Sclerosing Cholangitis

Background

This is a progressive and devastating disease involving the bile ducts occurring both inside and outside the liver. The disease begins with inflamation leading to scarring and eventual blockage of the ducts. Since the ducts carry bile out of the liver, an obstruction leads to damage to liver cells and may eventually cause liver failure.

This disease is more common in me, usually beginning between ages 30 and 60. The disease usually has an insidious onset and may slowly progress for several years. Symptoms may be subtle and include itching, fatigue, and jaundice. Rarely, malignancy may supervene upon the disease.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

AGE 3rd to 5th decades

SEX Males

GEOGRAPHY

SINGAPORE

Clinical profile of primary sclerosing cholangitis in Singapore.

Ang TL, Fock KM, Ng TM, Teo EK, Chua TS, Tan JY.

Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore.
J Gastroenterol Hepatol 2002 Aug;17(8):908-13 Abstract quote
BACKGROUND AND AIM: Primary sclerosing cholangitis (PSC) is a rare chronic disease in Singapore and its epidemiological profile has not been described previously. The present study aimed to define the demographic and clinical profile of patients with PSC in Singapore.

METHODS: The case records of patients with PSC seen at Changi General Hospital were analyzed in terms of demographic profile, clinical presentation, clinical course, treatment and complications.

RESULTS: Ten cases of PSC were diagnosed over a 10-year period. The male:female ratio was 9:1. The median age of diagnosis was 49.5 years (mean: 50.9 years; range: 35-63 years). With regards to clinical presentation, seven patients had hepatobiliary sepsis, two patients had asymptomatic liver biochemistry abnormalities while one patient had cholestatic jaundice. Prevalence rate of perinuclear antineutrophil cytoplasmic antibody (pANCA) was 20%. Symptomatic inflammatory bowel disease (IBD) was diagnosed in 20% of PSC cases. Eight patients (80%) had intrahepatic ductal involvement while two patients (20%) had combined intrahepatic and extrahepatic ductal involvement on endoscopic retrograde cholangiopancreatography (ERCP). The prevalence rate of recurrent cholangitis was 30% while that of recurrent liver abscess, cirrhosis and common bile duct stricture were all 10%. The mean duration of follow up was 6.6 years with one death from liver failure.

CONCLUSION: The clinical profile of patients with PSC in Singapore appears to differ with other published data, with a greater number presenting with hepatobiliary sepsis and less frequent association with IBD and pANCA. It is hypothesized that this may be related to differences in environmental triggers and genetic susceptibility.

DISEASE ASSOCIATIONS CHARACTERIZATION

CELIAC DISEASE

Association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in female siblings.

Habior A, Rawa T, Orlowska J, Sankowska M, Lewartowska A, Tilszer A, Pawlak J, Krawczyk M, Butruk E.

Department of Gastroenterology, Medical Centre for Postgraduate Education, Institute of Oncology, W.K. Roentgena 5, 02-781 Warsaw, Poland.

Eur J Gastroenterol Hepatol 2002 Jul;14(7):787-91 Abstract quote
Primary sclerosing cholangitis is a rare, cholestatic liver disease, most commonly affecting young men. The association of primary sclerosing cholangitis with other autoimmune disorders, although rare, indicates a genetic predisposition for this disease.

We describe, for the first time, the association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in two sisters. Ulcerative colitis was mild and preceded liver disease in both patients. There were no symptoms of coeliac disease, and its silent form was diagnosed on the basis of serological tests. Both patients carried HLA molecules DR3 and DQ2.

Although HLA DR4 was not found, there was a rapid progression of liver disease to cirrhosis and cholangiocarcinoma in one patient. The familial occurrence of primary sclerosing cholangitis, ulcerative colitis and coeliac disease supports the hypothesis of genetic predisposition for these diseases.

CROHN'S DISEASE

HEPATITIS

Autoimmune hepatitis overlapping with primary sclerosing cholangitis.

Takiguchi J, Ohira H, Rai T, Shishido S, Tojo J, Sato Y, Kasukawa R, Watanabe H, Funabashi Y, Kumakawa H.

Second Department of Internal Medicine, Fukushima Medical University School of Medicine.

Intern Med 2002 Sep;41(9):696-700 Abstract quote
A case of autoimmune hepatitis (AIH) complicated by primary sclerosing cholangitis (PSC) in a 36-year-old woman is reported. AIH overlapping with PSC has been rarely reported, and to the best of our knowledge, there have been no reports in Japan.

Based on the criteria for diagnosis of AIH and on typical endoscopic retrograde cholangiograph (ERC) findings, the patient was diagnosed as having AIH overlapping with PSC. Her transaminase levels normalized within 1 month after administration of prednisone, azathioprine and ursodeoxycholic acid, but her cholestatic enzyme level remained elevated.

The effect of treatment on the cholestatic features is thought to be an important factor for predicting the prognosis of AIH overlapping with PSC.

LICHEN PLANUS

Concurrent oral lichen planus and primary sclerosing cholangitis.

Tong DC, Ferguson MM.

Department of Stomatology, University of Otago, PO Box 647, Dunedin, New Zealand.

Br J Dermatol 2002 Aug;147(2):356-8 Abstract quote
Four patients with concomitant oral lichen planus (OLP) and primary sclerosing cholangitis (PSC) are presented.

Associations have been made between OLP and chronic liver disease, namely hepatitis C and primary biliary cirrhosis, but the aetiology and commonality between the diseases has yet to be confirmed.

An immunological link is currently favoured. PSC may be a further association with OLP, possibly involving the immune system.

PANCREATITIS

IgG4-related Sclerosing Cholangitis With and Without Hepatic Inflammatory Pseudotumor, and Sclerosing Pancreatitis-associated Sclerosing Cholangitis: Do They Belong to a Spectrum of Sclerosing Pancreatitis?

Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, Kurumaya H, Katayanagi K, Masuda S, Niwa H, Morimoto H, Miwa A, Uchiyama A, Portmann BC, Nakanuma Y.

*Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; daggerDepartment of Pathology, Fukui Saiseikai Hospital, Fukui, Japan; double daggerFirst Department of Pathology, Toyama Medical and Pharmaceutical University School of Medicine, Toyama, Japan; section signDepartment of Pathology, Kurobe City Hospital, Kurobe, Japan; paragraph signDepartment of Pathology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan; Department of Pathology, Kouseiren Takaoka Hospital, Takaoka, Japan; **Department of Gastroenterology, Kanazawa National Hospital, Kanazawa, Japan; daggerdaggerDepartment of Pathology, Toyama Prefectural Central Hospital, Toyama, Japan; and double daggerdouble daggerInstitute of Liver Studies, King's College Hospital, London, UK.

Am J Surg Pathol. 2004 Sep;28(9):1193-1203. Abstract quote

Sclerosing cholangitis (SC) is a heterogeneous disease entity. Different etiologies such as choledocholithiasis, biliary tumor, or pericholangitis can manifest as SC. Hepatic inflammatory pseudotumor (IP) is rarely associated with SC (sclerosing cholangitis associated with hepatic inflammatory pseudotumor; SC-hepatic IP), but sclerosing pancreatitis (SP) is not infrequently associated with bile duct lesions (sclerosing pancreatitis-associated sclerosing cholangitis; SP-SC).

In this study, we compared the histologic changes of hepatic hilar and extrahepatic bile duct lesions of SC (7 cases), SC-hepatic IP (5 cases), SP-SC (5 cases), and typical primary sclerosing cholangitis (PSC) (5 cases). Histologically, all SP-SC cases showed extensive and dense fibrosis with marked lymphoplasmacytic infiltration, many eosinophils, and obliterative phlebitis. Four cases of SC showed bile duct lesions similar to those of SP-SC, whereas other three cases of SC showed milder lymphoplasmacytic infiltration, scant eosinophilic cell infiltration, and no obliterative phlebitis. All SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC. Immunohistochemically, many IgG4-positive plasma cells were found in the bile duct lesions of all SP-SC cases, 4 SC cases with marked lymphoplasmacytic infiltration, and all SC-hepatic IP cases. By contrast, IgG4-positive plasma cells were scarce or hardly found in the remaining 3 SC cases and all PSC cases.

In conclusion, 4 SC cases and all SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC, suggesting that these three conditions may be a single disease entity. Their pathogenesis may be similar or closely related to that of SP, and in that respect they may represent an IgG4-related biliary disease. They may respond to steroid therapy as SP does.

Primary sclerosing cholangitis associated with autoimmune pancreatitis.

Ichimura T, Kondo S, Ambo Y, Hirano S, Ohmi M, Okushiba S, Morikawa T, Shimizu M, Katoh H.

Department of Surgical Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, N14 W5 Sapporo, 060-8638 Japan.
Hepatogastroenterology 2002 Sep-Oct;49(47):1221-4 Abstract quote
We present 2 cases of primary sclerosing cholangitis complicated with autoimmune pancreatitis with narrowing of the pancreatic duct.

In both cases, endoscopic retrograde cholangiography showed the characteristic findings of primary sclerosing cholangitis. In addition, positivity for autoantibody, hypergamma-globulinemia and narrowing of the pancreatic duct shown on endoscopic retrograde pancreatography were noticed in both. They were thus diagnosed as autoimmune pancreatitis. Whereas it is well known that primary sclerosing cholangitis is often complicated with chronic pancreatitis, it has rarely been studied whether the chronic pancreatitis is autoimmune pancreatitis or not.

In English literature, possibly 7 equivalent cases have been reported so far. In those cases, the onset was in the post-prime of life, and the disease was frequently accompanied with Sjogren's syndrome, but not with ulcerative colitis; frankly the nature of the disease was slightly different from what has traditionally been thought as a typical primary sclerosing cholangitis.

In primary sclerosing cholangitis complicated with autoimmune pancreatitis, the autoimmune mechanism seems to be much involved, and thus steroid therapy might be effective as in Case 2 in our series.

PREGNANCY

Pregnancy in a patient with primary sclerosing cholangitis.
Gossard AA, Lindor KD.

Divison of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, USA.
J Clin Gastroenterol 2002 Oct;35(4):353-5 Abstract quote
Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome that is characterized by fibrosing inflammatory destruction of intra- and/or extrahepatic biliary ducts. The etiology is unknown and there is no known effective treatment. The course of PSC is quite variable; however, the disease is typically slowly progressive. There is little known regarding the natural history and potential complications of pregnancy in a patient with PSC.

This case report details a 36-year-old woman with PSC who became pregnant. The pregnancy was complicated by the development of dominant stricture. A healthy baby boy was delivered at 33.5 weeks. The mother required cholangiography and stent placement immediately after delivery, but her postpartum course was otherwise unremarkable.

ULCERATIVE COLITIS

PATHOGENESIS CHARACTERIZATION

APOPTOSIS

Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis.

Tinmouth J, Lee M, Wanless IR, Tsui FW, Inman R, Heathcote EJ.

Department of Medicine, University Health Network, Toronto, Ontario, Canada.

Liver 2002 Jun;22(3):228-34 Abstract quote
BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestatic liver disease where the bile ducts are also destroyed. In this study, apoptosis and portal triad inflammation in liver tissue from patients with PBC is examined and compared to that from patients with PSC and patients with normal liver.

METHODS: Explanted liver tissue from patients with PBC and PSC and normal liver from patients with metastases to liver were examined. The liver samples were stained for apoptosis using the terminal deoxynucleotidyl triphosphate (TdT)-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay. The biliary epithelial cells (BEC) were then scored on the basis of their TUNEL stain and the degree of periductal inflammation.

RESULTS: In PBC, apoptosis of BEC, as detected by the TUNEL assay, was significantly increased in the presence of inflammation. Regardless of the presence or absence of inflammation, the small bile ducts in PBC liver tissue exhibited greater evidence of apoptosis than did similar ducts from PSC or control livers.

CONCLUSION: These findings suggest that in PBC, unlike PSC, the apoptosis of BEC in PBC is secondary to the invasion of inflammatory cells.

CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE

Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis.

Girodon E, Sternberg D, Chazouilleres O, Cazeneuve C, Huot D, Calmus Y, Poupon R, Goossens M, Housset C.

Service de Biochimie et de Genetique, AP-HP and INSERM U468, Hopital Henri Mondor, 94010 Creteil, France.
J Hepatol 2002 Aug;37(2):192-7 Abstract quote
BACKGROUND/AIMS: Because biliary tract lesions that resemble those of primary sclerosing cholangitis (PSC) may occur in cystic fibrosis (CF), we examined the prevalence and influence of CF transmembrane conductance regulator (CFTR) gene mutations in PSC patients.

METHODS: Genomic DNA was analyzed in 29 consecutive PSC patients and in 115 healthy control individuals. A scanning method followed by direct DNA sequencing was used to scan the CFTR coding regions.

RESULTS: Four patients (13.8%) were heterozygous for a CFTR mutation, including a new putative severe CF-causing mutation (N782K), and three mild defects (L997F, D1270N, and S1235R). The comparison of PSC patients with healthy controls showed no significant difference in the frequency of CFTR mutations (P=0.415). In addition, two patients (6.9%) were heterozygous for the IVS8-5T allele, which is not significantly different from the 5-6%-prevalence in the general population. Unusual clinical features including a severe outcome in childhood, with a lethal outcome at age 22, and biliary aspergillosis were recorded in patients with a CFTR mutation.

CONCLUSIONS: The proportion of CF carriers is not significantly higher in PSC patients than in the general population. The possibility that CFTR mutations may contribute to a severe clinical course in PSC patients is worth further examining.

INFECTION

A survey of infectious agents as risk factors for primary sclerosing cholangitis: are Chlamydia species involved?

Ponsioen CY, Defoer J, Ten Kate FJ, Weverling GJ, Tytgat GN, Pannekoek Y, Wertheim-Dillen PM.

Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
Eur J Gastroenterol Hepatol 2002 Jun;14(6):641-8 Abstract quote
OBJECTIVES: The aetiology of primary sclerosing cholangitis (PSC) is unknown, and the role of micro-organisms has been studied only to a limited extent. We tested the hypothesis that past or persisting infection with common viruses or atypical bacteria might play a role in genetically susceptible hosts. DESIGN: Case-control study.

METHODS: Serological screening for antibodies against 22 viruses as well as Chlamydia spp. and Mycoplasma pneumoniae was carried out in 41 well-established PSC patients. All 5110 sera tested in 1997 for these micro-organisms at our laboratory served as a background reference group. Subsequently, Chlamydia anti-lipopolysaccharide (LPS) antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in the PSC group and in three race-matched control groups (inflammatory bowel disease (IBD) group, n = 35; non-IBD patients group, n = 39; healthy blood donor group, n = 40). Subtyping in Chlamydia trachomatis and C. pneumoniae serotypes by specific anti-major outer membrane protein (MOMP) assays was carried out in the four groups. Immunohistochemical staining using specific markers for chlamydiae was carried out on liver biopsies of 14 PSC patients.

RESULTS: There was a markedly elevated seroprevalence of Chlamydia-LPS antibodies compared with the 1997 reference group. The odds ratios (ORs) for the presence of immunoglobulin G, immunoglobulin M and immunoglobulin A antibodies for the PSC patients versus the control group were 2.4 (95% confidence interval (CI) 1.1 to 5.4), 1.9 (95% CI 0.9 to 4.0) and 6.7 (95% CI 3.0 to 17.0), respectively. All other micro-organisms tested showed normal antibody profiles that did not differ from the 1997 reference group. The seroprevalence of Chlamydia-anti-LPS antibodies was elevated markedly in the PSC patients compared with the IBD, non-IBD and blood donor groups. The outcomes in the C. trachomatis and C. pneumoniae anti-MOMP assays did not correlate with the anti-LPS-positive PSC sera. The actual presence of Chlamydia bodies in liver tissue could not be demonstrated.

CONCLUSION: Our findings suggest an association between PSC and (previous) infection with Chlamydia.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

MR Imaging Features of Primary Sclerosing Cholangitis: Patterns of Cirrhosis in Relationship to Clinical Severity of Disease.

Bader TR, Beavers KL, Semelka RC.

Departments of Radiology and Internal Medicine, University of North Carolina at Chapel Hill, 101 Manning Dr, CB 7510, Chapel Hill, NC 27599-7510; and Department of Radiology, University of Vienna, Austria.
Radiology 2003 Mar;226(3):675-85 Abstract quote
PURPOSE: To evaluate the spectrum of magnetic resonance (MR) imaging appearances of the liver in primary sclerosing cholangitis (PSC) and to examine their correlation with clinical stage of disease.

MATERIALS AND METHODS: Fifty-two patients (25 female, 27 male; mean age, 43 years; age range, 11-87 years) with PSC underwent nonenhanced and gadolinium-enhanced MR imaging. Two abdominal radiologists retrospectively reviewed all images (independently and then in consensus) for the imaging pattern of the liver parenchyma, presence and grade of intrahepatic biliary ductal dilatation, and presence of areas of parenchymal atrophy or abnormal signal intensity and/or gadolinium enhancement. Imaging findings were correlated with Child class, Child-Turcotte-Pugh score, and Mayo end-stage liver disease (MELD) score. Statistical analyses (kappa scoring for interobserver agreement, McNemar test, Mann-Whitney U test, multiple regression analysis, Spearman correlation) were performed.

RESULTS: Of 52 patients, seven (13%) had no imaging findings of cirrhosis, 17 (33%) had a diffuse pattern of cirrhosis, and 28 (54%) had a large macronodular pattern (with nodules >/=3 cm) (kappa = 0.84). Intrahepatic biliary ductal dilatation was observed in 44 (85%) patients and was general in 18 (35%) and segmental in 26 (50%). Peripheral wedge-shaped areas of parenchyma were observed with atrophy in 23 (44%) and 25 (48%) patients by the two readers (kappa = 0.76) and without atrophy in 18 (35%) patients by both readers (kappa = 1.00). No correlation was found between imaging findings and clinical scores (P >.05, multiple regression analysis; P =.25-.75, Mann-Whitney U test; Spearman correlation coefficients between -0.33 and 0.33).

CONCLUSION: The spectrum of MR imaging appearances of PSC is diverse and comprises distinct patterns that do not appear to correlate with severity of disease. Large regenerative nodules are a frequent finding and may help to establish the diagnosis.

Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis.

Lindberg B, Arnelo U, Bergquist A, Thorne A, Hjerpe A, Granqvist S, Hansson LO, Tribukait B, Persson B, Broome U.

Department of Radiology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.
Endoscopy 2002 Nov;34(11):909-16 Abstract quote
BACKGROUND AND STUDY AIMS: Strictures of the bile ducts due to malignant changes are difficult to distinguish from benign changes, particularly in patients with primary sclerosing cholangitis (PSC). The aim of this study was to evaluate diagnostic methods for malignancy in biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography (ERCP).

PATIENTS AND METHODS: Bile duct strictures were identified during ERCP in 57 patients, who were thus included in the present study. Brush samples from the strictures were taken for cytology and for evaluation of DNA content by flow cytometry. The tumor markers CA 19-9 and CEA were determined both in serum and bile fluid. Two independent radiologists evaluated all cholangiograms. The diagnostic sensitivity, specificity, and accuracy of each diagnostic method were evaluated separately and in combination.

RESULTS: 32 patients were found to have malignant strictures and when the four methods: brush cytology, DNA analysis, serum CA 19-9 and serum CEA were combined, a diagnostic sensitivity of 88 % and specificity of 80 % were reached. Seven of the 20 patients with PSC were found also to suffer from cholangiocarcinoma, yielding a sensitivity and specificity of 100 % and 85 %, respectively. Analyses of CA 19-9 and CEA in bile fluid had no diagnostic significance.

CONCLUSION: An ERCP procedure with brush cytology, a DNA analysis, combined with serum analysis of CA 19-9 and CEA, can increase the possibility of distinguishing between malignant and benign biliary strictures, especially in PSC patients.

MR cholangiopancreatography in patients with primary sclerosing cholangitis: interobserver variability and comparison with endoscopic retrograde cholangiopancreatography.

Vitellas KM, El-Dieb A, Vaswani KK, Bennett WF, Tzalonikou M, Mabee C, Kirkpatrick R, Bova JG.

Department of Radiology, The Ohio State University Medical Center, 171 Means Hall, 1654 Upham Dr., Columbus, OH 43210-1250, USA.

AJR Am J Roentgenol 2002 Aug;179(2):399-407 Abstract quote
OBJECTIVE: The purpose of our study was to determine the degree of interobserver variability and correlation between MR cholangiopancreatography and endoscopic retrograde cholangiopancreatography (ERCP) for the presence of bile duct strictures in patients with primary sclerosing cholangitis.

MATERIALS AND METHODS: For this retrospective study involving 26 patients with primary sclerosing cholangitis, 31 MR cholangiopancreatograms were compared with 30 endoscopic retrograde cholangiopancreatograms. The MR cholangiopancreatograms were independently interpreted by two abdominal radiologists in a blinded, randomized manner for overall image quality, extent of ductal visualization, and the presence and location of bile duct strictures. Unweighted multirater kappa coefficient values were estimated for each comparison.

RESULTS: Visualization of more than 50% of the expected ductal length was possible in the extrahepatic, central intrahepatic, and peripheral intrahepatic bile ducts in 99%, 88%, and 69% of the MR cholangiopancreatograms and 100%, 86%, and 52% of the endoscopic retrograde cholangiopancreatograms, respectively. Strictures were detected in the extrahepatic, central, and peripheral ducts in 53%, 68%, and 87% of the MR cholangiopancreatograms and 73%, 67%, and 63% of the endoscopic retrograde cholangiopancreatograms, respectively. The interobserver agreement for stricture detection was 61% for MR cholangiopancreatography and 76% for ERCP. MR cholangiopancreatographic findings were consistent with ERCP findings for the presence of strictures in 69% of the cases.

CONCLUSION: In patients with primary sclerosing cholangitis, MR cholangiopancreatography better shows the bile ducts and can depict more strictures, especially of the peripheral intrahepatic ducts, than ERCP. MR cholangiopancreatography can be used to noninvasively diagnose and follow up patients with primary sclerosing cholangitis.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

VARIANTS

GALLBLADDER

In primary sclerosing cholangitis, gallbladder polyps are frequently malignant.

Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ.

Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.

Am J Gastroenterol 2002 May;97(5):1138-42 Abstract quote
OBJECTIVE: The management of gallbladder polyps/masses in patients with primary sclerosing cholangitis (PSC) (i.e., cholecystectomy vs observation) remains problematic. Given the risk of biliary tract cancer in PSC in the face of the benign nature of most gallbladder polyps in the general population, our aim was to determine the prevalence of gallbladder cancer in PSC patients with a gallbladder mass who had undergone cholecystectomy.

METHODS: The case records of all patients with PSC undergoing a cholecystectomy at the Mayo Clinic between 1977-1999 were reviewed.

RESULTS: Of the 102 patients with PSC who underwent a cholecystectomy, 14 of 102 (13.7%) had a gallbladder mass. In the subset of patients with gallbladder masses, eight of 14 (57%) had adenocarcinomas (seven primary adenocarcinomas and one metastatic cholangiocarcinoma); the other six had benign masses (five adenomas and one cholesterol polyp). In those patients with benign masses, 33% had associated epithelial cell dysplasia; in patients with primary gallbladder cancers, 57% had associated dysplasia. The patients with primary gallbladder adenocarcinoma had a favorable outcome after cholecystectomy, with a 36-month survival of 66%.

CONCLUSIONS: In conclusion, gallbladder neoplasms in PSC patients are malignant in approximately 40-60% of the cases. The presence of gallbladder epithelial cell dysplasia suggests a dysplasia-carcinoma sequence in PSC similar to that observed in ulcerative colitis. Consideration should be given to performing a cholecystectomy in PSC patients with gallbladder polyps. If a cholecystectomy is not performed, careful interval follow-up is warranted.

PANCREAS

Do patients with primary sclerosing cholangitis have a greater frequency of pancreatic abnormalities at MRI than patients with other liver diseases?

Resnick D, Krinsky GA, Lavelle MT, Lee VS, Keogan MT, Morrin MM.

Department of Radiology, NYU Medical Center, 530 First Avenue, Basement HCC, New York, NY 10016, USA.

J Comput Assist Tomogr 2002 Nov-Dec;26(6):994-9 Abstract quote
PURPOSE: It has been proposed that there is an increased frequency of pancreatic abnormalities in patients with primary sclerosing cholangitis (PSC). Our purpose is to compare the frequency of pancreatic abnormalities detected at MRI in patients with PSC and to compare these findings with those found in a matched cohort with other liver diseases.

METHOD: We identified 29 patients who had either a histologic or an endoscopic retrograde cholangiopancreatography diagnosis of PSC and 29 age- and gender-matched patients with liver disease without PSC who underwent MRI at 1.5 T. The protocol included breath-hold T1-weighted gradient echo, echo train, fast spin echo, T2-weighted images and dynamic gadolinium-enhanced MRI. Two blinded readers retrospectively evaluated the MR images for abnormalities of pancreatic size and morphology, T1 and T2 signal intensity, duct size and irregularities, arterial-phase contrast enhancement, focal pancreatic masses, cystic lesions, peripancreatic fluid/edema, ascites, and capsular-like rim surrounding the pancreas.

RESULTS: The prevalence of pancreatic and peripancreatic abnormalities was 10 of 29 (35%) in PSC patients and 14 of 29 (48%) in control patients. MR findings included ascites (9 PSC, 12 controls), peripancreatic edema (7 PSC, 11 controls), atrophy (4 PSC, 3 control), increased T2 signal (3 PSC, 4 controls), cystic lesions (2 PSC, 3 controls), abnormal T1 signal (1 PSC, 2 controls), and dilated pancreatic ducts (3 PSC, 2 controls). Quantitative parameters were not significantly different between PSC patients and the control subjects with pancreatic findings.

CONCLUSION: There is no significant difference in pancreatic abnormalities detected on MRI between patients with PSC and those with other liver diseases.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

DYSPLASIA

Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis.

Fleming KA, Boberg KM, Glaumann H, Bergquist A, Smith D, Clausen OP.

University of Oxford, Nuffield Department of Pathology & Bacteriology, John Radcliffe Hospital, Headington, UK.

J Hepatol 2001 Mar;34(3):360-5 Abstract quote
BACKGROUND/AIMS: Indentification of biliary dysplasia in a primary sclerosing cholangitis (PSC) liver biopsy may indicate developing cholangiocarcinoma. The objectives were to determine whether biliary dysplasia can be recognised reproducibly in PSC and to compare the frequency in cases with and without cholangiocarcinoma.

METHODS: Liver biopsies from 26 PSC cases with concurrent or subsequent cholangiocarcinoma (within 2 years) were assessed for biliary dysplasia independently by three liver pathologists. This was done in two stages: initially, without agreement on criteria, and subsequently after such agreement. Liver biopsies from 60 PSC cases without cholangio-carcinoma were also assessed.

RESULTS: Reproducibility for biliary dysplasia without prior agreement on criteria was only marginally better than random (kappa=0.129). In contrast, after prior agreement on criteria, reproducibility was moderate (kappa=0.44). Biliary dysplasia was agreed to be present by all three pathologists in 23% and 19% of biopsies in the first and second round, respectively, from patients with cholangiocarcinoma, but in none of the patients without cholangiocarcinoma.

CONCLUSION: Criteria for biliary dysplasia can be agreed and the entity recognised in liver biopsies. The strong association of biliary dysplasia with cholangiocarcinoma in PSC suggests use of dysplasia as a marker for current or developing malignancy.

EXTRAHEPATIC BILE DUCTS

The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis.

Katabi N, Albores-Saavedra J.

Am J Surg Pathol 2003 Mar;27(3):349-55 Abstract quote
We examined histologically the bile duct lesions from 53 patients with end-stage primary sclerosing cholangitis (PSC) and compared them with similar lesions found in 25 surgically excised carcinomas of the extrahepatic bile ducts not associated with PSC.

Of the 53 cases of PSC, 50 bile ducts were obtained at liver transplantation, two common bile ducts were segmentally resected for almost complete obstruction, and the entire extrahepatic biliary tract of another case was obtained at autopsy. Twenty bile ducts from patients who died without evidence of biliary tract disease served as controls. A modest increase in the number of intramural glands (mild hyperplasia) was noted in 13 cases (24.5%) of PSC. A marked increase in the number of intramural glands (florid hyperplasia) was found in 14 cases (26.4%) of PSC. In one case of florid hyperplasia, there was perineural and intraneural invasion of benign hyperplastic glands, which still maintained their lobular pattern. All cases of florid hyperplasia of intramural glands were accompanied by extensive fibrosis and marked nerve proliferation.

Three of 24 (12.5%) invasive adenocarcinomas of the extrahepatic bile ducts showed mild hyperplasia of intramural glands without excessive nerve proliferation. Four invasive adenocarcinomas and one in situ carcinoma of the extrahepatic bile ducts showed florid hyperplasia of intramural glands (16%). The hyperplastic intramural glands were p53 negative and had low proliferative activity as measured by the low MIB-1 labeling index.

In contrast, both in situ and invasive carcinoma expressed p53 protein and had a high MIB-1 labeling index. Focal high-grade dysplasia was found in one case of PSC (1.8%) and a small invasive adenocarcinoma in another (1.8%). Hyperplasia of intramural glands of the extrahepatic bile ducts is a reactive process that lacks specificity and is part of the morphologic spectrum of end-stage PSC.

The incidence of dysplasia in PSC is low. Small invasive adenocarcinomas may be incidentally found in end-stage PSC, and detecting their presence before liver transplantation may be impossible.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

VANISHING BILE DUCT SYNDROME

Delayed granuloma formation in a patient with vanishing bile duct syndrome 7 years post-liver transplantation.

Anania FA, Howell CD, Laurin JM, Drachenberg CI.

Department of Medicine, The University of Maryland Medical Center and School of Medicine, Baltimore, MD 21201-1595, USA.
Liver Transpl 2001 Nov;7(11):999-1001 Abstract quote
A patient was found to have numerous granulomata 7 years after orthotopic liver transplantation for primary sclerosing cholangitis (PSC) on a recent liver biopsy specimen. This histopathologic finding prompted a review of the literature to determine the commonality of this feature in the absence of the usual causes of granulomatous liver disease, none of which were found to be the cause of this patient's liver histopathologic state.

The presence of posttransplantation granulomata is rare, and although previously reported to occur shortly after liver transplantation, this finding has not been reported previously with either PSC or vanishing bile duct syndrome.

We are not aware of another case of granulomata associated with recurrent PSC or vanishing bile duct syndrome 7 years after liver transplantation.

PROGNOSIS CHARACTERIZATION

GENERAL

Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis.

Bjornsson E, Boberg KM, Cullen S, Fleming K, Clausen OP, Fausa O, Schrumpf E, Chapman RW.

Department of Internal Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Gut 2002 Nov;51(5):731-5 Abstract quote
BACKGROUND: Patients with cholestatic liver function tests and histological features of primary sclerosing cholangitis (PSC) but a normal cholangiogram are considered to have small duct PSC. The natural history of this condition is unknown.

METHODS: Thirty three patients with small duct PSC were identified among patients admitted for diagnostic workup of cholestatic liver function tests in one centre in the UK (Oxford) and one centre in Norway (Oslo). A total of 260 patients with large duct PSC were compared, and prognosis in terms of death, cholangiocarcinoma, biochemical features, histological features, and symptoms analysed.

RESULTS: Mean age at diagnosis was 38 years and 39 years in small duct and large duct PSC, respectively. Mean follow up was 106 months in small duct and 105 months in large duct patients. Four patients originally considered to have small duct developed large duct PSC. Two of these underwent liver transplantation during follow up. Of the remainder who did not develop large duct PSC, two patients died during follow up: one of liver failure and the other of cardiac death unrelated to her liver disease. A total of 122 (47%) large duct patients either required liver transplantation (34 patients) or died (88 patients). Small duct patients had a significantly better survival compared with large duct patients. Among small duct patients, none developed cholangiocarcinoma compared with 28 of 260 (11%) large duct patients.

CONCLUSIONS: Patients with small duct PSC seem to have a good prognosis in terms of survival and development of cholangiocarcinoma. Small duct PSC progresses to large duct PSC in a small proportion of patients.

MALIGNANCY

Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation.

Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U, Chapman R, Fausa O, Egeland T, Rocca G, Schrumpf E.

Medical Dept, Rikshospitalet, Oslo, Norway.
Scand J Gastroenterol 2002 Oct;37(10):1205-11 Abstract quote
BACKGROUND: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC.

METHODS: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC.

RESULTS: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis).

CONCLUSIONS: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.

Hepatobiliary carcinoma associated with primary sclerosing cholangitis and chronic ulcerative colitis.

Wee A, Ludwig J, Coffey RJ Jr, LaRusso NF, Wiesner RH.

Hum Pathol 1985 Jul;16(7):719-26 Abstract quote
Hepatobiliary carcinomas were found in eight patients with chronic ulcerative colitis (CUC) and primary sclerosing cholangitis (large-duct PSC; five cases) or "pericholangitis" (small-duct PSC; three cases).

The tumors were extrahepatic in five cases and intrahepatic in two; in one case the neoplasm affected both liver and gallbladder. The tumors in seven patients were glandular and, sometimes, cystic and papillary; in the remaining patient a combined hepatocellular carcinoma and cholangiocarcinoma was found. The latter tumor seemed to arise from regenerative nodules in secondary biliary cirrhosis complicating PSC.

The presence of carcinoma in situ in areas of fibrous cholangitis, the multicentric origin of the tumor, the presence of tumor-free large-duct PSC or small-duct PSC (pericholangitis) at a distance from the carcinomatous areas, and the documentation, in some cases, of long-standing inflammatory hepatobiliary disease prior to the discovery of the tumors would seem to confirm the clinical impression that carcinomas may develop in pre-existing PSC. The appearance of hepatobiliary carcinomas in patients with classic PSC and in patients with pericholangitis supports previous evidence indicating that cholangiographically diagnosed large-duct PSC and histologically diagnosed small-duct PSC (pericholangitis) are manifestations of a shared condition that could be named PSC syndrome.

The findings of the present study indicate that the PSC syndrome predisposes patients for the development of bile duct carcinoma. Most patients with CUC and bile duct carcinoma seem to have PSC prior to the development of the hepatobiliary tumor.

Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis.

Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO.

Gastroenterology Section, VA Palo Alto and Department of Medicine, Division of Gastroenterology, Stanford University School of Medicine, Palo Alto, California 94304, USA.
Gastrointest Endosc 2002 Jul;56(1):48-54 Abstract quote
BACKGROUND: Published data on the risk of colorectal neoplasia in patients with ulcerative colitis with and without primary sclerosing cholangitis are conflicting. A meta-analysis was performed to synthesize available publications and to compare the risk of colorectal neoplasia in patients with ulcerative colitis with and without primary sclerosing cholangitis.

METHODS: By using MEDLINE and manual search methods, studies were identified that compared the risk of colorectal neoplasia (dysplasia and carcinoma) in patients with ulcerative colitis with and without primary sclerosing cholangitis. In addition, citations were reviewed in relevant articles and proceedings from gastroenterology meetings, and investigators were contacted when data were incomplete. The summary odds ratio (OR) was then calculated for the risk for patients with ulcerative colitis and primary sclerosing cholangitis of having colorectal neoplasia develop compared with that of patients with ulcerative colitis without primary sclerosing cholangitis.

RESULTS: Eleven studies met all eligibility criteria for the meta-analysis. Patients with ulcerative colitis and primary sclerosing cholangitis are at increased risk of colorectal dysplasia and carcinoma compared with patients with ulcerative colitis alone; OR 4.79: 95% CI [3.58, 6.41] with the Mantel-Haenszel method, and OR 5.11: 95% CI [3.15, 8.29] with the Der Simonian and Laird method. This increased risk is present even when the risk of colorectal carcinoma alone is considered; OR 4.09: 95% CI [2.89, 5.76] and OR 4.26: 95% CI [2.80, 6.48] by using, respectively, the Mantel-Haenszel and the Der Simonian and Laird methods.

CONCLUSIONS: Patients with ulcerative colitis and primary sclerosing cholangitis have a significantly higher risk for the development of colorectal neoplasia than patients with ulcerative colitis but not primary sclerosing cholangitis. More intensive colonoscopic surveillance should be considered for patients with ulcerative colitis and primary sclerosing cholangitis.

RECURRENCE

Risk factors for recurrence of primary sclerosing cholangitis of liver allograft.

Vera A, Moledina S, Gunson B, Hubscher S, Mirza D, Olliff S, Neuberger J.

Liver Unit, Queen Elizabeth Hospital, B15 2TH, Birmingham, UK.

Lancet 2002 Dec 14;360(9349):1943-4 Abstract quote
Primary sclerosing cholangitis (PSC) is a disease of unknown cause that effects the biliary tree and is closely associated with inflammatory bowel disease.

We did a retrospective analysis of the risk factors associated with recurrence of PSC in an allograft after liver transplantation. Recurrence of disease, assessed by liver histology or imaging the biliary tree, occurred in 56 of 152 patients (37%) at a median of 36 months (range 1.4-120 months). Multivariate analysis showed that being male (relative risk 1.2, 95% CI 0.73-2.15) and an intact colon before transplantation (8.7, 1.19-64.48) were associated with recurrence.

These observations could help elucidate the pathogenesis of the disease.

Recurrence of primary sclerosing cholangitis after liver transplantation.

Graziadei IW.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospitals Innsbruck, Austria.
Liver Transpl 2002 Jul;8(7):575-81 Abstract quote
Orthotopic liver transplantation (OLT) has become the only effective therapeutic option for patients with end-stage liver disease caused by primary sclerosing cholangitis (PSC). Excellent long-term outcome has been reported, with 5-year patient survival rates of approximately 80%. In the last few years, increasing evidence has emerged that PSC recurs after OLT.

The diagnosis of PSC is based on well-defined cholangiographic features combined with biochemical and histological findings. However, none of these features is specific for PSC, particularly after OLT, because biliary strictures in the liver allograft can occur from a variety of causes other than recurrence. Therefore, PSC recurrence remains a controversial issue, especially because of a lack of a gold standard for diagnosis and well-established diagnostic criteria. Some reports provided cholangiographic evidence that post-OLT biliary strictures occurred more frequently in patients with PSC than in those who underwent OLT for other liver diseases (including patients with a Roux-en-Y biliary reconstruction). Because no other possible cause of biliary strictures could be invoked to explain the greater prevalence of these strictures, recurrent disease has been implicated. There also is histological evidence suggesting that PSC recurs after OLT.

Histological findings suggestive of PSC were found more often in PSC allografts compared with a control group. Furthermore, histological features typical for PSC (fibro-obliterative lesions) were seen exclusively in liver biopsy specimens from patients with PSC. Recurrence of PSC was defined in a recent study from the Mayo Clinic by means of strict cholangiographic and histological criteria in a large cohort of patients with PSC in whom other causes of biliary strictures were excluded. PSC recurrence was found in 20% of patients. No risk factor for PSC recurrence could be found, and recurrent disease did not influence patient or graft survival after a mean follow-up of 4.5 years.

In conclusion, several studies provided convincing evidence that PSC recurs after OLT, with an incidence of 5% to 20% and an interval to diagnosis of at least 1 year after OLT. To date, patient and graft survival do not appear to be negatively affected by disease recurrence in the intermediate term of follow-up.

TREATMENT CHARACTERIZATION

GENERAL

LIVER TRANSPLANTATION

Liver transplantation for primary sclerosing cholangitis: a long-term clinicopathologic study.

Khettry U, Keaveny A, Goldar-Najafi A, Lewis WD, Pomfret EA, Pomposelli JJ, Jenkins RL, Gordon FD.

Department of Anatomic Pathology and Liver Transplantation, Lahey Clinic Medical Center, Burlington, MA 01805, USA.

Hum Pathol. 2003 Nov;34(11):1127-36 Abstract quote.

The course and outcome of patients after liver transplantation (LT) for primary sclerosing cholangitis (PSC) are still debated. Our purpose is to define retrospectively, the post-LT clinicopathologic findings seen in 51 PSC patients with a follow-up of 2 to 14 years.

Of the total 51 patients, 16 with native liver hilar xanthogranulomatous cholangiopathy (XGC) had median graft and patient survival of 573 and 835 days, respectively compared with 2489 and 2794 days, respectively, in 35 patients without XGC. Perioperative complications resulted in 9 early deaths (day 0 to 52). Of the remaining 42 patients, 6 had recurrent PSC (R-PSC) with typical histologic and cholangiographic findings, 12 had autoimmune liver disease-not otherwise specified with histology of autoimmune hepatitis/overlap syndrome, 3 had chronic rejection, 4 had ischemic cholangiopathy, and 17 had no recurrence. The presence of inflammatory bowel disease, total ischemia time of > or =11 hours, recipient-donor ABO and HLA Class I and II matches, and the type of immunosuppression did not affect the post-LT outcome. Recipient-donor gender mismatch was more common in R-PSC than in the nonrecurrent group (P=0.045). Post-LT malignancies were significantly more common in the nonrecurrent cases compared with all others combined (P=0.031) and caused deaths in 4.

The majority of deaths (11/13) in other groups were due to sepsis complicating graft dysfunction. In conclusion, allograft autoimmune liver disease was seen in 18 (43%) of 42 long-term post-LT PSC patients, with progression in 5 of 18 patients. Features of PSC were seen in 6 (33%) of 18. Native liver XGC negatively impacted post-LT graft and patient survival. Increased incidence of malignancies in the nonrecurrent group may reflect overimmunosuppression in those patients.

The management of primary sclerosing cholangitis.

Chapman RW.

Department of Hepatology and Gastroenterology, Oxford Radcliffe Hospital, Oxford OX3 9DU, UK.
Curr Gastroenterol Rep 2003 Feb;5(1):9-17 Abstract quote
Primary sclerosing cholangitis (PSC) is a chronic cholestatic hepatobiliary disease that usually progresses to biliary cirrhosis and liver failure; it also predisposes to cholangiocarcinoma. The cause of PSC is unknown, although evidence suggests that the tissue damage is mediated by the immune system.

There is an unexplained close association between PSC and inflammatory bowel disease, particularly in ulcerative colitis, which coexists in the majority of patients with PSC. No medical therapy has been proven to halt or reverse disease progression; however, recent preliminary evidence suggests that ursodeoxycholic acid (UDCA) in a high dose of 20 to 25 mg/kg may slow the disease process. Evidence from a pilot study suggests that the combination of UDCA and immunosuppressive therapy, such as prednisolone or azathioprine, may also increase efficacy.

For patients with end-stage PSC, liver transplantation remains the only effective therapy, although there is clear evidence that PSC may recur in the liver allograft.

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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PATHOGENESIS	CHARACTERIZATION
APOPTOSIS
Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. Tinmouth J, Lee M, Wanless IR, Tsui FW, Inman R, Heathcote EJ. Department of Medicine, University Health Network, Toronto, Ontario, Canada.	Liver 2002 Jun;22(3):228-34 Abstract quote BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestatic liver disease where the bile ducts are also destroyed. In this study, apoptosis and portal triad inflammation in liver tissue from patients with PBC is examined and compared to that from patients with PSC and patients with normal liver. METHODS: Explanted liver tissue from patients with PBC and PSC and normal liver from patients with metastases to liver were examined. The liver samples were stained for apoptosis using the terminal deoxynucleotidyl triphosphate (TdT)-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay. The biliary epithelial cells (BEC) were then scored on the basis of their TUNEL stain and the degree of periductal inflammation. RESULTS: In PBC, apoptosis of BEC, as detected by the TUNEL assay, was significantly increased in the presence of inflammation. Regardless of the presence or absence of inflammation, the small bile ducts in PBC liver tissue exhibited greater evidence of apoptosis than did similar ducts from PSC or control livers. CONCLUSION: These findings suggest that in PBC, unlike PSC, the apoptosis of BEC in PBC is secondary to the invasion of inflammatory cells.
CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE
Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis. Girodon E, Sternberg D, Chazouilleres O, Cazeneuve C, Huot D, Calmus Y, Poupon R, Goossens M, Housset C. Service de Biochimie et de Genetique, AP-HP and INSERM U468, Hopital Henri Mondor, 94010 Creteil, France.	J Hepatol 2002 Aug;37(2):192-7 Abstract quote BACKGROUND/AIMS: Because biliary tract lesions that resemble those of primary sclerosing cholangitis (PSC) may occur in cystic fibrosis (CF), we examined the prevalence and influence of CF transmembrane conductance regulator (CFTR) gene mutations in PSC patients. METHODS: Genomic DNA was analyzed in 29 consecutive PSC patients and in 115 healthy control individuals. A scanning method followed by direct DNA sequencing was used to scan the CFTR coding regions. RESULTS: Four patients (13.8%) were heterozygous for a CFTR mutation, including a new putative severe CF-causing mutation (N782K), and three mild defects (L997F, D1270N, and S1235R). The comparison of PSC patients with healthy controls showed no significant difference in the frequency of CFTR mutations (P=0.415). In addition, two patients (6.9%) were heterozygous for the IVS8-5T allele, which is not significantly different from the 5-6%-prevalence in the general population. Unusual clinical features including a severe outcome in childhood, with a lethal outcome at age 22, and biliary aspergillosis were recorded in patients with a CFTR mutation. CONCLUSIONS: The proportion of CF carriers is not significantly higher in PSC patients than in the general population. The possibility that CFTR mutations may contribute to a severe clinical course in PSC patients is worth further examining.
INFECTION
A survey of infectious agents as risk factors for primary sclerosing cholangitis: are Chlamydia species involved? Ponsioen CY, Defoer J, Ten Kate FJ, Weverling GJ, Tytgat GN, Pannekoek Y, Wertheim-Dillen PM. Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands	Eur J Gastroenterol Hepatol 2002 Jun;14(6):641-8 Abstract quote OBJECTIVES: The aetiology of primary sclerosing cholangitis (PSC) is unknown, and the role of micro-organisms has been studied only to a limited extent. We tested the hypothesis that past or persisting infection with common viruses or atypical bacteria might play a role in genetically susceptible hosts. DESIGN: Case-control study. METHODS: Serological screening for antibodies against 22 viruses as well as Chlamydia spp. and Mycoplasma pneumoniae was carried out in 41 well-established PSC patients. All 5110 sera tested in 1997 for these micro-organisms at our laboratory served as a background reference group. Subsequently, Chlamydia anti-lipopolysaccharide (LPS) antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in the PSC group and in three race-matched control groups (inflammatory bowel disease (IBD) group, n = 35; non-IBD patients group, n = 39; healthy blood donor group, n = 40). Subtyping in Chlamydia trachomatis and C. pneumoniae serotypes by specific anti-major outer membrane protein (MOMP) assays was carried out in the four groups. Immunohistochemical staining using specific markers for chlamydiae was carried out on liver biopsies of 14 PSC patients. RESULTS: There was a markedly elevated seroprevalence of Chlamydia-LPS antibodies compared with the 1997 reference group. The odds ratios (ORs) for the presence of immunoglobulin G, immunoglobulin M and immunoglobulin A antibodies for the PSC patients versus the control group were 2.4 (95% confidence interval (CI) 1.1 to 5.4), 1.9 (95% CI 0.9 to 4.0) and 6.7 (95% CI 3.0 to 17.0), respectively. All other micro-organisms tested showed normal antibody profiles that did not differ from the 1997 reference group. The seroprevalence of Chlamydia-anti-LPS antibodies was elevated markedly in the PSC patients compared with the IBD, non-IBD and blood donor groups. The outcomes in the C. trachomatis and C. pneumoniae anti-MOMP assays did not correlate with the anti-LPS-positive PSC sera. The actual presence of Chlamydia bodies in liver tissue could not be demonstrated. CONCLUSION: Our findings suggest an association between PSC and (previous) infection with Chlamydia.

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EPIDEMIOLOGY	CHARACTERIZATION
AGE	3rd to 5th decades
SEX	Males
GEOGRAPHY
SINGAPORE
Clinical profile of primary sclerosing cholangitis in Singapore. Ang TL, Fock KM, Ng TM, Teo EK, Chua TS, Tan JY. Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore.	J Gastroenterol Hepatol 2002 Aug;17(8):908-13 Abstract quote BACKGROUND AND AIM: Primary sclerosing cholangitis (PSC) is a rare chronic disease in Singapore and its epidemiological profile has not been described previously. The present study aimed to define the demographic and clinical profile of patients with PSC in Singapore. METHODS: The case records of patients with PSC seen at Changi General Hospital were analyzed in terms of demographic profile, clinical presentation, clinical course, treatment and complications. RESULTS: Ten cases of PSC were diagnosed over a 10-year period. The male:female ratio was 9:1. The median age of diagnosis was 49.5 years (mean: 50.9 years; range: 35-63 years). With regards to clinical presentation, seven patients had hepatobiliary sepsis, two patients had asymptomatic liver biochemistry abnormalities while one patient had cholestatic jaundice. Prevalence rate of perinuclear antineutrophil cytoplasmic antibody (pANCA) was 20%. Symptomatic inflammatory bowel disease (IBD) was diagnosed in 20% of PSC cases. Eight patients (80%) had intrahepatic ductal involvement while two patients (20%) had combined intrahepatic and extrahepatic ductal involvement on endoscopic retrograde cholangiopancreatography (ERCP). The prevalence rate of recurrent cholangitis was 30% while that of recurrent liver abscess, cirrhosis and common bile duct stricture were all 10%. The mean duration of follow up was 6.6 years with one death from liver failure. CONCLUSION: The clinical profile of patients with PSC in Singapore appears to differ with other published data, with a greater number presenting with hepatobiliary sepsis and less frequent association with IBD and pANCA. It is hypothesized that this may be related to differences in environmental triggers and genetic susceptibility.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
GALLBLADDER
In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ. Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.	Am J Gastroenterol 2002 May;97(5):1138-42 Abstract quote OBJECTIVE: The management of gallbladder polyps/masses in patients with primary sclerosing cholangitis (PSC) (i.e., cholecystectomy vs observation) remains problematic. Given the risk of biliary tract cancer in PSC in the face of the benign nature of most gallbladder polyps in the general population, our aim was to determine the prevalence of gallbladder cancer in PSC patients with a gallbladder mass who had undergone cholecystectomy. METHODS: The case records of all patients with PSC undergoing a cholecystectomy at the Mayo Clinic between 1977-1999 were reviewed. RESULTS: Of the 102 patients with PSC who underwent a cholecystectomy, 14 of 102 (13.7%) had a gallbladder mass. In the subset of patients with gallbladder masses, eight of 14 (57%) had adenocarcinomas (seven primary adenocarcinomas and one metastatic cholangiocarcinoma); the other six had benign masses (five adenomas and one cholesterol polyp). In those patients with benign masses, 33% had associated epithelial cell dysplasia; in patients with primary gallbladder cancers, 57% had associated dysplasia. The patients with primary gallbladder adenocarcinoma had a favorable outcome after cholecystectomy, with a 36-month survival of 66%. CONCLUSIONS: In conclusion, gallbladder neoplasms in PSC patients are malignant in approximately 40-60% of the cases. The presence of gallbladder epithelial cell dysplasia suggests a dysplasia-carcinoma sequence in PSC similar to that observed in ulcerative colitis. Consideration should be given to performing a cholecystectomy in PSC patients with gallbladder polyps. If a cholecystectomy is not performed, careful interval follow-up is warranted.
PANCREAS
Do patients with primary sclerosing cholangitis have a greater frequency of pancreatic abnormalities at MRI than patients with other liver diseases? Resnick D, Krinsky GA, Lavelle MT, Lee VS, Keogan MT, Morrin MM. Department of Radiology, NYU Medical Center, 530 First Avenue, Basement HCC, New York, NY 10016, USA.	J Comput Assist Tomogr 2002 Nov-Dec;26(6):994-9 Abstract quote PURPOSE: It has been proposed that there is an increased frequency of pancreatic abnormalities in patients with primary sclerosing cholangitis (PSC). Our purpose is to compare the frequency of pancreatic abnormalities detected at MRI in patients with PSC and to compare these findings with those found in a matched cohort with other liver diseases. METHOD: We identified 29 patients who had either a histologic or an endoscopic retrograde cholangiopancreatography diagnosis of PSC and 29 age- and gender-matched patients with liver disease without PSC who underwent MRI at 1.5 T. The protocol included breath-hold T1-weighted gradient echo, echo train, fast spin echo, T2-weighted images and dynamic gadolinium-enhanced MRI. Two blinded readers retrospectively evaluated the MR images for abnormalities of pancreatic size and morphology, T1 and T2 signal intensity, duct size and irregularities, arterial-phase contrast enhancement, focal pancreatic masses, cystic lesions, peripancreatic fluid/edema, ascites, and capsular-like rim surrounding the pancreas. RESULTS: The prevalence of pancreatic and peripancreatic abnormalities was 10 of 29 (35%) in PSC patients and 14 of 29 (48%) in control patients. MR findings included ascites (9 PSC, 12 controls), peripancreatic edema (7 PSC, 11 controls), atrophy (4 PSC, 3 control), increased T2 signal (3 PSC, 4 controls), cystic lesions (2 PSC, 3 controls), abnormal T1 signal (1 PSC, 2 controls), and dilated pancreatic ducts (3 PSC, 2 controls). Quantitative parameters were not significantly different between PSC patients and the control subjects with pancreatic findings. CONCLUSION: There is no significant difference in pancreatic abnormalities detected on MRI between patients with PSC and those with other liver diseases.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
DYSPLASIA
Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis. Fleming KA, Boberg KM, Glaumann H, Bergquist A, Smith D, Clausen OP. University of Oxford, Nuffield Department of Pathology & Bacteriology, John Radcliffe Hospital, Headington, UK.	J Hepatol 2001 Mar;34(3):360-5 Abstract quote BACKGROUND/AIMS: Indentification of biliary dysplasia in a primary sclerosing cholangitis (PSC) liver biopsy may indicate developing cholangiocarcinoma. The objectives were to determine whether biliary dysplasia can be recognised reproducibly in PSC and to compare the frequency in cases with and without cholangiocarcinoma. METHODS: Liver biopsies from 26 PSC cases with concurrent or subsequent cholangiocarcinoma (within 2 years) were assessed for biliary dysplasia independently by three liver pathologists. This was done in two stages: initially, without agreement on criteria, and subsequently after such agreement. Liver biopsies from 60 PSC cases without cholangio-carcinoma were also assessed. RESULTS: Reproducibility for biliary dysplasia without prior agreement on criteria was only marginally better than random (kappa=0.129). In contrast, after prior agreement on criteria, reproducibility was moderate (kappa=0.44). Biliary dysplasia was agreed to be present by all three pathologists in 23% and 19% of biopsies in the first and second round, respectively, from patients with cholangiocarcinoma, but in none of the patients without cholangiocarcinoma. CONCLUSION: Criteria for biliary dysplasia can be agreed and the entity recognised in liver biopsies. The strong association of biliary dysplasia with cholangiocarcinoma in PSC suggests use of dysplasia as a marker for current or developing malignancy.
EXTRAHEPATIC BILE DUCTS
The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis. Katabi N, Albores-Saavedra J.	Am J Surg Pathol 2003 Mar;27(3):349-55 Abstract quote We examined histologically the bile duct lesions from 53 patients with end-stage primary sclerosing cholangitis (PSC) and compared them with similar lesions found in 25 surgically excised carcinomas of the extrahepatic bile ducts not associated with PSC. Of the 53 cases of PSC, 50 bile ducts were obtained at liver transplantation, two common bile ducts were segmentally resected for almost complete obstruction, and the entire extrahepatic biliary tract of another case was obtained at autopsy. Twenty bile ducts from patients who died without evidence of biliary tract disease served as controls. A modest increase in the number of intramural glands (mild hyperplasia) was noted in 13 cases (24.5%) of PSC. A marked increase in the number of intramural glands (florid hyperplasia) was found in 14 cases (26.4%) of PSC. In one case of florid hyperplasia, there was perineural and intraneural invasion of benign hyperplastic glands, which still maintained their lobular pattern. All cases of florid hyperplasia of intramural glands were accompanied by extensive fibrosis and marked nerve proliferation. Three of 24 (12.5%) invasive adenocarcinomas of the extrahepatic bile ducts showed mild hyperplasia of intramural glands without excessive nerve proliferation. Four invasive adenocarcinomas and one in situ carcinoma of the extrahepatic bile ducts showed florid hyperplasia of intramural glands (16%). The hyperplastic intramural glands were p53 negative and had low proliferative activity as measured by the low MIB-1 labeling index. In contrast, both in situ and invasive carcinoma expressed p53 protein and had a high MIB-1 labeling index. Focal high-grade dysplasia was found in one case of PSC (1.8%) and a small invasive adenocarcinoma in another (1.8%). Hyperplasia of intramural glands of the extrahepatic bile ducts is a reactive process that lacks specificity and is part of the morphologic spectrum of end-stage PSC. The incidence of dysplasia in PSC is low. Small invasive adenocarcinomas may be incidentally found in end-stage PSC, and detecting their presence before liver transplantation may be impossible.