Cholangiocytes (epithelial cells lining the intra- and extrahepatic bile ducts) and hepatocytes are two major components of liver epithelia. Although cholangiocytes are less numerous than hepatocytes, they are involved in both bile secretion and diverse cellular processes such as cell-cycle phenomena, cell signaling, and interactions with other cells, matrix components, foreign organisms, and xenobiotics. Cholangiocytes are also targets in several human diseases including cholangiocarcinoma, primary sclerosing cholangitis, autoimmune cholangitis, and vanishing bile-duct syndrome. The rapid advances in experimental biology technologies are greatly expanding interest in and knowledge of the physiology and pathophysiology of cholangiocytes. This review focuses on the progress of in vivo and in vitro experimental models in elucidating the physiologic functions of cholangiocytes and the pathophysiology of various cholangiopathies. The following aspects are reviewed: isolation of cholangiocytes from the liver and their heterogeneity, various culture systems, establishment of cholangiocyte cell lines, isolation and usage of intrahepatic bile-duct units, three-dimensional modeling of the bile duct, experimental models for inducing cholangiocyte proliferation, and various cholangiopathies such as cholangiocarcinoma, primary sclerosing cholangitis, and autoimmune cholangitis.

Hepatic allograft rejection is presently classified into acute and chronic rejection based on histological features, timing and reversibility. However, because features of both types of rejection can occur at any time, and in many combinations, the terms "acute" and "chronic" seem inappropriate in some instances. Thus the term "cellular rejection" better defines the histological features of portal hepatitis, nonsuppurative destructive cholangitis and endotheliitis, which are independent of time and response to therapy. Similarly, because progressive bile duct destruction leading to a decrease in the number of interlobular and septal bile ducts is the major histological feature of "chronic rejection," the term "ductopenic rejection," defined as the loss of bile ducts in 50% or more of portal tracts independent of time and reversibility, seems more appropriate. The pathogenesis of cell-mediated rejection has not been completely explained; however, direct immunocytic attack on small bile ducts and small arteries appear to be the major feature. The process may lead to bile duct loss ("ductopenia"). The pathogenetic role of foam-cell arteritis resulting in ischemic bile duct injury and the role of humoral mechanisms in causing ductopenic rejection awaits further clarification. In the past, irreversible ductopenic rejection occurred in approximately 10% of all patients who underwent their first liver transplantation; this figure, however, appears to be decreasing. The clinical features of irreversible rejection include persistent and progressive cholestasis; rising serum levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase; and a decrease in hepatic synthetic function. Ductopenic rejection can occur early (2 to 5 wk after liver transplantation) but most often develops between 6 wk and 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND & AIMS: Because the mechanisms leading to bile duct damage in sclerosing cholangitis are unknown, we aimed to determine the pathogenesis of bile duct injury in multidrug resistance gene (Mdr2)(Abcb4) knockout mice (Mdr2(-/-)) as a novel model of the disease. METHODS: Mdr2(-/-) and wild-type controls (Mdr2(+/+)) were studied at 2, 4, and 8 weeks of age. Liver histology, ultrastructure, immunofluorescence microscopy (to study inflammatory cells, tight junction protein ZO-1, basement membrane protein laminin, fluorescence-labeled ursodeoxycholic acid), immunohistochemistry (for alpha-smooth muscle actin, nitrotyrosine), sirius red staining, bacterial cultures of intra-abdominal organs, and polymerase chain reaction (PCR) for Helicobacter bilis DNA were compared between both genotypes. Hepatic cytokine expression was determined by reverse-transcription PCR. RESULTS: Bile ducts of Mdr2(-/-) showed disrupted tight junctions and basement membranes, bile acid leakage into portal tracts, induction of a portal inflammatory (CD11b, CD4-positive) infiltrate, and activation of proinflammatory (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta) and profibrogenic cytokines (transforming growth factor [TGF]-beta1). This resulted in activation of periductal myofibroblasts, leading to periductal fibrosis, separating the peribiliary plexus from bile duct epithelial cells and, finally, causing atrophy and death of the bile duct epithelium. Bacterial translocation was not increased and H. bilis was not detectable in Mdr2(-/-). CONCLUSIONS: Sclerosing cholangitis in Mdr2(-/-) mice is a multistep process with regurgitation of bile from leaky ducts into the portal tracts, leading to induction of periductal inflammation, followed by activation of periductal fibrogenesis, finally causing obliterative cholangitis owing to atrophy and death of bile duct epithelial cells.

BACKGROUND: Sphincter of Oddi manometry as performed at ERCP is the most accepted method to evaluate for sphincter of Oddi dysfunction. To fully assess for sphincter of Oddi dysfunction, both the pancreatic and the bile ducts must be evaluated. We assessed the frequency of pancreatic and biliary sphincter abnormalities in a large series of patients. METHODS: A total of 593 patients underwent manometry of the biliary and pancreatic ducts at one endoscopic retrograde cholangiopancreatography session. Basal sphincter pressure greater than or equal to 40 mm Hg was considered abnormal. Phasic waves were not evaluated. Manometric abnormalities were correlated with the clinical presentation as categorized using a modified Geenen/Hogan classification. RESULTS: Of 360 patients with intact sphincters, 18.9% had abnormal pancreatic sphincter basal pressure alone, 11.4% had abnormal biliary basal sphincter pressure alone, and in 31.4% the basal pressure was abnormal for both sphincters; thus, 60.1% of the patients had sphincter dysfunction. The frequency of sphincter of Oddi dysfunction did not differ whether typed by biliary or pancreatic criteria: approximately 65% type II and 59% type III. Of patients without pancreatitis, 55.9% had an abnormal basal sphincter pressure, whereas sphincter dysfunction was present in 72.3% of those with idiopathic pancreatitis and 53.9% of patients with chronic pancreatitis. Of patients with an ablated biliary sphincter, 45.9% had abnormal basal pancreatic sphincter pressure and only 0.6% had an abnormal biliary sphincter pressure alone. Abnormal pressure in both sphincters was found in 9.3%. CONCLUSION: If both portions of the sphincter of Oddi are studied simultaneously, abnormalities are found very commonly (55% to 72%). Assessment of both sides of the sphincter is necessary. Classifying patients according to both pancreatic and biliary sphincter segments is cumbersome, and may be replaced by an overall type. Using this modified classification, the frequency of sphincter of Oddi dysfunction is similar in both type II and type III patients (59% to 67%).

Although the clinical features of sclerosing cholangitis from opportunistic infections of the biliary tree in patients with acquired immunodeficiency syndrome (AIDS) are well known, the mechanisms by which associated pathogens, such as Cryptosporidium parvum, cause disease are obscure. Using an in vitro model of biliary cryptosporidiosis, we observed that C. parvum induces apoptosis in cultured human biliary epithelia. Both caspase protease inhibitors and neutralizing antibodies to either Fas receptor (Fas) and Fas ligand (FasL) inhibited this process; neutralizing antibodies to other apoptotic cytokines [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF-beta)] had no effect. C. parvum stimulated FasL membrane surface translocation, increased both FasL and Fas protein expression in infected biliary epithelia, and induced a marked increase of soluble FasL (but not IL-1beta, TNF-alpha, and TGF-beta) in supernatants from infected cells. When a coculture model is used in which infected and uninfected cell populations were physically separated by a semipermeable membrane, both uninfected biliary epithelia and uninfected Fas-sensitive Jurkat cells (but not a Fas-resistant Jurkat cell line) underwent apoptosis when cocultured with infected biliary epithelia. Moreover, both a neutralizing antibody to FasL and a metalloprotease inhibitor blocked the apoptosis in uninfected cocultured cells. Activation of caspase activity was also observed in uninfected cocultured biliary epithelia. The data suggest that C. parvum induces apoptosis in biliary epithelia by a Fas/FasL-dependent mechanism involving both autocrine and paracrine pathways. These observations may be relevant to both the pathogenesis and therapy of the cholangitis seen in AIDS patients with biliary cryptosporidiosis.

In 6 patients with upper abdominal pain of unknown origin presenting with pancreas divisum, the pressure in the pancreatic duct was measured via the minor papilla into which in these patients the main part of the pancreatic duct system drains. For comparison intraductal manometry via the major papilla (papilla of Vater) was performed in 8 patients with normal pancreatic duct system. The pressure in the pancreatic duct of the control group was 10.5 +/- 0.9 mm Hg, whereas in the patients with pancreas divisum it was 23.7 +/- 1.3 mm Hg. The results demonstrate that in patients with pancreas divisum, intraductal pressure may be largely increased even in the fasting state.

In this study both pancreatic and bile duct sphincter pressures were measured on the same occasion by means of endoscopic manometry in 42 patients with long-standing upper abdominal pain. Nine (53%) of the 17 patients with abnormal sphincter function had a marked difference between the pancreatic duct sphincter pressure (PSOP) and the bile duct sphincter pressure (BSOP): 6 patients with a clinical diagnosis of biliary dyskinesia showed elevated BSOPs, whereas the PSOPs were normal. The reverse, an abnormal PSOP but normal or only a slightly elevated BSOP, was registered in the three patients with chronic pancreatitis. These findings indicate that a motor abnormality may be restricted to only one of the sphincters. Thus, when the sphincter of Oddi is investigated only from the pancreatic duct, manometry may either fail to show an abnormal BSOP in some patients with biliary dyskinesia, or it may falsely suggest this diagnosis in patients with unrecognized pancreatitis.

Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis. This article gives a comprehensive overview of the molecular and cellular mechanisms of sepsis-associated cholestasis. Recent advances in the understanding of intrahepatic cholestasis have allowed us to delineate the molecular mechanisms that underlie sepsis-associated cholestasis and to describe their potential clinical and therapeutic applications. The mechanisms and clinical presentation of sepsis-associated liver injury vary according to the severity of the bacterial infection. Proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. Ischemic liver injury and, rarely, progressive sclerosing cholangitis can also be found in patients with septic shock, or major trauma with systemic inflammatory response syndrome. Treatment is mainly focused on eradication of the underlying infection and managing the sepsis. The use of ursodeoxycholic acid or extracorporeal liver support as treatments for sepsis-associated cholestasis is under investigation, but neither can be recommended in routine clinical practice at present. Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation.

If basal sphincter of Oddi pressures measured from the pancreatic duct and the bile duct are essentially equal, then measurement of basal pressures from only one duct would be adequate in evaluating sphincter of Oddi dysfunction. We report a series of 88 patients whom we evaluated with sphincter of Oddi manometry. Cannulation of both the biliary sphincter segment and pancreatic sphincter segment was achieved in these patients. Basal sphincter pressures were measured (normal, less than 40 mm Hg). In 45 of the 88 patients (51%), normal sphincter of Oddi basal pressures were seen in both ducts. Elevated basal sphincter of Oddi pressures were seen in both ducts in 28 of 88 patients (32%). In 15 of 88 cases (17%) there was an elevation of only one sphincter segment. Elevation in only the biliary sphincter segment occurred in 7 of 88 patients (8%). Elevation in the pancreatic sphincter segment alone occurred in 8 of 88 patients (9%). We conclude that sphincter of Oddi manometry of both the pancreatic and bile ducts is needed if complete manometric information is desired.