Septal Bile Ducts Research Articles

Surgical interpretation of the WHO subclassification of intrahepatic cholangiocarcinoma: a narrative review.

Intrahepatic cholangiocarcinoma (iCCA) has been subclassified by its gross morphology into the mass-forming (MF), periductal-infiltrating (PI), and intraductal growth (IG) types and their combinations. This classification correlates well with clinical features; for example, MF-iCCA has less lymph-node metastasis and a better prognosis than PI-iCCA. According to the recently accumulated evidence from histological investigations, the WHO classification endorsed a subclassification scheme in which iCCA cases are classified into small- and large-duct types. Small-duct iCCA is considered to originate from septal or smaller bile ducts and is characterized by less frequent lymph-node metastasis, a favorable prognosis, and an MF appearance. Large-duct iCCA arises around the second branch of the biliary tree and has more aggressive biology and distinct genetic abnormalities. According to the practice guidelines for iCCA from the Liver Cancer Study Group of Japan and the National Comprehensive Cancer Network, upfront surgery is recommended for iCCA without distant metastasis regardless of the morphological subtype, based on clinical experience. In consideration of the biological heterogeneity of iCCA, the treatment strategy for iCCA needs to be reconsidered based on the WHO subtypes.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

Primary biliary cholangitis—cause or association with psoriasis: a case report

Primary biliary cholangitis is a chronic progressive cholestatic granulomatous and destructive inflammatory lesion of small intralobular and septal bile ducts that primarily affects women. The exact etiology of this disease has not yet been elucidated; however, it is believed to be the result of a combination of environmental triggers in genetically predisposed individuals. It can manifest itself simultaneously with, before, or after the onset of psoriasis and other skin autoimmune diseases. Standard treatment is ursodeoxycholic acid. A 65-year-old patient presenting with elevated hepatic laboratory findings that had persisted for several years and normal abdominal ultrasound was additionally diagnosed with primary biliary cholangitis after 2 years on a biological drug for psoriasis. She did not have other symptoms except elevated liver tests. The skin showed a strong response to biological therapy and treatment with ursodeoxycholic acid prompted lowering of liver enzymes. The skin was clear all throughout the treatment. This article emphasizes the importance of additional diagnostic workups in patients with psoriasis and elevated hepatic laboratory findings.

2473 The Mystery of the “Vanishing” Bile Ducts

INTRODUCTION: The etiologies of cholestatic liver disease is extensive, including immunological, ischemic, infectious, metabolic, and toxic causes. We present a rare case of a patient who was diagnosed with idiopathic vanishing bile duct syndrome (VBDS) after a thorough work-up. CASE DESCRIPTION/METHODS: A 61-year-old female with a history of hypertension, type II diabetes mellitus, congestive heart failure, and end stage renal disease presented with generalized pruritus and jaundice. Laboratory tests revealed a total bilirubin 10.5 mg/dL, AST 27 IU/L, ALT 27 IU/L, alkaline phosphatase 596 IU/L. Further workup was negative for viral hepatitis, autoimmune hepatitis, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson's Disease. An MRCP showed hepatosplenomegaly without ductal dilatation, and upper endoscopy with ultrasound revealed a normal biliary duct without evidence of obstruction. Pathology from fine needle biopsy was significant for chronic cholestatic changes with ductopenia (43% duct loss), obliterative portal venopathy, and congestive hepatopathy. Without an identifiable cause, these findings are most consistent with idiopathic VBDS. The patient was referred for liver transplant evaluation due to concern for progression to cirrhosis. DISCUSSION: VBDS is a rare hepatic condition characterized by progressive loss of the interlobular and septal bile ducts resulting in cholestasis and potentially biliary cirrhosis and liver failure. The cause of bile duct destruction is poorly understood but likely results from biliary apoptosis due to immunologic, ischemic, infectious, metabolic, and toxic assaults. 1 Approximately 1% of cases classify as idiopathic VBDS, which likely comprises of several disease processes with atypical features, such as late-onset non-syndromic paucity of intrahepatic bile ducts, small-duct primary sclerosing cholangitis without large duct involvement, non-suppurative viral cholangitis, and autoimmune cholangitis without typical autoantibodies. 2 The disease course is unpredictable, ranging from benign to fatal or necessitating transplantation.2 Treatment of VBDS includes drug withdrawal, choleretic agents, and immunosuppression. The uncertain etiology of idiopathic VBDS precludes a causative treatment. Liver transplantation has been the only successful treatment. 2

Florid biliary duct lesions in an AMA -positive patient in absence of cholestatic liver biochemistry

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease, diagnosed by the presence of anti-mitochondrial antibodies (AMA) or highly PBC-specific anti-nuclear antibodies, in the appropriate context of cholestatic liver biochemistry.We present a case with histological features of destructive granulomatous lymphocytic cholangitis affecting interlobular and septal bile ducts suggestive of PBC, with strong positive AMA, Anti-M2 and anti-nuclear dot, but with persistently normal alkaline phosphatase (ALP). On the contrary to previous reports suggesting that those individuals in whom ALP remains persistently below 1.5 times ULN appear to have a benign course and a better prognosis, our patient progressed to liver cirrhosis.

Observations on the ex situ perfusion of livers for transplantation.

Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH < 7.4) from those that did not (pH > 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25‐50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid‐base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.

Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.

Reovirus type-2–triggered autoimmune cholangitis in extrahepatic bile ducts of weanling DBA/1J mice

Reovirus is a proposed cause of infantile biliary atresia. However, mechanistic insight regarding Reo-2 as a potential cholangiotropic virus is lacking. Furthermore, it is unknown whether Reo-2 infection can induce autoimmune-mediated bile duct injury. Lesions of bile ducts in newborn DBA/1J mice infected with Reo-2 were analyzed immunopathologically. Damage to biliary epithelia occurs after Reo-2 infection. In addition, nonsuppurative cholangitis with fibrosis in extrahepatic (especially septal) bile ducts developed following complete viral clearance from the liver. At the inflamed ducts, major histocompatibility complex class I expressing((+)) and FAS(+) cholangiocytes were associated with FAS ligand(+) lymphocytes and tumor necrosis factor-α(+) mononuclear cells (macrophages and lymphocytes). These cholangiocytes were apoptotic and necrotic. Moreover, affected ducts were infiltrated by CD3(+), CD4(+), CD8(+), IFN-γ(+), and FAS(+) lymphocytes. Analysis of blood from Reo-2-infected mice revealed that they developed anticholangiocyte cytoplasm antibodies and had high serum IFN-γ concentration. Notably, there was no increase in Foxp3(+) lymphocytes at inflamed ducts, lymph nodes, and thymi. Reo-2 infection induced T-helper cell type 1-dependent injury to bile ducts in weanling mice. The lesions observed in mice may be analogous to those associated with human infantile biliary atresia, which are caused by an autoimmune-mediated process.

Histological characteristics of biliary intraepithelial neoplasia-3 and intraepithelial spread of cholangiocarcinoma

The increasing grades of biliary intraepithelial neoplasia (BilIN) reflect multistep carcinogenesis of cholangiocarcinoma, BilIN-3 representing the carcinoma in situ stage. A different form of in situ growth form of cancer cells is the intraepithelial spreading of cholangiocarcinoma cells. We examined the histological characteristics of carcinoma in situ in the biliary tract on 64 partial hepatectomy specimens with a diagnosis of hepatolithiasis. We distinguished two forms of carcinoma in situ: BilIN-3 and intraepithelial spread of carcinoma (IES). BilIN-3 is defined by epithelial atypia gradually decreasing towards the transition to adjacent normal biliary epithelium. In IES, the lesion shows an abrupt transition to normal biliary epithelium, in which the intraepithelial carcinoma then tends to spread. BilIN-3 and IES were observed in 17 (94 %) and seven (39 %), respectively, in cases of invasive cholangiocarcinoma (n = 18), and neither of them was observed in cases without invasive cholangiocarcinoma (n = 46). Most lesions of BilIN-3 and IES microscopically showed a flat or pseudopapillary pattern. The less frequent micropapillary configuration was noted more often in BilIN-3. BilIN-3 was not observed in septal and small intrahepatic bile ducts, while IES was regularly observed in such bile ducts. Immunohistochemical analysis showed p53 to be expressed significantly more frequently in IES (29 %) than in BilIN-3 (8 %). In conclusion, carcinoma in situ in the biliary tract is morphologically heterogeneous, and it is important to distinguish BilIN-3 and intraepithelial carcinoma spreading as distinct lesions, to better understand their biology.

Bile duct changes in different etiologic types of end-stage chronic liver disease: a study on native explant livers

AimsBile duct changes in the form of intraepithelial neoplasia or dysplasia have been well studied in chronic biliary tract diseases. It is important to analyse the morphologic spectrum of bile...

Primary Biliary Cirrhosis and Granulomatous Pulmonary Infiltrates: Causal Association or Casual Association?

Purpose: Introduction: Primary biliary cirrhosis (PBC) is thought to be a systemic disease and is characterized by granulomatous inflammation of the septal and interlobular bile ducts. Extrahepatic granuloma as an extrahepatic manifestation of PBC has rarely been reported. We report a case of PBC presented with granulomatous pulmonary infiltrates. Case Report: A 44-yearold woman, who underwent a medical checkup every year, demonstrated an abnormal shadow on chest X-ray. CT scan showed abnormal interstitial shadow of the lung in this patient. Examination of broncho-alveolar lavage fluid (BALF) and the specimen from transbronchial lung biopsy (TBLB) showed cryptogenic interstitial pneumonia with marked granulomatous lesions. Two months later, the patient showed liver function test disorder. The laboratory data disclosed the following values (normal reference ranges are given in parentheses): total protein, 8.3 g/dl (6.5-8.2 g/dL); albumin, 4.0 g/dL (3.8-5.4 g/dL); total bilirubin, 0.6 mg/dL (0.2-1.0 mg/dL); aspirate aminotransferase (AST), 61 IU/L (<40 IU/L); alanine aminotransferase (ALT), 85 IU/L (<40 IU/L); alkaline phosphatase, 1,158 IU/L (100-340 IU/L); and gamma-glutamyl transpeptidase, 365 IU/L (<30 IU/L). The patient tested negative for anti-mitochondrial antibody by indirect immunofluorescence assay (IF) but tested positive by enzyme-linked immunosorbent assay (ELISA). Histopathological examination of the specimen from liver biopsy demonstrated epithelioid cells in the peripheral portal area and disappearance of the bile duct in the portal area. These findings indicated a diagnosis of PBC. Liver function test of the patient returned to almost the normal level following oral administration of ursodeoxycholic acid. Discussion: Granuloma is commonly found in the liver of patients with PBC, which consists of epithelioid cells without necrosis and is similar to the sarcoid type. Very occasionally extrahepatic granuloma has been found. A case of PBC presenting with granulomatous skin lesions has been reported. An overlap of pulmonary sarcoid and PBC has long been recognized as well. Interstitial pneumonia is rarely accompanied by PBC and is not considered related to PBC itself but to the presence of an associated connective tissue disease such as Sjogren's syndrome. In the case presented here, neither the clinical symptoms nor a variety of blood examinations detected any associated connective tissue diseases. Therefore, we thought it most appropriate to consider that granulomatous pulmonary infiltration in this case may have been an extrahepatic manifestation of PBC. Further research and accumulation of cases are required to fully clarify this association.

Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma

A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy, in addition to HCCs, an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular cores was found in the dilated large bile ducts in the left lobe, and this papillary carcinoma was associated with an invasive mucinous carcinoma (invasive IPNB). Interestingly, extensive intraductal spread of the cholangiocarcinoma was found from the reactive bile ductular level to the interlobular bile ducts and septal bile ducts and to the large bile ducts in the left lobe. Neural cell adhesion molecule, a hepatic progenitor cell marker, was detected in IPNB cells. It seems possible in this case that hepatic progenitor cells located in reactive bile ductules in liver cirrhosis may have been responsible for the development of the cholangiocarcinoma and HCC, and that the former could have spread in the intrahepatic bile ducts and eventually formed grossly visible IPNB.

Immunohistochemical study of the local immune response in lambs experimentally infected with Dicrocoelium dendriticum (Digenea)

Phenotypic expression of inflammatory cells in liver and hepatic lymph nodes (HLN) has been examined in lambs experimentally infected with Dicrocoelium dendriticum using immunohistochemical techniques. Thirty-two lambs, 12 infected with 1,000 D. dendriticum metacercariae, 12 with 3,000, and 8 controls were used. Half the lambs in each group were slaughtered on days 60 and 180 post-infection (p.i.), respectively. Primary antibodies (Abs) against T cell epitopes (CD3+, CD4+, CD8+ and WC1+ gammadelta), B cell epitopes (CD79alphacy+, CD45R+), immunoglobulin (IgG)-bearing plasma cells, macrophages (CD14+, VPM32+) and major histocompatibility complex (MHC) class IIbeta antigen were used. T lymphocytes (CD3+, CD4+ and CD8+) and B lymphocytes (CD79alphacy+ and CD45R+) with diffuse pattern or forming lymphoid aggregates and follicles surrounded the septal bile ducts (SBD) and inter-lobular bile ducts, whereas the WC1 gammadelta T cells were scattered. Numerous IgG+ plasma cells were observed around SBD. CD14 and VPM32+ macrophages intermingled with lymphocytes were immunostained by the anti-MHC class IIbeta. This Ab also reacted with lymphoid cells. Likewise, increased positive immunostaining for all Abs used was observed in the HLN of infected lambs. There was no qualitative difference regarding the phenotype expression of inflammatory cells between the lambs infected with D. dendriticum. The humoral and cell-mediated local immune responses observed were similar in the two groups of lambs infected with different doses.

Recurrent primary sclerosing cholangitis: Clinical diagnosis and long-term management issues

1. Primary sclerosing cholangitis (PSC) in the nontransplant setting is a chronic, progressive liver disease characterized by diffuse stricturing of the biliary tree, cholestatic liver enzymes, and a compatible liver biopsy. 2. Cholangiography reveals irregularity of the bile duct wall, strictures, beading, and diverticula. 3. The typical biopsy reveals inflammation and fibrosis of the interlobular and septal bile ducts, often with obliteration or biliary-type cirrhosis. 4. The precise pathogenetic mechanism remains elusive but is assumed to be an autoimmune phenomenon. 5. For patients with end-stage complications of PSC, such as liver failure, recurrent bacterial cholangitis, and intractable pruritus, liver transplantation is an acceptable treatment option.

Characterization of biliary intra‐epithelial lymphocytes at different anatomical levels of intrahepatic bile ducts under normal and pathological conditions: Numbers of CD4+CD28– intra‐epithelial lymphocytes are increased in primary biliary cirrhosis

Distribution of intra-epithelial lymphocytes along intrahepatic biliary tree (bIEL), and their density and phenotype were examined in normal and diseased livers, particularly in primary biliary cirrhosis (PBC). Immunohistochemically, bIEL were examined in 28 normal livers, 13 cases of chronic viral hepatitis (CVH), 13 cases of PBC, five cases of primary sclerosing cholangitis (PSC), seven cases of extrahepatic biliary obstruction (EBO), and 16 hepatolithiatic livers. In normal livers, bIEL were relatively dense at large and septal bile ducts compared to interlobular ducts. Most of them were positive for CD3 and CD8, while a few were positive for CD4, CD20 and CD57. In CVH, PSC and EBO, neither distribution, phenotype nor density of bIEL differed from normal liver. In hepatolithiasis, numbers of CD8(+)bIEL were increased in stone-containing ducts. In PBC, numbers of CD4(+)CD28(-)bIEL, which are reportedly responsible for target tissue destruction in autoimmune diseases, were markedly increased in damaged interlobular ducts. In conclusion, CD3(+)CD8(+)bIEL may be involved in immune homeostasis of intrahepatic bile ducts in normal livers and in CVH, PSC and EBO. Altered distribution and phenotypes of bIEL in PBC and hepatolithiasis may reflect their participation in biliary lesions. Increased CD4(+)CD28(-)bIEL in damaged bile ducts of PBC may be related to immune-mediated biliary damage.

Field and experimental studies on Dicrocoelium dendriticum and dicrocoeliasis in northern Spain

The transmission, control and the relationship between Dicrocoelium dendriticum and its definitive (sheep and cattle) and intermediate (molluscs and ants) hosts under natural and experimental conditions are described. Eleven species of molluscs and four of ants were found infected with larval D. dendriticum in León province, north-west Spain. Infected ants were observed between April and November and in tetania at 7.5-26.9 degrees C. The highest shedding of eggs by sheep and cattle was detected in winter. Two treatments applied in November and January were the most effective. In experimentally infected molluscs, the parasite was not visible under the stereomicroscope, at least until 50 days post-infection (p.i.). The prepatent period in experimentally infected lambs was 49-79 days p.i. The number of eggs per gram increased with the days p.i. and the parasite burden. The aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, leukocyte and neutrophil values of infected lambs increased, but those of lymphocytes decreased. Using the enzyme-linked immunosorbert assay technique, the IgG antibody response to excretory-secretory and somatic antigens of D. dendriticum was positive from day 30 p.i., although the maximum antibody levels were observed on day 60 p.i. The number of worms per lamb ranged between 30 and 2063. Cholangitis and cholangiectasia of the septal bile and hepatic ducts were observed. The best enzymatic systems for adult and larval D. dendriticum characterization were lactate dehydrogenase, glucose phosphate isomerase and phosphoglucomutase. Genetic variability of adult D. dendriticum was high using the random amplified polymorphic DNA technique.

Case Report: Histologic Features of Steatohepatitis in Patients with a Clinical Diagnosis of Autoimmune Cholestasis

Nonalcoholic steatohepatitis (NASH) is a disease included in the spectrum of nonalcoholic fatty liver disease, which is able to continue progression toward cirrhosis (1). The definition of NASH relies on the common exclusion of significant alcohol use (<20 g/day) and the characteristic histological lesions include some degree of steatosis in addition to mixed lobular inflammation and hepatocyte damage (ballooning degeneration with or without Mallory’s hyaline) (2). NASH has been found in patients suffering from chronic hepatitis C (3) and also in other forms of liver diseases, such as chronic hepatitis B, autoimmune hepatitis, drug-induced liver disease, and α-1 antitrypsin deficiency (4). Primary biliary cirrhosis (PBC) should be considered when patients show a biochemical and histological cholestatic pattern along with positive serum antimitochondrial antibodies (AMA), including immunoblot studies, or PBC-specific antinuclear antibodies (ANA), mainly anti-SP100 and anti-GP210 (5), while patients showing a cholestatic pattern together with negative AMA and positive ANA (different from rim-like or multiple nuclear dots) need to be classified as having autoimmune cholangitis (AIC) (5, 6). Differences found between both groups according to biochemical or histological features are minimal. Indeed, histopathologic features of both entities consist of characteristic interlobular and septal bile ducts lesions (florid duct lesion), cholestasis, ductular proliferation, portal and periportal hepatitis, usually mild

Stromal Cell–Derived Factor-1 from Biliary Epithelial Cells Recruits CXCR4-Positive Cells: Implications for Inflammatory Liver Diseases

Although stromal cell–derived factor-1 (SDF-1) plays an important role in hematopoiesis in the fetal liver, the role after birth remains to be clarified. We investigated the role of SDF-1 and its receptor, CXCR4, in 75 patients; this included controls and patients with viral hepatitis, liver cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Interestingly, SDF-1 appeared up-regulated in biliary epithelial cells (BEC) of inflammatory liver disease. Furthermore, in inflammatory liver diseases, SDF-1 was expressed by BEC of interlobular and septal bile ducts and by proliferated bile ductules. The message expression of SDF-1 in BEC was confirmed at a single-cell level by RT-PCR and laser capture microdissection. The plasma levels of SDF-1 were significantly higher in patients with liver diseases than in normal controls. Flow cytometric analysis of the surface expression of CXCR4 showed that most liver-infiltrating lymphocytes express CXCR4 and the intensity was up-regulated more significantly in liver-infiltrating lymphocytes than in peripheral blood lymphocytes. These results suggest that increased SDF-1 production by BEC may play an important role in the recruitment of CXCR4-positive inflammatory cells into the diseased livers. These data are significant because modulation of the SDF-1/CXCR4 interaction has therapeutic implications for inflammatory liver diseases.

Expression of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 protein and messenger RNA in primary biliary cirrhosis.

This study examined the role of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) in the autoimmune process of bile duct destruction in the early stages of primary biliary cirrhosis (PBC). Ten PBC liver samples and five control samples were studied. Immunohistochemical studies of ICAM-1 and LFA-1, and Western blot of ICAM-1 were performed. Immunoelectron microscopy was conducted using immunoglobulin-gold and silver staining. Human ICAM-land LFA-1 peptide nucleic acid probes were used for in situ hybridization. In PBC liver samples, immunohistochemistry showed aberrant ICAM-1 expression on bile duct epithelial plasma membrane and also luminal sites of endothelial plasma membrane of terminal portal venules. Western blot confirmed ICAM-1 protein expression. LFA-1-positive lymphocytes were associated with epithelial cells of septal and interlobular bile ducts. Immunoelectron microscopy localized ICAM-1 on the luminal and basal surfaces as well as on lymphocytes around damaged bile duct epithelial cells, and LFA-1 on lymphocytes around damaged bile ducts. Messenger RNA expression of ICAM-1 was demonstrated in bile ducts, and LFA-1 in lymphocytes around bile ducts. De novo expression of ICAM-1 and LFA-1 at protein and mRNA levels in PBC may imply an inductive role of ICAM-1 through binding with its ligand LFA-1 in the extravasation of activated lymphocytes and lymphocyte-mediated bile duct destruction.

Differential expression of intestinal trefoil factor in biliary epithelial cells of primary biliary cirrhosis

Intestinal trefoil factor (ITF) promotes epithelial cell migration and mucosal restitution during inflammation. We used real-time quantitative PCR, in situ nucleic acid hybridization, and immunohistochemistry to study the expression of the ITF gene and protein expression in the liver of primary biliary cirrhosis (PBC) and controls. There were significantly higher levels of ITF messenger RNA (mRNA) in PBC liver compared with primary sclerosing cholangitis (PSC) ( P < .05) or normal controls ( P < .001) and also higher in hepatitis C virus (HCV) liver ( P < .05) and cryptogenic cirrhosis ( P < .01) compared with normal controls. However, only in PBC was there a significant difference between small (interlobular and bile ductules) and large (intrahepatic and septal) bile ducts. Using in situ hybridization, the highest levels of ITF gene expression were localized to the large bile ducts in PBC. This differential expression of ITF was also noted at the protein level. Thus, in PBC, although 92% of large bile ducts expressed the ITF protein, only 2% of small bile ducts ( P < .0001) expressed ITF. In contrast, in control livers, 34% of large bile ducts and 13% of small bile ducts expressed ITF. ITF protein is absent in small bile ducts in all stages of PBC. In conclusion, the expression of ITF may play an important role in bile duct damage. In small bile ducts, ITF production in response to damage is absent, making such cells vulnerable to damage and providing a thesis for the selective loss of small, but not large, bile ducts in PBC. (H EPATOLOGY 2002;36:1227-1235.)