathological findings of eight patients with intrahepatic cholesterol gallstones. When examining the clinical features, one patient was found to have developed intrahepatic cholesterol gallstones 3 years after a complete lithotomy. The cholangiograms of two patients revealed small gallstones in the peripheral bile ducts of the lateral segment of the liver, and these bile ducts showed localized cystic dilatation and were tightly filled with gallstones. Conversely, their other bile ducts which contained no gallstones showed an entirely normal cholangiogram. Pathologically, these two cases showed mild chronic cholangitis, and cholesterol crystals in the peripheral bile ducts. The other six cases showed moderate or severe dilatation of the bile duct and severe chronic proliferative cholangitis. From the above results, we proposed the following theory to explain the pathogenesis and process of the formation of intrahepatic cholesterol stones: The cholesterol crystals in the peripheral intrahepatic bile ducts may be a primitive form of intrahepatic cholesterol gallstones, and the formation of intrahepatic cholesterol gallstones may precede and cause such deformities of the bile ducts as strictures or dilatations.

Clonorchiasis of the pancreas

Three patients with pancreatic clonorchiasis were examined with endoscopic retrograde pancreatography. On each of the three cases there was diffuse irregular dilatation of tributaries of the pancreatic duct in the pancreatic tail. The main pancreatic duct and tributaries draining into the body and head portion were not dilated. A sonogram from one patient showed diffuse enlargement of the pancreas, especially the tail. All three patients showed typical cholangiographic findings of hepatic clonorchiasis, namely diffuse peripheral intrahepatic bile duct dilatation with no or minimal dilatation of the extrahepatic duct. When the tributaries of the pancreatic duct in the tail of the pancreas are diffusely dilated, in the appropriate clinical setting, pancreatitis caused by Clonorchis sinensis should be considered.

Two cases in siblings of congenital multiple cystic dilatation of peripheral intrahepatic bile ducts (so called Caroli's disease)

Two cases in siblings of congenital multiple cystic dilatation of peripheral intrahepatic bile ducts (so called Caroli's disease)