胆管上皮的病理生理学

本文简述了胆管上皮细胞的生理学研究实验模型和技术发展、病理生理学的新知识。

Hepatitis B virus infection:A favorable prognostic factor for intrahepatic cholangiocarcinoma after resection

AIM： To study the prognostic factors for intrahepatic cholangiocarcinoma （ICC） and evaluate the impact of chronic hepatitis B virus （HBV） infection on survival rate of ICC patients. METHODS： A total of 155 ICC patients who underwent macroscopic curative resections （R0 and R1） were enrolled in this retrospective study and divided into group A with HBV infection and group B without HBV infection according to their chronic HBV infection, represented by positive hepatitis B surface antigen （HBsAg） in serum or in liver tissue. Clinicopathological characteristics and survival rate of the patients were evaluated. RESULTS： All patients underwent anatomical resection. Their 1- and 3-year survival rates were 60.6% and 32.1%, respectively. Multivariate analyses revealed that HBV infection, hepatolithiasis, microscopic satellite lesion, and lymphatic metastasis were the independent prognostic factors for the survival rate of ICC patients. The median disease-free survival time of the patients was 5.0 too. The number of tumors, microscopic satellite lesion, and vascular invasion were the independent prognostic factors for the disease-free survival rate of the patients. The prognostic factors affecting the survival rate of ICC patients with HBV infection and those without HBV infection were not completely consistent. Alkaline phosphatase 〉 119 U/L, microscopic satellite lesion, vascular invasion, and lymphatic metastasis were the independent factors for the patients with HBV infection, while r-glutamyltransferase 〉 64 U/L, microscopic satellite lesion, and poor tumor differentiation were the independent factors for the patients without HBV infection. CONCLUSION： HBV infection is a valuable clinical factor for predicting tumor invasiveness and clinical outcome of ICC patients. ICC patients with HBV infection should be distinguished from those without HBV infection because they have different dinicopathological characteristics, prognostic factors and outcomes after surgical resection.

Taurolithocholate impairs bile canalicular motility and canalicular bile secretion in isolated rat hepatocyte couplets

AIM: To investigate the effects of taurolithocholate (TLC)on the canalicular motility in isolated rat hepatocyte cou-plets (IRHC).METHODS: TLC was added to IRHC at concentrationsof 10 and 50 μmol/L, respectively. In each group, fi vetime-lapse movies containing 3 representative bile cana-liculi were taken under phase-contrast microscopy for12 h. The number of bile canalicular contractions andthe intervals between consecutive canalicular contrac-tions were calculated. Furthermore, the effects of TLC onIRHC were examined by transmission electron micros-copy.RESULTS: The bile canalicular contractions were spon-taneous and forceful in the controls. Active vesicularmovement was observed in the pericanalicular region.Immediately after the addition of TLC, the bile canaliculiwere deformed, and canalicular bile was incorporatedinto the vacuoles. The canaliculi were gradually dilated,and canalicular contractions were markedly inhibited byTLC. The vesicular movements became extremely slowin the pericanalicular region. The number of canalicularcontractions significantly decreased in the TLC-treatedgroups, as compared with that in the controls. The timeintervals were prolonged, as the TLC dosage increased,indicating that bile secretion into the canaliculi wasimpaired with TLC. Transmission electron microscopyrevealed the lamellar transformation of the canalicularmembranes in IRHC treated with TLC.CONCLUSION: TLC impairs both the bile canalicularcontractions and the canalicular bile secretion, possiblyby acting directly on the canalicular membranes in TLC-induced cholestasis.

Effect of transforming growth factor-β1 on human intrahepatic cholangiocarcinoma cell growth

AIM： To elucidate the biological effects of transforming growth factor-β1 （TGF-β1） on intrahepatic cholangiocarcinoma （ICC）.METHODS： We investigated the effects of TGF-β1 on human ICC cell lines （HuCCT1, MEC, and HUH-28） by monitoring the influence of TGF-β1 on tumor growth and interleukin-6 （IL-6） expression in ICC cells.RESULTS： All three human ICC cell lines produced TGF-β1 and demonstrated accelerated growth in the presence of TGF-β1 with no apoptotic effect. Studies on HuCCT1 revealed a TGF-β1-induced stimulation of the expression of TGF-β1, as well as a decrease in TGF-β1 mRNA expression induced by neutralizing anti-TGF-β1 antibody. These results indicate that TGF-β1 stimulates the production and function of TGF-β1 in an autocrine fashion. Further, IL-6 secretion was observed in all three cell lines and exhibited an inhibitory response to neutralizing anti-TGF-β1 antibody. Experiments using HuCCT1 revealed a TGF-β1-induced acceleration of IL-6 protein expression and mRNA levels. These findings demonstrate a functional interaction between TGF-β1 and IL-6. All three cell lines proliferated in the presence of IL-6. In contrast, TGF-β1 induced no growth effect in HuCCT1 in the presence of small interfering RNA against a specific cell surface receptor of IL-6 and signal transducer and activator of transcription-3.CONCLUSION： ICC cells produce TGF-β1 and confer a TGF-β1-induced growth effect in an autocrine fashion.TGF-β1 activates ILo6 production, and the functional interaction between TGF-β1 and IL-6 contributes to ICC cell growth by TGF-β1.

Quantitative evaluation of long-term liver repopulation and the reconstitution of bile ductules after hepatocellular transplantation

AIM： The treatment of liver disease is severely limited by a shortage of donor livers. In trying to address this growing problem, hepatocellular transplantation （HTx） has received much attention as an alternative to whole organ transplant. However, the expansion of transplanted cells is at low level, and the reconstitution of functional liver tissue is limited by this cellular property. We set up an animal model to better understand cell dose effect and the kinetics of liver repopulation following HTx. METHODS： Dipeptidyl peptidase Ⅳ （DPPⅣ）-deficient rats treated with retrorsine and subjected to partial hepatectomy were infused with DPPⅣ-positive hepatocytes. Rats were injected with varying numbers of donor hepatocytes down to 100 cells low, and liver repopulation was examined at different time points up to 20 mo long. Repopulation was assessed by computer-aided quantitative detection. RESULTS： Transplanted hepatocytes underwent multiple rounds of proliferation and stably repopulated the injured livers after 20 mo and at all cell doses. Transplanted cells divided 14 times within the 3-mo time period following infusion, and the liver repopulation reached a plateau between 3 and 20 too. Approximately 90% replacement occurred. Donor-derived cells also reconstituted the bile ductules of the recipients. CONCLUSION： The ability of transplanted hepatocytes to fully reconstitute injured livers strongly supports further investigation into the clinical potential of HTx. Additionally, the observation that transplanted hepatocytes also form components of the biliary system suggests that these cells may have bi-potential property of the stem cells.

Carcinosarcoma of the liver with mesenchymal differentiation

We report an extremely rare case where a mesenchymal differentiation, especially embryonal sarcoma, was demonstrated in cholangiocarcinoma. At autopsy, a yellowish-white tumor （15 cm× 12 cm） was found in the right hepatic lobe, and there were several daughter nodules in both hepatic lobes. Histologically, most of the main tumor and all of the daughter nodules examined showed sarcomatous changes （spindle cells, pleomorphic ceils and hyalization）. Histologic examination of a part of the main tumor disclosed a focus of adenocarcinoma within the tumor. The frequent transitions between the adenocarcinomatous areas and the sarcomatous areas suggested that sarcomatous transformation occurred in the cholangiocarcinoma and then spread rapidly. Immunohistochemically, the adenocarcinomatous elements were positive for cytokeratin, carcinoembryonic antigen （CEA） and epithelial membrane antigen, and negative in the sarcomatous cells. Vimentin was positive only in the sarcomatous elements. The findings of the present case support the view that carcinosarcomas represent carcinomas that develop sarcomatous elements via metaplasia of the epithelial element.

Effects of endoscopic sphincterotomy on biliary epithelium:A case-control study

AIM: To study the long-term effects of endoscopic sphincterotomy on biliary epithelium. METHODS: This is a prospective case-control study. A total of 25 patients with a median age of 71 years (range 49-89 years) and prior endoscopic sphincterotomy (ES) for benign disease formed the fi rst group. The median time from ES was 42 mo (range 8-144 mo). Another 25 patients with a median age of 76 years (range 44-94 mo) and similar characteristics who underwent current endoscopic retrograde cholangio-pancreatography (ERCP) and ES for benign disease formed the second group (control group). Brush cytology of the biliary tree with p53 immunocytology was performed in all patients of both groups. ERCPs and recruitment were conducted at the Endoscopic Unit of Aretaieion University Hospital and Tzaneio Hospital, Athens, from October 2006 to June 2010. RESULTS: No cases were positive or suspicious for malignancy. Epithelial atypia was higher in the first group (32% vs 8% in the second group, P = 0.034). Acute cholangitis and previous biliary operation rates were also higher in the fi rst group (acute cholangitis, 60% vs 24% in the second group, P = 0.01; previous biliary operation, 76% vs 24% in the second group, P = 0.001). Subgroup analysis showed that previous ES was the main causal factor for atypia, which was not related to the time interval from the ES (P = 0.407). Two patients (8%) with atypia in the fi rst group were p53-positive. CONCLUSION: ES causes biliary epithelial atypia that represents mostly reactive/proliferative rather than premalignant changes. The role of p53 immunoreactivity in biliary atypia needs to be further studied.

Genetic epidemiology of primary sclerosing cholangitis

The aetiology of primary sclerosing cholangitis (PSC) is not known. A more than 80-fold increased risk of PSC among first-degree relatives emphasizes the importance of genetic factors. Genetic associations within the human leukocyte antigen (HLA) complex on chromosome 6p21 were detected in PSC 25 years ago. Subsequent studies have substantiated beyond doubt that one or more genetic variants located within this genetic region are important. The true identities of these variants,however,remain to be identified. Several candidate genes at other chromosomal loci have also been investigated. However,according to strict criteria for what may be denominated a susceptibility gene in complex diseases,no such gene exists for PSC today. This review summarises present knowledge on the genetic susceptibility to PSC,as well as genetic associations with disease progression and clinical subsets of particular interest (inflammatory bowel disease and cholangiocarcinoma).

Xanthogranulomatous cholangitis causing obstructive jaundice:A case report

This article reports the case of a 34-year-old woman with xanthogranulomatous cholangitis who developed obstructive jaundice. Microscopically, the bile duct was surrounded and narrowed by a xanthogranulomatous lesion, but no xanthogranulomatous cholecystitis was seen. Although percutaneous cholangiograms done via the transhepatic biliary drainage showed smooth narrowing of the upper to middle bile duct, the cytology of bile was diagnosed as class V adenocarcinoma. Therefore, right extended hepatectomy and extrahepatic bile duct resection were performed. The differentiation of benign and malignant strictures at the hepatic hilum is often difficult. Xanthogranulomatous cholangitis is one possible diagnosis of a bile duct stricture. Precise review of all the preoperative information is required to make a correct diagnosis.

Role of adjuvant(chemo)radiotherapy for resected extrahepatic cholangiocarcinoma:a meta-analysis

Background:Adjuvant(chemo)radiotherapy(A(C)RT)may be an important supplement to surgery for extrahepatic cholangiocarcinoma(EHCC).However,whether all patients would achieve benefits from A(C)RT and which adjuvant regimen,adjuvant radiotherapy(ART)or adjuvant chemoradiotherapy(ACRT),would be preferred,are still undetermined.The low incidence of EHCC makes it difficult to carry out randomized controlled trials(RCTs);therefore,almost all clinical studies on radiotherapy are retrospective.We have conducted a meta-analysis of these retrospective studies.Methods:We conducted a meta-analysis of current retrospective studies using PubMed,Embase,and ClinicalTrials databases.All studies published in English that were related to A(C)RT and which analyzed overall survival(OS),disease-free survival(DFS),or locoregional recurrence-free survival(LRFS)were included.Estimated hazard ratios(HRs)were calculated for OS,DFS,and LRFS.Results:Data from eight studies including 685 patients were included.Our analysis showed that A(C)RT significantly improved OS(HR 0.69,95%confidence interval(CI)0.48–0.97,P=0.03),DFS(HR 0.60,95%CI 0.47–0.76,P<0.0001),and LRFS(HR 0.27,95%CI 0.17–0.41,P<0.00001)of EHCC overall.In subgroups,patients with microscopically positive resection margin(R1)could achieve a benefit from A(C)RT(HR 0.44,95%CI 0.27–0.72,P=0.001).No statistically OS difference was observed in negative resection margin(R0)subgroup(HR 0.98,95%CI 0.30–3.19,P=0.98).Significant OS benefit was found in patients who received concurrent ACRT(HR 0.40,95%CI 0.26–0.62,P<0.0001),while the result of ART without chemotherapy showed no significant benefit(HR 1.14,95%CI 0.29–4.50,P=0.85).In the distal cholangiocarcinoma subgroup,no significant difference was seen when ACRT and ART were included(HR 0.61,95%CI 0.14–2.72,P=0.52),but a significant difference was seen ewOshSpe,enDc iaFanlSla,yl yianzn iddn igsL ttRahlF ep Sca iotinne cEnutHrsr.C eCnt pAaCtieRnTt so,nelys p(eHcRi a0 ll.y2 i9 n,t9 h5 o%s eC Iw i0 t.h13 R–10 r.e6 s4 e,cPti=o0 n.0 m0 a2 r).g iCnso.n AclCusRioT nms:aAy(bCe)RsTu pmeraiyo ri tmop rAoRvTe .