Normal Intrahepatic Bile Ducts Research Articles

Distinct sulfated glycans expressed in intrahepatic cholangiocarcinoma: a potential target for new therapy.

Cholangiocytes exhibit morphological and functional heterogeneity, depending on their anatomical localization; however, like other ductal organs, their mucosal surface is covered with mucin, which functions to prevent the entry of foreign substances, lubricateand prevent clogging by bile. Recently, the authors discovered that distinct sulfated glycans recognized by a series of antisulfated glycan antibodies are expressed not only in normal intrahepatic bile ducts but also in intrahepatic cholangiocarcinoma (iCCA). In this review, the authors first describe the anatomy of bile ducts and the biochemical characteristics of bile-duct-associated mucins, and then describe differences in structure and expression patterns of these sulfated glycans in physiological and pathological conditions. Finally, potential therapeutic strategies foriCCAusing antisulfated glycan antibodies are discussed.

Upregulation of Stress-Induced Protein Kinase CK1 Delta is associated with a Poor Prognosis for patients with Hepatocellular Carcinoma.

Objective: This study was designed to analyze the expression of CSNK1D in hepatocellular carcinoma (HCC) and investigate the relationship between the expression of CSNK1D and the prognosis of HCC patients. Methods: The CSNK1D and alpha-fetoprotein (AFP) expression levels in patients with HCC and their corresponding clinical data were downloaded from The Cancer Genome Atlas (TCGA) and sorted with a Perl program. CSNK1D and AFP expression differences in liver tissue and liver cancer were compared and analyzed, based on the online database human cancer metastasis database, the relationships between the expression levels of CSNK1D and AFP and the proliferation and metastases of HCC were explored. The immunohistochemical data obtained from the Human Protein Atlas Database further verified the differences in the expression levels of CSNK1D and AFP in liver tissues and liver cancer tissues. Through Kaplan-Meier survival analysis, the effects of CSNK1D and AFP expression levels on the prognosis of patients with HCC were investigated, and the influences of and patients' gender, age and grades of cancer cells, tumor size, the status of lymph node metastasis, distant metastasis, and tumor stage on the expression of CSNK1D were analyzed with R language. The influence of differential expressions of CSNK1D on survival time was compared and the prognostic factors influencing the survival of HCC patients were statistically explored by univariate analysis and multivariate analysis. The potential influencing mechanism of CSNK1D on the prognosis of HCC patients was explored by Gene Set Enrichment Analysis (GSEA) enrichment. Results: The expression level of CSNK1D and AFP in cancer foci was significantly higher than that in normal tissues, However, in the same patient, the expression levels of AFP in paracarcinoma tissues and cancer tissues showed no significant difference. The expression level of CSNK1D in HCC with distant metastases was higher than that in those without metastasis, but the expression level of AFP in metastatic HCC was lower than that in those HCC without metastases. In immunohistochemical tests, CSNK1D was moderately positive in normal liver tissues, slightly positive in normal bile duct tissues, and highly positive in HCC. AFP was slightly positive in normal liver tissues and negative in HCC, but it was not detected in normal intrahepatic bile duct tissue. Survival analysis results suggested that the higher expression level of CSNK1D corresponded to the shorter survival period, whereas the expression level of AFP showed no significant influence on survival time. The expression level of CSNK1D was not correlated with gender, age, the status of lymph node metastasis status, or distant metastasis of patients. The main factors influencing the expression level of CSNK1D included tumor size, cancer cell grade, and tumor stage. The expression levels of CSNK1D in T2 and T3 were higher than that in T1. The expression levels of CSNK1D in G3 and G4 were higher than that in G1. The expression levels of CSNK1D in Stage II and Stage III were higher than that in Stage I. Univariate analysis suggested that tumor size, cell grade, distant metastasis, clinical stage, and CSNK1D expression level were the prognostic factors influencing the survival of patients. Multivariate analysis suggested that CSNK1D expression level was an independent factor influencing the prognosis of HCC patients. GSEA enrichment analysis indicated that CSNK1D mainly affected the prognosis of HCC patients through cell cycle, WNT signaling pathway, amino acid degradation metabolism, and other pathways. Conclusion: CSNK1D is an independent influencing factor for the prognosis of HCC patients and has the potential to be developed as a potential therapeutic target for HCC, and better than AFP in predicting the prognosis of HCC.

Correlation between Expression Differences of Epithelial-Mesenchymal Transition (EMT) in Cholangiocarcinoma Tissue

Background: By studying the expression of epithelial-mesenchymal transition regulators in cholangiocarcinoma and intrahepatic duct stones, the correlation between the expression of epithelial-mesenchymal transition regulators and cholangiocarcinoma was revealed. Objective: The objective is to investigate the correlation between the expression of epithelial-mesenchymal transition (EC) regulatory factors and cholangiocarcinoma in patients with intrahepatic duct stones and cholangiocarcinoma, to investigate the relationship between clinicopathological features and prognosis, and to observe the expression of molecular markers of epithelial-mesenchymal transition (EMT) in intrahepatic duct stones and bile duct carcinoma. Methods: Twenty cases of primary cholangiocarcinoma, 20 cases of intrahepatic cholangiolithiasis complicated with cholangiocarcinoma, and 20 cases of intrahepatic cholangiolithiasis specimens were collected from the Fourth People’s Hospital and the friendly medical unit of Haikou. Immunohistochemistry was used to detect the expression differences of EMT-related molecular markers Twisit1, Twisit2, E-cadherin, N-cadherin, and Vimentin in paraffin sections of normal intrahepatic bile duct tissues and patients with intrahepatic duct stones and cholangiocarcinoma. Results: Immunohistochemical staining revealed epithelial-mesenchymal transition (EMT) in intrahepatic cholangiocarcinoma tissue, intrahepatic cholangiolithiasis with cholangiocarcinoma, intrahepatic cholangiolithiasis with normal intrahepatic cholangiolithiasis, such as Sit1, Twisit2, E-cadherin, N-cadherin, and Vimentin proteins were different. The expression of E-cadherin was decreased in cholangiocarcinoma tissue and intrahepatic cholangiolithiocarcinoma combined with cholangiocarcinoma (P 0.05). There was no difference in the expression of intrahepatic bile duct stones and EMT (P > 0.05). Conclusion: The expression of E-cadherin, the molecular marker of EMT, was down-regulated, while the expression of N-cadherin and Vimentin was up-regulated. Age, gender, depth of tumor invasion, degree of tumor differentiation and lymph node metastasis were correlated with the expression of EMT in intrahepatic cholangiocarcinoma.

Ultrasonic characteristics of intraductal papillary mucinous neoplasm of the bile duct

Objective To explore the ultrasound characteristics of intraductal papillary mucinous neoplasm of the bile duct(IPMN-B) and evaluate its diagnostic value. Methods Seventeen cases of IPMN-B were diagnosed by ultrasonic examination and confirmed by surgery and pathology. The ultrasound findings and distribution of color Doppler flow signals were observed and analyzed in comparison with the surgical and pathological results. Results Ultrasound revealed the characteristics of IPMN-B: ①Bile duct mural nodules that looked like papillary or polypoid were observed; ②Asymmetry bile duct dilatation, namely obvious dilatation in the lesion intrahepatic bile duct, but only mild dilatation in the normal intrahepatic bile duct; ③Typical lesions showed mucus in bile duct along bile duct wall without acoustic shadow or move. High frequency ultrasound revealed that mucus in bile duct could float that looked like gelatin when operator vibrated probe in those superficial lesions. This is reliable characteristics of IPMN-B by ultrasound. Conclusions Ultrasound is of high value in the diagnosis of IPMN-B. Key words: Ultrasonography; Bile duct neoplasms; Papillary mucinous neoplasm

How to do: bile duct ultrasound

Grey-scale US of the common bile duct is helpful in detecting the cause of biliary obstruction. We describe bile duct anatomy, its implication for transducer placement and the process of a systematic US evaluation of normal intrahepatic bile ducts and the common bile duct.

Identification of a novel microRNA signature associated with intrahepatic cholangiocarcinoma (ICC) patient prognosis

BackgroundThe clinical significance of microRNAs (miRNAs) in intrahepatic cholangiocarcinoma (ICC) is unclear. The objective of this study is to examine the miRNA expression profiles and identify a miRNA signature for the prognosis of ICC.MethodsUsing a custom microarray containing 1,094 probes, the miRNA expression profiles of 63 human ICCs and nine normal intrahepatic bile ducts (NIBD) were assessed. The miRNA signatures were established and their clinical significances in ICC were analyzed. The expression levels of some miRNAs were verified by quantitative real-time RT-PCR (qRT-PCR).ResultsExpression profile analysis showed 158 differentially expressed miRNAs between ICC and NIBD, with 77 up-regulated and 81 down-regulated miRNAs. From the 158 differentially expressed miRNAs, a 30-miRNA signature consisting of 10 up-regulated and 20 down-regulated miRNAs in ICC was established for distinguishing ICC from NIBD with 100% accuracy. A separate 3-miRNA signature was identified for predicting prognosis in ICC. Based on the 3-miRNA signature, a formula was constructed to compute a risk score for each patient. The patients with high-risk had significantly lower overall survival and disease-free survival than those with low-risk. The expression level of these three miRNAs detected by microarray was verified by qRT-PCR. Multivariate analysis indicated that the 3-miRNA signature was an independent prognostic predictor.ConclusionsIn this study, a 30-miRNA signature for distinguishing ICC from NIBD, and a 3-miRNA signature for evaluating prognosis of ICC were established, which might be able to serve as biomarkers for prognosis of ICC. Further studies focusing on these miRNAs may shed light on the mechanisms associated with ICC pathogenesis and progression.

Expression and signification of NF-κB, EGFR and MUC1 in hepatolithiasis associated with intrahepatic cholangiocarcinoma

Objective To investigate the role of nuclear factor kappa B (NF-κB), epidermal growth factor (EGFR) and Mucin 1 (MUC1) in hepatolithiasis associated with intrahepatic cholangiocarcinoma. Methods Specimens were taken from 90 patients who underwent hepatectomies from August 1989 to June 2009 at the Second Affiliated Hospital of Sun Yat-sen University. The specimens were stained immunohistochemically for NF-κB, EGFR and MUC1. There were 33 patients who had hepatolithiasis associated with intrahepatic cholangiocarcinoma (the experiment group). 32 patients with hepatolithiasis served as the control group, and 25 patients with normal intrahepatic bile ducts taken at 1-2cm distal to benign hepatic neoplasm served as the blank group. The immunohistochemical staining were performed on tissue slices. Results NF-κB positive rate was 51.5％ (17/33), 25％(8/32) and 4％ 1/25) in the experiment group, the control group and the blank group respectively,P＜0. 01 ; EGFR positive rates were 57. 6％ (19/33), 31.3％ (10/32) and 0 (0/25) respectively,P＜0. 01; MUC1 positive rates were 54. 5％ (18/33), 28. 1 ％ (9/32), 0 (0/25) respectively,P＜0. 01. There were significant differences for high level expressions of EGFR and MUC1 among histopathologic grading, tumor invasion and metastasis. The survival rates of patients with EGFR and MUC1 expressed tumor were lower than of patients with non-expressed tumout (P＜0. 01). Conclusions NF-κB is probably involved in the early stage of intrahepatic cholangiocarcinogenesis. Overexpressions of NF-κB, EGFR and MUC1 play coordinately and important roles during intrahepatic cholangiocarcinogenesis. High level expressions of EGFR and MUC1 are related to the malignant degree of cholangiocarcinoma and to worse prognosis. Key words: Nuclear factor kappa B; Epidermal growth factor; Mucin 1 ; Cholangiocarcinoma; Cholelithiasis

Clinicopathologic significance of slug expression in human intrahepatic cholangiocarcinoma

To explore the expression and function of slug, a transcriptional repressor, in human intrahepatic cholangiocarcinoma (IHCC) and identify its role in IHCC progression. Expression of slug was detected in 36 cases of IHCC and 12 cases of normal intrahepatic bile ducts and liver parenchyma by immunohistochemistry. The patients were divided into low slug expression group (< 20% of carcinoma cells stained) and high slug expression group (> or = 20% of carcinoma cells stained). Slug expression was correlated with clinicopathological parameters of IHCC patients. The patients were defined as short-term survivors if their survival time was < 12 mo and as long-term survivors if their survival time was > or = 12 mo. Slug was not expressed in normal liver epithelium samples, lowly expressed in 15 tissue samples (10 -, 5 +) and highly expressed in 21 tissue samples (16 ++; 5 +++) from IHCC patients. The survival rate of patients with a low slug expression was 33.3% (n = 5) and 66.7% (n = 10), respectively. The survival rate of patients with a high slug expression was 61.9% (n = 13) and 38.1% (n = 8), respectively (P = 0.02). Lymph node metastasis was found in 4 (26.7%) out of the 15 patients with a low slug expression and in 14 (66.7%) out of the 21 patients with a high slug expression, respectively. The incidence rate of lymph node metastasis increased with the increasing slug expression level (P = 0.003), and higher in patients with a high slug expression than in those with a low slug expression. Slug expression did not significantly correlate with the tumor size and stage or histologic grade, or with the gender and age of patients Slug expression is a novel prognostic marker for IHCC with lymph node metastasis.

Claudin-1, −2, −3, −4, −7, −8, and −10 Protein Expression in Biliary Tract Cancers

Biliary tract cancers are relatively common malignant gastrointestinal tumors in the elderly. Claudins are integral components of tight junctions that play important roles in maintaining epithelial cell polarity, controlling paracellular diffusion, and regulating cell growth and differentiation. The expression profile of claudins has been extensively characterized, but few reports exist on their expression in the normal and neoplastic biliary tract. Our aim was therefore to study claudins by IHC reactions in normal and neoplastic biliary tract samples. We detected that claudin expressions differ in the normal sample groups: the normal gallbladder strongly expressed claudin-2, -3, -4, and -10, but only weak reactions were seen in normal intrahepatic bile ducts. Although each cancer type expressed several claudins with various intensities, only claudin-4 presented especially strong immunoreactions in extrahepatic bile duct cancers and gallbladder carcinomas, whereas claudin-1 and -10 presented in intrahepatic bile duct cancers. Comparing the normal and carcinoma groups, the most significant decrease was detected in the expression of claudin-10. In conclusion, the expression pattern of claudins is different in the various parts of the normal and neoplastic biliary tract; moreover, an unequivocal decrease was detected in the carcinomas compared with their corresponding normal samples. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Morphological and Functional Features of Hepatic Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [(3)H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.

Evaluation of Biliary Abnormalities with 64-Channel Multidetector CT

Precise preoperative assessment of the vascular and biliary anatomy is important in ensuring the safety of hepatobiliary surgical procedures, including laparoscopic cholecystectomy, living donor liver transplantation, and tumor resection of the liver. Endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography clearly depict the biliary anatomy but are considered invasive procedures. Magnetic resonance cholangiopancreatography is noninvasive but sometimes fails to depict the normal intrahepatic bile ducts. Multidetector computed tomography (CT) has contributed greatly to the evaluation of the normal anatomy, anatomic variants, and disease extent in this setting. With 64-channel multidetector CT, high-resolution three-dimensional images can be reconstructed from isotropic data with a 0.625-mm section thickness. Because of its capacity for thin-section scanning and multiplanar reformation, 64-channel multidetector CT cholangiography can clearly demonstrate the biliary anatomy, a variety of anatomic variants, and the extent of disease--information that is indispensable for successful hepatobiliary surgery.

Expression of DPC4/Smad4 gene in stone‐containing intrahepatic bile duct

Hepatolithiasis is etiologically related to cholangiocarcinoma. We underwent this study with an attempt to examine the expression of DPC4/Smad4 gene in stone-containing intrahepatic bile ducts (IHD) and intrahepatic cholangiocarcinoma (ICC). The immunohistochemical method and RT-PCR analysis were used to study the expression of DPC4/Smad4 gene in normal IHD, stone-containing IHD, and ICC. All the specimens were from hepatic resection. The immunohistochemical study showed that all specimens from 24 normal IHD had marked expression of DPC4/Smad4 gene, while there was 4.4% (2/46) and 33.3% (3/9) loss of DPC4/Smad4 expression in stone-containing IHD and ICC, respectively. Among the specimens of stone-containing IHD, all the hyperplastic epithelial cells showed normal expression of DPC4/Smad4 gene while dysplastic epithelial cells showed 20% (2/10) loss expression of DPC4/Smad4. The RT-PCR analysis showed that the normal IHD had the highest content of DPC4/Smad4 mRNA, which was threefold and sixfold higher than that of stone-containing IHD and ICC, respectively. Loss expression of DPC4/Smad4 gene was found both in stone-containing IHD and ICC. Dysplastic epithelium of stone-containing IHD had higher potential for malignant transformation.

Intrahepatic cholestasis: Summary of an American Association for the Study of Liver Diseases single-topic conference

Intrahepatic cholestasis: Summary of an American Association for the Study of Liver Diseases single-topic conference

Expression of endogenous galectin-1 and galectin-3 in intrahepatic cholangiocarcinoma

Galectins, a family of β-galactoside—binding animal lectins, might be involved in tumor progression. In this study, the expression patterns of galectin-1 and -3 were examined immunohistochemically in intrahepatic cholangiocarcinoma (ICC), with emphasis on its development and progression as well as its histopathologic features, by use of samples of normal intrahepatic bile duct (n = 20), biliary epithelial dysplasia (n = 15), ICC (n = 40), and a cholangiocarcinoma cell line, CCKS1. In normal intrahepatic bile ducts, galectin-3 was constitutively but weakly expressed, whereas galectin-1 was not expressed. In hepatolithiasis, biliary epithelial dysplasia was strongly positive for galectin-3 but negative for galectin-1. Galectin-3 was frequently and strongly expressed in the cytoplasm of well-differentiated ICCs, and its expression was significantly decreased and less intense or even absent in poorly differentiated ICCs. Galectin-1 was expressed in carcinoma cells in ICC, and its incidence and extent were correlated with histologic dedifferentiation of ICC. Proliferative cell nuclear antigen (PCNA) labeling index (LI) was higher in ICC cases positive for galectin-1 than in those that were negative. Galectin-1 was strongly expressed in cancerous stroma of ICC, and this stromal expression was related to histologic dedifferentiation of ICC. In the carcinoma cell line CCKS1, galectin-1 and -3 were expressed in the cytoplasm of carcinoma cells, and galectin-1 was additionally detected in the culture medium. These results suggest that galectin-1 was newly expressed on carcinoma cells of ICC, and its overexpression seems to be associated with neoplastic progression and proliferative activities, and the expression of galectin-1 in cancerous stroma may also be related to the progression of ICC. Galectin-3 expression in epithelial cells is up-regulated in the preneoplastic and early neoplastic stages of ICC, although galectin-3 tends to disappear at later stages of ICC. HUM PATHOL 32:302-310. Copyright © 2001 by W.B. Saunders Company

Up-regulation of Fas Ligand at Early Stages and Down-regulation of Fas at Progressed Stages of Intrahepatic Cholangiocarcinoma Reflect Evasion From Immune Surveillance

We examined immunohistochemically the possible participation of the Fas/Fas ligand (FasL) system in intrahepatic cholangiocarcinoma (ICC) during the escape from immune surveillance, using 68 cases of ICC, 29 cases of normal intrahepatic large bile ducts, and 18 cases of biliary dysplasia. Apoptosis of tumor-infiltrating lymphocytes (TIL) was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Fas was weakly expressed in normal intrahepatic bile ducts. Almost all biliary dysplasia and well-differentiated ICCs showed moderate to marked expression of Fas, while Fas expression was variable in moderately and poorly differentiated ICCs. Down-regulation of Fas expression was significantly correlated with histologic de-differentiation, vascular invasion, the size of ICCs, and short survival of ICC patients. By in situ hybridization, FasL mRNA were frequently and strongly expressed in biliary dysplasia compared with non-neoplastic intrahepatic bile duct. In well-differentiated ICCs, FasL mRNA expression was frequent and intense. But, the expression gradually decreased in moderately and poorly differentiated ICCs. Down-regulation of FasL mRNA expression in ICCs was correlated with perineural invasion and tumor size (over 4 cm) (P < .05). Apoptotic TIL were more frequent in ICC foci than in non-neoplastic foci remote from ICC foci. These findings suggest that a tumor evasion mechanism involving Fas/FasL exists in ICC; frequent and intense expression of FasL mRNA in well-differentiated ICCs enable them to escape immune surveillance by counterattacking Fas-bearing TIL. This counterattack becomes insensitive in poorly differentiated ICCs, in which the down-regulation of Fas gives them a resistance against the FasL-expressing TIL. These mechanisms may be involved in the tumor progression.(Hepatology 2000;32:761-769.)

Expression of E-cadherin, alpha-catenin, beta-catenin, and CD44 (standard and variant isoforms) in human cholangiocarcinoma: an immunohistochemical study.

Immunolocalization of E-cadherin (E-cad), alpha-catenin, beta-catenin, and CD44 has rarely been investigated in human cholangiocarcinoma (CC). We, therefore, immunohistochemically examined the expression of E-cad, alpha-catenin, beta-catenin, CD44 standard (CD44s), and CD44 variants (CD44v) including CD44v5, CD44v6, CD44v7-8, and CD44v10 in normal adult livers and in 47 cases of CC; and the results were then correlated with tumor grade, vascular invasion, metastasis, p53 expression, proliferative fraction (Ki-67 labeling), and c-erbB2 expression. In normal livers, E-cad, alpha-catenin and beta-catenin, but not CD44s, CD44v5, CD44v6, CD44v7-8, and CD44v10, were expressed at the cell membrane of normal intrahepatic bile ducts. In CC, membranous expression of E-cad, alpha-catenin, and beta-catenin was the same or reduced when compared with non-cancerous bile ducts in the majority of CC. We found that the down-regulation of E-cad, alpha-catenin, and beta-catenin expression significantly correlated with tumor high grade, but not with vascular invasion, metastasis, p53 expression, Ki-67 labeling, or c-erbB2 expression, except for beta-catenin, the down-regulation of which was associated with c-erbB2 down-regulation. CD44s, CD44v5, CD44v6, CD44v7-8 and CD44v10 were frequently expressed at the membrane of CC cells. There were, however, no significant correlations between these aberrant CD44 expression and tumor grade, metastasis, vascular invasion, p53 expression, Ki-67 labeling, or c-erbB2 expression, with a few exceptions of CD44s and CD44v5. We found that CD44s aberrant expression significantly correlated with absence of metastasis and vascular invasion, and that CD44v5 aberrant expression significantly correlated with p53 under-expression. These results suggest that membranous expression of E-cad, alpha-catenin, and beta-catenin is reduced in a majority of CC and this down-regulation correlates with CC high grade, and that beta-catenin down-regulation is associated with c-erbB2 down-regulation. The data also suggested that CD44s, CD44v5, CD44v6, CD44v7-8, and CD44v10 may be neoexpressed during carcinogenesis of CC but this neoexpression does not correlate with tumor progression in CC, with the exception of CD44s and CD44v5.

Abnormal expression of MUC1 apomucin and mature MUC1 mucin in biliary epithelial cells in various cystic liver diseases

MUC1 apomucin is proposed as an "oncofetal" antigen in the biliary system. We surveyed the biliary expression of MUC1 apomucin and mature MUC1 mucin (highly-glycosylated MUC1 apomucin) in hepatic cysts, biliary microhamartomas, and intrahepatic bile ducts in various cystic liver diseases and clarified the relationship between the expression of these mucins and cystogenesis in the liver. The expression of MUC1 apomucin and mature MUC1 mucin were detected immunohistochemically using the monoclonal antibodies DF3 and SM3, and HMFG1, respectively. We surveyed six livers with adult-type polycystic disease (APCD), six with multiple hepatic cysts without polycystic kidney, 11 with solitary hepatic cysts, and 11 "histologically normal" livers. Biliary microhamartomas were frequently found in the former three. MUC1 apomucin was frequently expressed at the luminar surface of the epithelial cells lining cysts and also in biliary microhamartomas, independent of the type of cystic disease. MUC1 apomucin detected by both monoclonal antibodies (MAbs) DF3 and SM3 was also frequently expressed in the intrahepatic bile ducts from polycystic diseases, particularly the adult-type, whereas such expression was rare in the intrahepatic bile ducts in normal livers. Mature MUC1 mucin was expressed on the luminal surface of the epithelial cells lining cysts in approximately half of hepatic cysts studied, but it was infrequently expressed in biliary microhamartomas and almost absent in the intrahepatic bile ducts. The biliary epithelial cells lining hepatic cysts, biliary microhamartomas, the apparently normal intrahepatic bile ducts in APCD, multiple hepatic cysts, and to a lesser degree, solitary hepatic cysts, express abnormal levels MUC1 apomucin. This implies that biliary epithelial cells expressing MUC1 apomucin are related to the whole cystogenetic process in these diseases. In contrast, the expression of mature MUC1 mucin may be related to the late cystogenetic process in these diseases. (Hepatology 1996 Sep;24(3):539-43)

Topometry of normal intrahepatic bile ducts.

This paper focuses on practical problems which may also prove to be of theoretical importance, by presenting a method of establishing an exact topometry of the intrahepatic bile ducts. Measurements were made on corrosive casts of the intrahepatic bile ducts from 13 human livers. On the basis of the topometric results presented it is possible to construct an adequate model by means of plastic tubes and to use it for the study of bile flow.

Transforming growth factor-β1 and mannose 6-phosphate/insulin-like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat

These studies investigate the role of transforming growth factor-beta 1, a potent inhibitor of epithelial cell proliferation and stimulator of extracellular matrix biosynthesis, during intrahepatic bile duct hyperplasia and biliary fibrosis. These pathogenic responses were induced in rats by common bile duct ligation. Bile duct cell replication, measured by the bromodeoxyuridine labeling index, was significantly increased 24 hr after common bile duct ligation. This response diminished to baseline by 1 wk. Liver collagen content, determined by quantification of hydroxyproline, was increased significantly after 1 wk of common bile duct ligation, and by 4 wk was increased by a factor of 4. Immunohistochemistry revealed low levels of TGF-beta 1 in normal intrahepatic bile duct epithelium. In contrast, the bile duct epithelium in bile duct-ligated rats stained strongly positive for transforming growth factor-beta 1 at 1 and 4 wk after ligation. These results suggest that transforming growth factor-beta 1 may play a role in both the termination of the bile duct epithelial cell proliferative response and the induction of fibrogenesis after common bile duct ligation. In addition, the mannose 6-phosphate/insulin-like growth factor II receptor was up-regulated in hyperplastic bile duct epithelium 1 and 4 wk after ligation. Because the mannose 6-phosphate/insulin-like growth factor-II receptor has been shown to facilitate the proteolytic activation of transforming growth factor-beta 1, these results suggest that the bile duct epithelium may also be involved in the activation of transforming growth factor-beta 1.

The biliary tract: imaging for the 1990s.

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