Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intra- and/or extrahepatic bile ducts leading to the formation of multifocal strictures alternated to bile duct dilatations. The diagnosis of the most common subtype of the disease, the large duct PSC, is based on the presence of elevation of cholestatic indices, the association of typical cholangiographic findings assessed by magnetic resonance cholangiography and the exclusion of causes of secondary sclerosing cholangitis. Liver biopsy is not routinely applied for the diagnosis of large duct PSC but is mandatory in the case of suspicion of small duct PSC or overlap with autoimmune hepatitis.

Cholangiocarcinoma, a tumor of biliary epithelium, is increasing in incidence. The imaging appearance, behavior, and treatment of cholangiocarcinoma differ according to its location and morphology. Cholangiocarcinoma is usually classified as intrahepatic, perihilar, or distal. The three morphologies are mass-forming, periductal sclerosing, and intraductal growing. As surgical resection is the only cure, prompt diagnosis and accurate staging is crucial. In staging, vascular involvement, longitudinal spread, and lymphadenopathy are important to assess. The role of liver transplantation for unresectable peripheral cholangiocarcinoma will be discussed. Locoregional therapy can extend survival for those with unresectable intrahepatic tumors. The main risk factors predisposing to cholangiocarcinoma are parasitic infections, primary sclerosing cholangitis, choledochal cysts, and viral hepatitis. Several inflammatory conditions can mimic cholangiocarcinoma, including IgG4 disease, sclerosing cholangitis, Mirizzi's syndrome, and recurrent pyogenic cholangitis. The role of PET in diagnosis and staging will also be discussed. Radiologists play a crucial role in diagnosis, staging, and treatment of this disease.

Magnetic resonance cholangiography (MRC) has become the standard of reference for imaging of the biliary ducts. The use of three-dimensional (3D) sequences has resulted in improved spatial resolution with virtually isotropic voxel and improved signal/noise ratio. In addition to MRC images, 3D fat suppressed T1-weighted MR images should be systematically obtained to search for intrahepatic calculi. MRC plays a major role in the diagnosis of cholangiocarcinoma and assessment of its resectability. With modern MR systems the performance of MR is basically the same that of CT for evaluation of arterial and portal vein extent. MRC is a key imaging modality for the diagnosis of primary sclerosing cholangitis. Different imaging patterns may be observed including multifocal intra- and extrahepatic strictures alternating with slightly dilated ducts. Focal signal abnormality of the liver parenchyma and focal parenchymal atrophy represent the consequences of biliary duct obstruction on liver parenchyma. Diagnosis of biliary lithiasis is performed by combination of MRC and T1-weighted MR imaging. MRC can be performed for the diagnosis of secondary cholangitis including ascending cholangitis, ischemic cholangitis and IgG4-related sclerosing cholangitis. Hepatobiliary contrast agents could be used for demonstrating the site of biliary duct leakage after surgery and for functional imaging. MR imaging can also be used to determine the prognosis of PSC. The inherent limitations of MRC of bile ducts are still the suboptimal spatial resolution for evaluation of distal intrahepatic biliary ducts.

Bile duct strictures in adults are secondary to a wide spectrum of benign and malignant pathologic conditions. Benign causes of bile duct strictures include iatrogenic causes, acute or chronic pancreatitis, choledocholithiasis, primary sclerosing cholangitis, IgG4-related sclerosing cholangitis, liver transplantation, recurrent pyogenic cholangitis, Mirizzi syndrome, acquired immunodeficiency syndrome cholangiopathy, and sphincter of Oddi dysfunction. Malignant causes include cholangiocarcinoma, pancreatic adenocarcinoma, and periampullary carcinomas. Rare causes include biliary inflammatory pseudotumor, gallbladder carcinoma, hepatocellular carcinoma, metastases to bile ducts, and extrinsic bile duct compression secondary to periportal or peripancreatic lymphadenopathy. Contrast material-enhanced magnetic resonance (MR) imaging with MR cholangiopancreatography is extremely helpful in the noninvasive evaluation of patients with obstructive jaundice, an obstructive pattern of liver function, or incidentally detected biliary duct dilatation. Some of these conditions may show characteristic findings at MR imaging-MR cholangiopancreatography that help in making a definitive diagnosis. Although endoscopic retrograde cholangiopancreatography with tissue biopsy or surgery is needed for the definitive diagnosis of many of these strictures, certain MR imaging characteristics of the narrowed segment (eg, thickened wall, long-segment involvement, asymmetry, indistinct outer margin, luminal irregularity, hyperenhancement relative to the liver parenchyma) may favor a malignant cause. Awareness of the various causes of bile duct strictures in adults and familiarity with their appearances at MR imaging-MR cholangiopancreatography are important for accurate diagnosis and optimal patient management.

The interaction between inflammatory bowel disease (IBD) and hepatobiliary manifestations represents a classic example of liver-gut crosstalk. The importance of liver-gut crosstalk in IBD is demonstrated in the pathogenesis and outcome of primary sclerosing cholangitis (PSC) in IBD patients. Immunoglobulin G4-associated cholangitis (IAC), which has recently been described in UC patients, may also illustrate the significance of gut-liver interaction in these patients. Presence of these hepatobiliary manifestations influences the outcome of associated IBD, in particular ulcerative colitis (UC), and vice versa. The pathogenesis of PSC is postulated to be related to gut inflammation in IBD that results in inflammation in the portal tracts (the 'leaky gut'). Enterohepatic circulation of lymphocytes from the gut to the liver is also of potential relevance to PSC pathogenesis and outcomes. The presence of PSC and gut inflammation in IBD influences the course and outcomes of both diseases. Further research is required, to understand the mutual effect of liver-gut crosstalk in the outcomes of UC patients, and highlights the importance of an interdisciplinary approach-involving gastroenterologists, hepatologists, advanced endoscopists and liver transplant surgeons-in the management of these patients.

Magnetic resonance imaging (MRI) with magnetic resonance cholangiography (MRC) has become the radiologic standard of reference for diagnosis of primary sclerosing cholangitis (PSC). However, natural history of radiologic features of PSC is poorly known. In the current study, we aimed at analyzing the course of PSC using three-dimensional (3D) MRC and liver MRI to find predictive radiologic features of progression. PSC patients, followed up in our center, with at least two 3D MRCs performed in at least a 1-year interval, were retrospectively reviewed. We built an interpretation standard model to score precisely bile ducts and liver parenchyma features. The primary endpoint was overall radiologic course, including worsening, improvement, or stabilization. Radiologic features were analyzed by logistic regression. We reviewed 289 MRIs from 64 patients upon a mean radiologic follow-up of 4 years (range, 1-9). Radiologic features worsened in 37 patients (58%) and stabilized in 27 (42%); no patient showed improvement. Multivariate analysis resulted in two MRI progression risk scores, based on the combination of predictive radiologic features (score without gadolinium administration = 1 × dilatation of intrahepatic bile ducts + 2 × dysmorphy + 1 × portal hypertension; score with gadolinium administration = 1 × dysmorphy + 1 × parenchymal enhancement heterogeneity). These scores were associated with radiologic progression, with an area under the curve of 80 and 83% ± 4%.

A majority of PSC patients develop radiologic aggravation upon MRI over 4 years. Two simple scores can predict radiologic progression.

The impact of ulcerative colitis (UC) on the outcome of primary sclerosing cholangitis (PSC) outcome remains unclear.

To investigate whether the presence of UC is associated with a worse clinical of associated PSC.

A total of 222 patients with PSC (167 with UC and 55 without UC) seen and followed at a single centre from 1985 to 2011 were included. Clinical and demographic variables were obtained and patients were followed until the date of their last clinic visit.

The median age at presentation of PSC with associated UC was 38 vs. 47 years without UC (P < 0.001). At presentation, median serum bilirubin (2.1 vs. 4.5, P < 0.001) and the Mayo PSC Risk Score (0.95 vs. 1.69, P < 0.001) were lower in those with UC vs. those without UC. A total of 55 of 167 (32.9%) patients with PSC-UC developed colon neoplasia in contrast to 1 of the 55 (1.8%) patients with PSC. (P < 0.001) On proportional hazards analysis, UC (hazard ratio (HR) = 0.90 [95% confidence interval (CI): 0.60-1.34, P = 0.60] was not associated with death or orthotopic liver transplantation (OLT), when adjusting for gender, Mayo risk score and year of PSC diagnosis; whereas the revised Mayo risk score [HR = 5.08, 95% CI: (2.62-9.86), P < 0.001] was associated with a greater risk of OLT or death.

Primary sclerosing cholangitis often is recognised at an early stage in patients with concurrent ulcerative colitis; ulcerative colitis has no impact on long-term prognosis in terms of liver-related outcomes when adjusted for the severity of liver disease.

Several hepatobiliary abnormalities have been described in association with inflammatory bowel disease (IBD), including primary sclerosing cholangitis (PSC), small duct PSC, chronic hepatitis, cryptogenic cirrhosis, cholangiocarcinoma, and cholelithiasis. PSC is the most common biliary condition in patients with IBD, with an incidence ranging from 2.5% to 7.5%. PSC usually progresses insidiously and eventually leads to cirrhosis independent of inflammatory bowel disease activity. There is a very high incidence of cholangiocarcinoma and an elevated risk for developing colon cancer in patients with PSC. Medical therapy has not proven successful in slowing disease progression or prolonging survival. Treatment of symptoms due to cholestasis, such as pruritis and steatorrhea, is an important aspect of the medical care of patients with PSC. Our preferred treatment of pruritis due to cholestasis is with bile acid binding exchange resins, such as cholestyramine or colestipol. Endoscopic manipulation is recommended for treating complications of recurrent cholangitis or worsening jaundice in the setting of a dominant stricture, but endoscopic approaches have not been conclusively demonstrated to improve survival or decrease the need for liver transplantation. Liver transplantation remains the only effective treatment of advanced PSC, and should be considered in patients with complications of cirrhosis or intractable pruritis or fatigue.

One of typical examples of liver-gut cross talk is the interaction and impact of inflammatory bowel disease (IBD) and hepatobiliary (HB) abnormalities on each other's disease course. There are several layers of association between IBD and HB diseases: (i) HB diseases and IBD share pathogenetic mechanisms; (ii) HB diseases parallel structural and pathophysiological changes seen with IBD; and (iii) hepatic toxicity is associated with medical therapy for IBD. Interdisciplinary approach, involving gastroenterologists, hepatologists and, in advanced cases, general, colorectal, and liver transplant surgeons, is advocated.

Diseases involving the hepatopancreatobiliary (HPB) system are frequently encountered in patients with inflammatory bowel disease (IBD). Hepatobiliary manifestations constitute some of the most common extraintestinal manifestations of IBD. They appear to occur with similar frequency in patients with Crohn's disease or ulcerative colitis. HPB manifestations may occur in following settings: 1) disease possibly associated with a shared pathogenetic mechanism with IBD including primary sclerosing cholangitis (PSC), small-duct PSC/pericholangitis and PSC/autoimmune hepatitis overlap, acute and chronic pancreatitis related to IBD; 2) diseases which parallel structural and physiological changes seen with IBD, including cholelithiasis, portal vein thrombosis, and hepatic abscess; and 3) diseases related to adverse effects associated with treatment of IBD, including drug-induced hepatitis, pancreatitis (purine-based agents), or liver cirrhosis (methotrexate), and reactivation of hepatitis B, and biologic agent-associated hepatosplenic lymphoma. Less common HPB manifestations that have been described in association with IBD include autoimmune pancreatitis (AIP), IgG4-associated cholangitis (IAC), primary biliary cirrhosis (PBC), fatty liver, granulomatous hepatitis, and amyloidosis. PSC is the most significant hepatobiliary manifestation associated with IBD and poses substantial challenges in management requiring a multidisciplinary approach. The natural disease course of PSC may progress to cirrhosis and ultimately require liver transplantation in spite of total proctocolectomy with ileal-pouch anal anastomosis. The association between AIP, IAC, and elevated serum IgG4 in patients with PSC is intriguing. The recently reported association between IAC and IBD may open the door to investigate these complex disorders. Further studies are warranted to help understand the pathogenesis of HPB manifestations associated with IBD, which would help clinicians better manage these patients. An interdisciplinary approach, involving gastroenterologists, hepatologists, and, in advanced cases, general, colorectal, and transplant surgeons is advocated.

Most extrahepatic bile-duct carcinomas are usually diagnosed when they are already in an advanced stage, which is the main reason for the poor prognosis of this tumor.

To examine the usefulness of MRCP followed by EUS in the early diagnosis of extrahepatic bile-duct carcinoma in the nonicteric stage.

This study included patients who were nonicteric, who had abnormal serum concentrations of alkaline phosphatase and gamma glutamyl transpeptidase, and whose common hepatic duct was more than 8 mm in diameter on abdominal US because of unknown reasons.

A single-center, prospective study.

An academic medical center.

The sensitivity and specificity of MRCP followed by EUS for the early diagnosis of extrahepatic bile duct carcinoma in the nonicteric stage.

A total of 142 patients who were nonicteric underwent prospective MRCP, and 26 of them underwent EUS. Ten patients (5 with stricture, 4 with filling defect, and 1 with no stricture or filling defect) had extrahepatic bile-duct carcinoma, including 5 patients with an incidentally diagnosed T1 stage tumor. The sensitivity and specificity of MRCP followed by EUS were 90% and 98%, respectively.

A single center and small number of patients.

MRCP followed by EUS was highly sensitive and specific for the early diagnosis of extrahepatic bile-duct carcinoma in the nonicteric stage, including T1 stage tumors. Filling defects, as well as stenosis in the bile duct, are important MRCP findings of T1 stage carcinoma.

Magnetic resonance pancreatography (MRCP) is now established as a robust noninvasive tool for the evaluation of biliary and pancreatic pathology. Its diagnostic performance is comparable with endoscopic retrograde cholangiopancreatography without the associated risks. This article aims to familiarize the reader with the technique, clinical indications, and limitations of the investigation. Common pitfalls in interpretation also are addressed. Emerging applications and techniques are discussed that include recent advances in technology and the development of functional imaging.

Primary sclerosing cholangitis (PSC) is an important liver disease with major morbidity and mortality. The diagnosis of PSC is confirmed by magnetic resonance cholangiopancreaticography, and endoscopic retrograde cholangiopancreaticography is performed in patients needing therapeutic endoscopy. As a result of the unknown cause of the disease, current medical therapies are unsatisfactory. Nevertheless, high-dose ursodeoxycholic acid should be recommended for treatment of PSC patients because there is a trend toward increased survival. Dominant bile duct stenoses should be treated endoscopically. However, liver transplantation continues to be the only therapeutic option for patients with advanced disease. Estimation of prognosis and timing of liver transplantation should be determined individually for each PSC patient on the basis of all results. The diagnosis and treatment of cholangiocarcinoma (CC) still remain a challenge in PSC patients. Early diagnosis of CC certainly is a prerequisite for successful treatment with surgical resection or innovative strategies such as neoadjuvant radiochemotherapy with subsequent orthotopic liver transplantation. Therefore, endoscopic techniques such as cholangioscopy and/or intraductal ultrasound may be useful diagnostic tools in patients with stenoses suspicious for malignancy.

Primary sclerosing cholangitis (PSC) is associated with the development of cholangiocarcinoma (CC) in approximately 9% of patients. Neither cholangiography nor endoscopic tissue sampling can reliably distinguish between CC and benign dominant bile duct stenosis. The aim of the present study was to assess the value of intraductal ultrasonography (IDUS) in distinguishing between benign and malignant dominant stenoses in PSC patients.

Forty PSC patients with dominant bile duct stenoses were studied prospectively. Transpapillary IDUS and endoscopic tissue sampling were performed in addition to endoscopic retrograde cholangiography (ERC). Cholangiography and IDUS findings were classified as malignant or benign by the investigators. Final diagnosis of malignant stenosis was based on positive histology and/or cytology, whereas a benign character was assumed in cases of negative tissue sampling and uneventful extended clinical follow-up.

Eight PSC patients (20%) had dominant bile duct stenoses caused by CC, whereas 32 out of 40 patients (80%) had benign dominant bile duct stenoses. IDUS was significantly superior to ERC for detection of malignancy in terms of sensitivity (87.5% versus 62.5%, p=0.05), specificity (90.6% versus 53.1%, p<0.001), accuracy (90% versus 55%, p<0.001), positive predictive value (70% versus 25%, p<0.001), and negative predictive value (96.7% versus 85%, p=0.049).

Transpapillary IDUS significantly increases the ability to distinguish malignant from benign dominant bile duct stenoses in patients with PSC.

Primary sclerosing cholangitis (PSC) confers a high risk of development of hepatobiliary carcinoma (HBC). The aim of the study was to identify indicators and risk factors for developing HBC in PSC patients.

Thirty-nine PSC patients with HBC at time of HBC diagnosis were compared with 101 PSC patients without HBC at time of acceptance for liver transplantation.

Eighteen of these patients (46.2%) developed HBC within one year after diagnosis of PSC. In PSC patients with HBC male gender, nicotine abuse, long duration of inflammatory bowl disease (IBD), clinical symptoms, elevation of CA 19-9, as well as dominant bile duct stenosis were significantly more frequent (p<0.05) compared with the PSC control group. A cross-validated sensitivity and specificity of 85% and 97%, respectively, for the detection of HBC was obtained using the following parameters: weight loss, elevation of CA 19-9 >or= 200 kU/l, and dominant bile duct stenosis.

HBC is not necessarily a late complication of end-stage PSC. A long history of IBD, male gender, and nicotine abuse are risk factors for the development of HBC. In particular, CA 19-9, body-weight and dominant bile duct stenosis are valuable indicators in detecting HBC in PSC patients.

Primary sclerosing cholangitis is a progressive cholestatic disease of unknown etiology leading to cirrhosis and liver failure. Several imaging modalities have been used to study this disease, including ultrasonography, computed tomography and hepatobiliary scintigraphy, but accurate diagnosis was found to be best made with endoscopic retrograde cholangiopancreatography or direct cholangiography. However, these 2 methods are invasive and may produce serious complications. Magnetic resonance cholangiopancreatography is a noninvasive imaging technique that has become very useful for diagnosing primary sclerosing cholangitis. Contrast enhanced magnetic resonance imaging provides pertinent information of extraductal abnormalities in addition to biliary ductal changes.

Endoscopic therapy for biliary tract disease in patients with end-stage liver disease (ESLD) before liver transplantation is safe and effective. Reported results in patients with choledocholithiasis, primary sclerosing cholangitis (PSC), and symptomatic gallbladder diseases are encouraging. Prompt recognition and appropriate treatment of symptomatic gallbladder and bile duct disease are important in reducing morbidity and mortality in these high-risk patients while they await liver transplantation. Confirmation of tissue diagnosis of cholangiocarcinoma in patients with sclerosing cholangitis is still difficult. Better screening tools and diagnostic methods are necessary for early detection. Because liver transplantation is the only definitive therapy for patients with advanced cirrhosis, maintenance of their candidacy with either endoscopic or radiologic therapeutic interventions is warranted until transplantation. Endoscopic therapy is the preferred method when feasible. If necessary, percutaneous transhepatic biliary drainage (PTBD) is a viable alternative because both avoid the attendant risks of surgery in a high-risk population with advanced liver disease.

Assess the role of cholangioscopy in primary sclerosing cholangitis for 1) detection of cholangiocarcinoma using cholangioscopy-assisted biopsy 2) detection of stones not seen on cholangiography 3) stone removal with cholangioscopy-directed lithotripsy.

Prospective cohort of consecutive patients referred for cholangioscopy to evaluate dominant strictures or stones. A data collection sheet was employed. Follow-up was by chart review/phone contact. Clinical improvement was defined as resolution of jaundice or > or =50% reduction in pain or cholangitis episodes requiring hospitalization.

41 patients (30M, 11F) had 60 cholangioscopy procedures (55 per oral, 5 percutaneous). 33/41 (80%) patients underwent 44 tissue sampling events.

positive for extrahepatic cholangiocarcinoma (N = 1), negative/atypical (N = 31), and inadequate (N = 1). Stones were found in 23/41 (56%) patients, of which 7/23 (30%) were missed on cholangiography and detected only by cholangioscopy. 9/23 (39%) underwent cholangioscopy-directed lithotripsy. Stone clearance: complete (N = 10, 7 by cholangioscopy-directed lithotripsy after failed conventional stone extraction); partial (N = 7); and not attempted (N = 6). Median follow-up was 17.0 months (range 1-56). Clinical improvement was achieved in 25/40 (63%). Eight patients have undergone transplant and cholangiocarcinoma was present in the explant of two at 1 and 12 months post-cholangioscopy, respectively.

This is the first series of patients with primary sclerosing cholangitis undergoing cholangioscopy for the evaluation of dominant strictures and cholangioscopy-directed stone therapy with demonstrable clinical benefits. Stones detected by cholangioscopy were missed by cholangiography in nearly one of three patients. Cholangioscopy-directed lithotripsy may be superior to conventional ERCP for achieving complete stone clearance. Despite the use of cholangioscopy, diagnosis of cholangiocarcinoma remains technically challenging.

Inflammatory bowel disease (IBD) is associated with an increased risk of developing intestinal cancer at sites of chronic inflammation. Aminosalicylates, including both sulfasalazine and mesalamine, are the most commonly prescribed anti-inflammatory agents prescribed in IBD. On balance, the body of literature to date suggests that aminosalicylates confer some protection against the development of colonic neoplasia in patients with IBD and in a variety of models, including in the noninflamed gut. This latter observation implies that aminosalicylates may be of chemopreventive value in normal as well as IBD individuals. The current review examines and gives an overview of the evidence from a variety of sources, including epidemiological, in vivo and in vitro studies that have investigated the potential anticancer effects of aminosalicylates.

Hepatobiliary disorders occur frequently in patients with IBD, with PSC and cholangiocarcinoma being the most clinically significant for endoscopists. Endoscopic therapy for PSC is effective in improving symptoms, biochemical parameters, and radiographic abnormalities. Endoscopic therapy may also confer survival benefit, but this has yet to be confirmed in randomized, controlled trials. Treatment should be restricted to those individuals with a rapid decline in liver function testing or those with recurrent cholangitis. Cholangiocarcinoma is a serious complication of PSC and carries an extremely poor prognosis. ERCP with brush cytology has a relatively low sensitivity and the diagnosis is usually made after the disease has become metastatic. Malignant biliary obstruction can be palliated by endoscopic stenting. Photodynamic therapy is a promising experimental technique that may confer symptomatic and survival benefit in patients with nonresectable, advanced cholangiocarcinoma. IBD patients also have an elevated risk for developing acute and chronic pancreatitis as well as pancreatic insufficiency. The majority of cases of acute pancreatitis are likely due to medication side effects and local structural complications of IBD. The remainder may possibly represent true extraintestinal manifestations of IBD. Chronic pancreatitis is frequently subclinical, but may be accompanied by clinically relevant exocrine insufficiency. ERCP is the test of choice for the diagnosis of chronic pancreatitis, but the role of endoscopy in the therapeutic management of IBD-associated chronic pancreatitis remains to be defined.

The objective of our study was to determine the value of CT and cholangiography for diagnosing biliary tract carcinoma complicating primary sclerosing cholangitis.

One hundred thirteen abdominal CT examinations and cholangiograms in 45 patients with primary sclerosing cholangitis, including 18 patients with established biliary tract carcinoma, were analyzed for tumor. Four radiologists who were unaware of the presence or absence of carcinoma rated each study as to the probability of malignancy. Receiver operating characteristic curve analysis was used to assess the diagnostic performance of CT and cholangiography, the value of imaging signs, and the degree of inter-observer variation in interpretation. Sensitivity and specificity values were calculated.

CT outperformed cholangiography in the detection of carcinoma. The average area under the receiver operating characteristic curve was 0.82 for CT and 0.57 for cholangiography (p = 0.003). Sensitivity and specificity for detecting carcinoma using CT were good, with average values of 82% and 80%, respectively. Average sensitivity and specificity for cholangiography were 54% and 53%, respectively. The most reliable sign of tumor on CT was a discrete mass. Progressive biliary dilatation on sequential studies was the most useful sign on cholangiography. Interobserver agreement assessed using the Cronbach alpha was fair for cholangiography and good for CT.

CT provides good sensitivity and specificity and significantly outperforms cholangiography in detecting biliary tract carcinoma complicating primary sclerosing cholangitis. Despite limitations, CT and cholangiography provide useful information not otherwise available in the treatment of patients with primary sclerosing cholangitis.

The increased risk for cholangiocarcinoma in primary sclerosing cholangitis (PSC) is well established, but the factors responsible for the malignant development in the bile ducts in this disease are not known. The pathogenesis of cholangiocarcinoma in PSC including the role of chronic inflammation and oncogenic mutations will be discussed. Cholangiocarcinoma is a leading cause of death in PSC and the prognosis even after liver transplantation is poor, with a median survival after cancer diagnosis of 5 months. Therefore, it is of great importance to identify PSC patients who are at risk of developing cholangiocarcinoma in order to transplant them before cancer has developed.

[corrected] Hepatobiliary carcinoma (HBC) has been considered to be a late complication of end-stage primary sclerosing cholangitis (PSC). The incidence of HBC is approximately 20% in PSC patients evaluated for liver transplantation. The diagnosis of HBC is difficult, at least at an early stage and the prognosis is poor even after liver transplantation. The aim of the study was to look for signs and risk factors for developing hepatobiliary carcinoma in patients with PSC.

Thirty-six consecutive patients with PSC and HBC (32 with bile duct carcinoma, BDC, and four with hepatocellular carcinoma, HCC) were pair-matched to control patients referred for liver transplantation because of PSC but who did not have HBC. Gender and age at referral were used as matching factors. Clinical and biochemical data were registered.

PSC patients with BDC had a shorter median duration of PSC (1 year) compared with the controls (7 years) and PSC patients with HCC (8 years). There were no statistically significant differences in the liver biochemistry between the patient groups. Varices were more common in patients with PSC and HCC (100%) than in controls (56%) or patients with PSC and HBC (12%) (P < 0.0005).

The relatively short duration of PSC and the absence of varices in patients with BDC suggest that BDC, unlike HCC, is not necessarily a late complication of end-stage PSC, as was previously assumed.

The aims of this retrospective study were to assess the frequency with which we used different treatment modalities for patients with primary sclerosing cholangitis (PSC) and cholangiocellular carcinoma (CCA).

A total of 41 patients with known CCA complicating PSC with a median age of 49 yr (range, 27-75 yr) were identified from a group of 1009 patients (4%) with PSC seen over 10 yr at the Mayo Clinic.

These patients received mainly five forms of treatment: 10 patients were treated with radiation therapy (RT) with or without 5-fluorouracil (5-FU) (seven with palliative and three with curative intent), nine with stent placement for cholestasis, 12 with conservative treatment, four with surgical resection (one of four received RT and 5-FU), and three patients with orthotopic liver transplantation and RT, with or without 5-FU. One patient was treated with 5-FU alone, one with photodynamic therapy, and one patient with somatostatin analog. A total of 36 patients died, whereas four (10%) patients survived (two with surgical resection, one with orthotopic liver transplantation and RT, and one with stent placement) during a median follow-up of 5.5 months (range, 1-75 months). One patient was lost to follow-up.

In highly selective cases, resective surgery seems to be of benefit in PSC patients with CCA. However, these therapies are rarely applied to these patients because of the advanced nature of the disease at the time of diagnosis. Efforts should be directed at earlier identification of potential surgical candidates.

1. The major identified risk factor for the development of cholangiocarcinoma in Western countries is primary sclerosing cholangitis (PSC). 2. The diagnosis of cholangiocarcinoma in PSC requires a high index of suspicion because endoscopic brush cytology and/or biopsies and imaging studies are often negative for malignancy. Positron emission tomography is a promising imaging modality for the diagnosis of cholangiocarcinoma, even in patients with PSC. 3. A serum carbohydrate antigen 19-9 value greater than 100 U/mL has a sensitivity and specificity for cholangiocarcinoma of approximately 75% and 80%, respectively. 4. Liver transplantation is a viable therapeutic option for selected patients with early-stage cholangiocarcinoma. Outcomes are optimized by using preoperative radiation and chemotherapy and ensuring the absence of metastases by an exploratory laparotomy.

Magnetic resonance cholangiopancreatography (MRCP) is a relatively new, noninvasive cholangiographic technique that is comparable with invasive endoscopic retrograde cholangiopancreatography (ERCP) in the detection and characterization of extrahepatic bile duct abnormalities. The role of MRCP in evaluation of the intrahepatic bile ducts, especially in patients with primary or secondary sclerosing cholangitis, is under investigation. The key cholangiographic features of primary sclerosing cholangitis are randomly distributed annular strictures out of proportion to upstream dilatation. As the fibrosing process worsens, strictures increase and the ducts become obliterated, and the peripheral ducts cannot be visualized to the periphery of the liver at ERCP. In addition, the acute angles formed with the central ducts become more obtuse. With further progression, strictures of the central ducts prevent peripheral ductal opacification at ERCP. Cholangiocarcinoma occurs in 10%-15% of patients with primary sclerosing cholangitis; cholangiographic features that suggest cholangiocarcinoma include irregular high-grade ductal narrowing with shouldered margins, rapid progression of strictures, marked ductal dilatation proximal to strictures, and polypoid lesions. Secondary sclerosing and nonsclerosing processes can mimic primary sclerosing cholangitis at cholangiography. These processes include ascending cholangitis, oriental cholangiohepatitis, acquired immunodeficiency syndrome-related cholangitis, chemotherapy-induced cholangitis, ischemic cholangitis after liver transplantation, eosinophilic cholangitis, and metastases.

To determine the accuracy of magnetic resonance (MR) cholangiography for detection of primary sclerosing cholangitis (PSC) and localization of PSC in the biliary tract.

In a prospective case-control study involving 102 patients, the MR cholangiograms obtained in 34 patients with PSC established with endoscopic retrograde cholangiopancreatography (ERCP) were compared with the MR cholangiograms obtained in 68 age-matched control patients with hepatobiliary diseases other than PSC. Two abdominal radiologists conducted an independent, blinded random review of the MR cholangiograms to assess for the presence or absence of PSC and determine the location of PSC in the biliary tract, and then compared the findings with those at ERCP.

MR cholangiography was found to be accurate in detecting PSC and in defining the extent of disease. In the detection of PSC, the sensitivities were 88% and 85%; specificities, 97% and 92%; positive predictive values, 94% and 85%; and negative predictive values, 94% and 93% for readers 1 and 2, respectively. Interobserver agreement was excellent (kappa = 0.79). In the localization of extrahepatic PSC, the sensitivities were 83% and 89%; and specificities, 83% and 83% for readers 1 and 2, respectively. Interobserver agreement was good (kappa = 0.62). In the localization of intrahepatic PSC, the sensitivity was 87% for both readers; interobserver agreement was good (kappa = 0.71).

MR cholangiography enables accurate detection and localization of PSC.

Patients with primary sclerosing cholangitis (PSC) have a substantial predisposition to develop bile duct carcinoma. The mechanism is still unclear but the observation that patients with chronic Clonorchis sinensis infection are also prone to cholangiocarcinoma suggests a role for long standing inflammation. However, there is still no effective medical therapy which can halt the progression of the disease or prevent the development of cholangiocarcinoma. The only effective treatment for advanced PSC is orthotopic liver transplantation (OLT) which in the absence of cholangiocarcinoma has a 5 year survival of 89%. Patients with cholangiocarcinoma who undergo liver transplantation have a high risk of recurrence and a dramatically worse survival. Therefore, the identification of patients with a sufficient deterioration in liver function to warrant OLT before they develop cholangiocarcinoma remains a central goal in the management of PSC. Ideally, screening patients with PSC would allow the identification of those with dysplastic change in the biliary epithelia before the development of overt carcinoma. However, although serum tumour markers such as CA 19.9 and CEA can be of value in aiding the diagnosis of cholangiocarcinoma in PSC there is currently no evidence that they are helpful in identifying those patients with premalignant changes of the biliary epithelia who would benefit from surgery. There are also no genetic markers to identify those at particular risk of malignant change. A recent report has suggested that regular biliary cytology sampling to detect dysplasia can predict the development of cholangiocarcinoma. However, regular instrumentation of the biliary tree to obtain cytology is unlikely to be widely adopted.

Patients with primary sclerosing cholangitis (PSC) are at increased risk of developing cholangiocarcinoma, which adversely affects their survival especially after orthotopic liver transplantation. All CT scans of patients with PSC referred to the Liver Unit at the Queen Elizabeth Hospital since 1992 were reviewed. The location of any lymph node with a short axis diameter greater than normal was documented. The incidence of lymphadenopathy and cholangiocarcinoma was also documented. 36 scans are reviewed, including eight with cholangiocarcinoma as well as PSC. Abdominal lymphadenopathy was present in 26 cases (66%) and 45 separate lymph node groups were involved in these patients. There were eight cases of cholangiocarcinoma; five were detectable on CT, but only four had significant lymphadenopathy. The remaining three cases of cholangiocarcinoma were not detectable on CT and only one of these had lymphadenopathy. Follow-up of the remaining patients has not demonstrated the development of cholangiocarcinoma. Lymphadenopathy is commonly demonstrated by CT in PSC patients, but does not imply malignancy and should not exclude a patient from undergoing liver transplantation. Conversely cholangiocarcinoma may develop without significant lymphadenopathy.

Chronic cholestatic liver disease may be complicated by hepatobiliary malignancy. The early detection of hepatocellular carcinoma and cholangiocarcinoma is of paramount importance in the evaluation of candidates for liver transplantation, which remains the only effective treatment modality for advanced primary biliary cirrhosis and primary sclerosing cholangitis. This article reviews the identification of patients at high risk, current techniques for diagnosis, and makes recommendations for screening high-risk patients. This article also reviews preliminary data from the Mayo Clinic regarding liver transplantation for cholangiocarcinoma following radiation therapy.

The purpose of this study was to assess the efficacy of spiral computed tomography (CT) in determining the etiology of biliary tract obstruction. Spiral CT studies performed over a 9-month period in 42 consecutive patients with suspected biliary tract obstruction were reviewed. Analysis of scans included localizing the obstruction and then defining a specific etiology. Pertinent associated findings such as porta hepatis or peripancreatic adenopathy, hepatic or peritoneal metastases, and pancreatic pseudocyst or abscess formation were also assessed. Spiral CT demonstrated the level of obstruction in all 30 patients in whom there was biliary tract dilatation. Thirty-two diagnoses were rendered in 30 patients, with specific obstructing lesions identified in 28 instances (88%). Twenty-five (78%) of 32 specific pathological diagnoses were correct. The positive predictive value for neoplasms in the pancreatic head was 100% (n = 17). Two patients with characteristic CT changes of sclerosing cholangitis were diagnosed as having superimposed cholangiocarcinoma, although the results of biopsies for neoplasm were negative. The sensitivity of spiral CT for detection of common duct calculi was 67% (n = 3). Due to optimal contrast enhancement of both hepatic and pancreatic parenchyma, spiral CT enables excellent visualization of the biliary system and provides a specific explanation for biliary tract obstruction in nearly all cases. Spiral CT can usually distinguish neoplastic from nonneoplastic causes of jaundice. When distal common duct obstruction is detected in the absence of an identifiable mass or focal ductal wall thickening, neoplasia is unlikely. It is difficult to exclude sclerosing cholangitis from cholangiocarcinoma on the basis of spiral CT findings, and in these patients, biopsy or close follow-up is recommended to exclude the possibility of a biliary neoplasm.

The c-fos gene encodes a 55 kDa nuclear protein product that complexes to a cellular protein, p39. The pattern of expression of c-fos is particularly complex with increased expression of the protein observed in undifferentiated cultured cells while reduced expression is found during terminal differentiation. The expression of c-fos gene was studied by immunohistochemistry in carcinoma of the gall-bladder (n = 13), biliary tract (n = 5) and ampulla of Vater (n = 9). Non-malignant conditions investigated include chronic cholecystitis (n = 11), gall-bladder dysplasia (n = 3) and adenoma (n = 1), and ampullary carcinoma in situ (n = 3). Strong positive granular cytoplasmic immunostaining for c-fos oncoprotein was present in most gall-bladder adenocarcinomas (n = 11; 85%). The single gall-bladder adenoma and only one of the dysplasia cases were positive. Most of the cases of chronic cholecystitis showed either absent or only focal to patchy and weak to moderate c-fos immunoreactivity in the deeper glands and Rokitansky-Aschoff sinuses but not in the superficial epithelium. None of the biliary tract and ampullary tumors showed immunostaining for c-fos. The difference in c-fos immunoreactivity between gall-bladder carcinoma and chronic cholecystitis was statistically significant (P = 0.0002; chi 2 test with continuity correction). In conclusion, c-fos protein may be important in the development of gall-bladder neoplasia with increased c-fos immunoreactivity in gall-bladder carcinoma but not in chronic cholecystitis, biliary tract and ampullary neoplasms. These findings suggest that gall-bladder carcinoma may arise from a different genetic basis compared to biliary tract and ampullary cancers.

The majority of cholestatic liver diseases can be diagnosed with a carefully performed history taking, physical examination, and appropriate imaging studies. In a minority of cases, however, liver biopsy may be necessary to establish the diagnosis. In addition to the treatment of the specific liver disease, therapy should address the management of complications unique to cholestasis and progressive liver failure.

The diagnosis of cholangiocarcinoma in primary sclerosing cholangitis (PSC), even with the use of current imaging techniques and brush cytology, is difficult and particularly important in patients being assessed for liver transplantation. This study investigated the accuracy of serum levels of a combination of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in the diagnosis of cholangiocarcinoma in patients with PSC.

Seventy-four patients with PSC were studied. Fifteen patients had tumors (11 occult on imaging), 22 had severe PSC that necessitated transplantation (with explanted liver known to be free of tumor), and 37 patients had stable PSC.

An index of the two serum tumor markers [using the formula CA19-9 + (CEA x 40)] gave an accuracy of 86% in diagnosis of cholangiocarcinoma, with 10 of the 15 cases of cholangiocarcinoma having an increased value compared with none in a group of 22 comparable cases with no tumor. In addition, 6 of the 11 patients with occult tumors had abnormal values. Ultrasonography, computerized tomographic scanning, and endoscopic retrograde cholangiopancreatography were poor predictors of the presence of tumor.

A combination of serum tumor markers will identify most occult tumors and will improve selection of appropriate cases for orthotopic liver transplantation.

To determine the value of sonography of the upper abdomen in primary sclerosing cholangitis (PSC).

In a prospective study of 23 patients with PSC we performed upper abdominal sonography. Sonographic findings of the bile ducts were correlated with endoscopic retrograde cholangiographic (ERC) findings. Signs of advanced disease and complications were also sought.

The major limitation of ultrasound was its inability to exclude intrahepatic duct disease. In six patients with multiple strictures and pruning but without dilatations on ERC, sonography showed no intrahepatic duct abnormalities. Extrapheptic duct disease was adequately demonstrated on ultrasound. Mural thickening of the common bile duct (CBD), the hallmark of PSC in the appropriate clinical setting, was demonstrated in 17 of 18 cases with a stenosis on ERC. Ultrasound confirmed advanced disease manifested by signs of portal hypertension in seven patients. Marked nonsegmental intrahepatic duct dilation and the presence of a mass lesion occurred in two of three cases in which complicating cholangiocarcinoma was found.

Despite its inability to exclude intrahepatic duct disease, sonography is useful in diagnosing and following PSC.

Several hepatobiliary disorders may be associated with inflammatory bowel disease (IBD). These various disease states can be diagnosed before, concomitant with, or after the diagnosis of IBD is made. This article describes these disorders, clinical features, evaluation, and possible treatment.