Good article covering broad range of topics by leading experts on PSC

[Guest guest]

Sorry if this has been posted before but I found this to be a rather

good article covering multiple subjects related to PSC, it's treatment

and management of symptoms by leading doctors in the field. It is a

long article so I will post the web address rather than the article

itself.

http://www.niddk.nih.gov/fund/other/PSCSept2006.pdf

in Seattle

UC 1991, PSC 2001

[Guest guest]

,

This link isn't working for me. It's giving me an error after tyring to open abode reaier. do you need to be a member of niddk? would you mind posting the article?

Ian

Sorry if this has been posted before but I found this to be a rather good article covering multiple subjects related to PSC, it's treatment and management of symptoms by leading doctors in the field. It is a long article so I will post the web address rather than the article itself.

http://www.niddk.nih.gov/fund/other/PSCSept2006.pdf in SeattleUC 1991, PSC 2001 -- Ian Cribb P.Eng.

[Guest guest]

.

Its okay I got it.

Thanks Ian

,

This link isn't working for me. It's giving me an error after tyring to open abode reaier. do you need to be a member of niddk? would you mind posting the article?

Ian

On 7/10/07, jasonsea <kingpolo@...

> wrote:

Sorry if this has been posted before but I found this to be a rather good article covering multiple subjects related to PSC, it's treatment and management of symptoms by leading doctors in the field. It is a long article so I will post the web address rather than the article itself.

http://www.niddk.nih.gov/fund/other/PSCSept2006.pdf in SeattleUC 1991, PSC 2001

-- Ian Cribb P.Eng. -- Ian Cribb P.Eng.

[Guest guest]

>Hi -

Trev and I both tried to get to this, but had the same problem Ian

wrote about. Any tips on how to make it work? Also, do you know of

PSC/Crohn's/etc support groups in the Seattle area? Trev is looking

for one.

Thanks,

katy

> Sorry if this has been posted before but I found this to be a rather

> good article

>

> http://www.niddk.nih.gov/fund/other/PSCSept2006.pdf

>

> in Seattle

> UC 1991, PSC 2001

>

[Guest guest]

> >Hi -

>

> Trev and I both tried to get to this, but had the same problem Ian

> wrote about. Any tips on how to make it work?

-

I too had trouble and the article looked great (I got to see it once,

then couldn't get it to re-load on computer when I wanted to print

it!). Thanks for any advice on how to print the article.

Joanne

(, CA)

[Guest guest]

Katy,

After a lot of searching on the internet II ended up getting it a HTML copy of the document, which I have attached.

Ian

>Hi -

Trev and I both tried to get to this, but had the same problem Ianwrote about. Any tips on how to make it work? Also, do you know ofPSC/Crohn's/etc support groups in the Seattle area? Trev is looking

for one. Thanks, katy> Sorry if this has been posted before but I found this to be a rather > good article > >

http://www.niddk.nih.gov/fund/other/PSCSept2006.pdf> > in Seattle> UC 1991, PSC 2001> -- Ian Cribb P.Eng.

This is the html version of the file http://www3.niddk.nih.gov/fund/other/PSCSept2006.pdf.G o o g l e automatically generates html versions of documents as we crawl the web.To link to or bookmark this page, use the following url: http://www.google.com/u/PSCLiterature?q=cache:VNy11FY8qiYJ:www3.niddk.nih.gov/fund/other/PSCSept2006.pdf+pscsept2006 & hl=en & ct=clnk & cd=1 & ie=UTF-8Google is neither affiliated with the authors of this page nor responsible for its content.These terms only appear in links pointing to this page: pscsept2006 Page 1SPECIALARTICLEPrimary Sclerosing Cholangitis: Summary of a Workshop F. LaRusso,1 L. Shneider,2Dennis Black,3 J. Gores,1 P. ,4 Doo,4andJay H. Hoofnagle4Primary sclerosing cholangitis (PSC) is a rare but important liver disease that leads to cirrhosis andneedforlivertransplantationinahighproportionofcases.Thediseaseoccursinapproximately1per100,000populationperyear,usuallypresentsinadulthood,andaffectsmenmoreoftenthanwomen.Typicalserumbiochemicalresults,autoantibodiesandliverbiopsyaresuggestivebutnotdiagnosticofPSC, the diagnosis requiring cholangiographic demonstration of stricturing and dilatation of theintra-and/orextra-hepaticbileducts.ThenaturalhistoryofPSCisvariable,theaveragesurvivalbeing12to17years.ThecauseofPSCisstillunknown.Althoughconsideredanautoimmunedisease,PSChas several atypical features and a strong genetic component. The therapy of PSC is unsatisfactory.Standarddosesofursodeoxycholicacid(UDCA)leadtoimprovementsinbiochemicalabnormalitiesbutnotinhistology,cholangiographicappearanceorsurvival.Severalinnovativetherapieshavebeentried in PSC, but with scant evidence of benefit. For patients with high grade strictures, endoscopicdilatation is beneficial. Liver transplantation is successful for end-stage liver disease due to PSC andimproves survival. PSC may recur after transplantation but is rarely progressive. The most dreadedcomplicationofPSCischolangiocarcinoma.Diagnosisofthishighlymalignanttumorisdifficult,andthere are no biomarkers for its early detection. Liver transplantation for cholangiocarcinoma has anexceedingly poor outcome, although transplantation with neoadjuvant chemoirradiation holdspromiseinselectedpatients.Thus,significantopportunitiesremainforbasicandclinicalresearchintothe cause, natural history, and therapy of PSC.(HEPATOLOGY2006;44:746-764.)Primary sclerosing cholangitis (PSC) is a rare but im-portant cause of chronic liver disease. The disease ischaracterized by chronic inflammation and oblitera-tive fibrosis of the intra- and/or extra-hepatic biliary treewhich leads to bile stasis, hepatic fibrosis, and ultimately tocirrhosis,end-stageliverdisease,andneedforlivertransplan-tation. PSC can also lead to cholangiocarcinoma, a highlymalignant tumor. The cause of PSC is unknown. Whileoften associated with autoantibodies and closely linked toinflammatory bowel disease (IBD), PSC is not a typical au-toimmune disease and responds poorly, if at all, to typicalimmunosuppressive therapies. Indeed, no therapies havebeen proven to improve survival or ameliorate the naturalhistoryofPSC.Livertransplantationissuccessfulforpatientswith end-stage liver disease, and PSC now accounts for 5%of liver transplants done in the United States.Despite its importance, there have been few advances inunderstanding the pathogenesis of PSC. Furthermore, thereare uncertainties regarding optimal means of diagnosis,monitoring, and therapy. These needs led the Liver DiseaseResearchBranchoftheNIDDKtoorganizea2-dayresearchworkshoponPSC,focusingonsummarizingcurrentknowl-edgeanddefiningneedsforfutureresearch.Themeetingwascosponsored by the Office on Rare Diseases in the Office ofthe Director, NIH, and the Musette and Jr.Foundation for Study of PSC. This review summarizesthat workshop, which is available as a videocast at www.videocast.nih.govSession One. Clinical Features andEpidemiologyDr. Wiesner (Mayo Clinic, Rochester, MD)described the clinical features and modes of presentationAbbrevations: PSC, primary sclerosing cholangitis; IBD, inflammatory bowel disease;ALT,alanineaminotransferase;ANA,antinuclearantibody;SMA,smoothmuscleantibody;GGT, gamma-glutamyl transpeptidase; CPT, Child-Pugh-Turcotte score; MELD, Modelfor End-Stage Liver Disease; ERCP, endoscopic retrograde cholangio-pancreatography;MRCP, magnetic resonance cholangio-pancreatography; pANCA, antibody to perinuclearneutrophilcytoplasmicantigen;PBC,primarybiliarycirrhosis;IL,interleukin;TNF,tumornecrosis factor; TGF, transforming growth factor; MHC, major histocompatibility complex;HLA,humanleukocyteantigen;NK,naturalkiller;PFIC,progressivefamilialintrahepaticcholestasis; MDR, multi-drug resistance; CFTR, cystic fibrosis transmembrane conductanceregulator; BSEP, bile salt export protein; UDCA, ursodeoxycholic acid; TLR, toll-like recep-tor; NF, nuclear factor; iNOS, inducible nitric oxide synthetase; SPLIT, Study of PediatricLiver Transplantation; PELD, Pediatric Model for End-Stage Liver Disease; SEER, Sur-veillance, Epidemiology and End Results; CEA, carcinoembryonic antigen.From the1Department of Internal Medicine, Mayo Clinic College of Medicine,Rochester, MN;2Division of Pediatric Hepatology, Mount Sinai School of Medi-cine, New York, NY;3Children’s Foundation Research Center of Memphis, Uni-versity of Tennessee Health Science Center, Memphis, TN; and the4Division ofDigestive Diseases and Nutrition, National Institute of Diabetes and Digestive andKidney Diseases, National Institutes of Health, Bethesda, MD.Received February 24, 2006; accepted June 30, 2006.Summary of a workshop held September 19-20, 2005 in the Lister Hill Audito-rium, National Institutes of Health, Bethesda, MD.Address reprint requests to: Jay H. Hoofnagle, M.D., Building 31, Room 9A27A,31 Center Drive, National Institutes of Health, Bethesda, MD, 20892. E-mail:hoofnaglej@...; fax: .Copyright © 2006 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.21337Potential conflict of interest: Dr. Shneider was on the Speakers’ Bureau for AxcanScandipharm. He received grants from Schering-Plough and Gilead.746Page 2of PSC in adults. PSC typically presents during the 4th or5th decade, the average age of onset being 42 years.1-4Thedisease is more common in men than women and amongCaucasians and Northern Europeans, than in SouthernEuropeans, Asians, or Africans. Typical symptoms of PSCare pruritus and fatigue, but some patients are diagnosedbefore the onset of symptoms on the basis of abnormalliver enzymes. PSC is closely linked to IBD, and somecases come to medical attention when patients with IBDare screened for liver disease.5A rare presentation is withvariceal hemorrhage, end-stage liver disease, or cholangio-carcinoma.The clinical course of PSC is typically one of insidiousworsening of cholestasis and eventual development ofjaundiceandend-stageliverdisease(Fig.1).2,6Aboutone-third of patients have episodes of bacterial cholangitisespecially following biliary interventions, during whichthe disease can materially progress. Cholangiocarcinomadevelops in 10% of patients and can occur relatively earlyand before onset of cirrhosis. Patients with PSC are fre-quently categorized as symptomatic versus asymptomatic,withsmallversuslargeductdisease,withIBDversuswith-out, and with features of autoimmune hepatitis versuswithout.PSC typically affects both intra- and extra-hepatic bileducts. “Small duct PSC†refers to disease that affects bileducts that are too small to be identified by endoscopicretrograde cholangiopancreatography (ERCP).7,8Amongadults with PSC, 75% have involvement of both smalland large ducts, 15% small ducts only, and 10% largeducts only. Small duct PSC typically presents with insid-ious onset of symptoms or with end-stage liver disease.Episodes of cholangitis are rare. Small duct PSC can beassociated with IBD, has a more favorable prognosis, andis less likely than large duct PSC to lead to cholangiocar-cinoma.9Many patients with PSC have IBD as well, typicallyulcerative colitis and less commonly Crohn’s disease withcolonic involvement.10IBD is diagnosed before PSC in75% of cases and afterward in the remainder. Indeed, thediagnosis of IBD may not become evident until after livertransplantation for end-stage PSC; and conversely, PSCmay not become apparent in patients with ulcerative co-litis until after colectomy. There is little or no correlationbetween the severity of PSC and that of the associatedIBD. Furthermore, therapy of IBD has little effect on thecourse of PSC, and vice versa. Other less common diseaseassociations are thyroiditis, ankylosing spondylitis, andceliac disease.PSC with autoimmune hepatitis-like features has beenreferred to as autoimmune cholangitis.11,12These patientsusually present with high serum alanine aminotransferase(ALT) levels, modest or no elevations in serum alkalinephosphatase, high titers of antinuclear (ANA) and anti-smooth muscle antibodies (SMA) and liver histology typ-ical of autoimmune hepatitis. Corticosteroid therapy maylead to improvements in symptoms and liver enzyme ab-normalities. Eventually, however, patients become resis-tant to therapy and serum enzymes rise again, withprominent elevations in alkaline phosphatase and gammaglutamyl transpeptidase (GGT). Thus, PSC is a hetero-geneous condition that can present with distinct clinicalpatterns that may have important implications for patho-genesis, prognosis and therapy.Dr. Eve (Hospital for Sick Children, To-ronto, Canada) described the clinical features of PSC inchildren. PSC is uncommon in children and must beseparated from secondary forms of sclerosing cholangi-tis.13-16Neonatal sclerosing cholangitis is likely a separatedisease process.17,18In children, PSC usually presentswith nonspecific symptoms and pruritus, and rarely withjaundice.11,13,18-22An autoimmune hepatitis-like presen-tation is common.11,22ERCP may demonstrate bile ductabnormalities in these children,23but their course is typ-ical of autoimmune hepatitis, although with time, fea-tures of PSC become prominent. A rare mode ofpresentation is with advanced disease as shown by markedsplenomegaly or gastrointestinal hemorrhage. Most caseseries of PSC in children show a male predominance withan average age of onset in preteens (Table 1). Rarely, PSCpresents before the age of two. IBD (usually ulcerativecolitis) is found in 33% to 81% of children, but often notat initial presentation; up to 5% of children with IBD willdevelop PSC.Fig. 1. Concept of the natural history of PSC. A gradual loss of bileducts causes a progressive cholestasis followed by fibrosis. Early stagesare reversible, whereas later stages are not. Modified with permissionfrom Dr. Wiesner.HEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.747Page 3The natural history of PSC in children is only partiallydefined. Dominant strictures and recurrent cholangitisare uncommon. The prognosis is only fair, survival beingbetter than in adults, but resulting in need for liver trans-plantation in up to one-third of patients by early adult-hood. The risk of cholangiocarcinoma is not well defined,but appears to be rare. Thus, PSC is uncommon in chil-dren but is clinically distinct and challenging.Dr. W. Ray Kim (Mayo Clinic, Rochester, MN) de-scribed current understanding of the natural history ofPSC. PSC is a life-long disease that limits the life span.2While this disease is typically insidious and progressesslowly, spontaneous resolution does not occur. The me-dian time from diagnosis to death or liver transplantationis only 8 years (Fig. 2), but the actual time varies due tothree factors: (1) the stage of disease at time of diagnosis;(2) interpatient variability in the rate of progression; and(3) the possibility that PSC represents several diseaseswith different natural histories.Defining the natural history of PSC is difficult. PSC isoften separated into four phases: (1) small duct cholangi-tis, (2) progressive cholestasis, (3) cirrhosis, (4) decom-pensation. In only a small number of patients can thesefour phases be distinctly demarcated. Large duct lesionsdeveloping during the second phase may speed progres-sion. Furthermore, cholangiocarcinoma can develop atany time. Some of the variability in disease progressioncan be resolved by categorizing patients as symptomaticversus asymptomatic, with small duct versus large ductPSC, and with versus without IBD.Asymptomatic patients may have a better prognosisthan those with symptoms. This distinction, however,may be due to “lead time biasâ€, patients without symp-toms being those with earlier stages of disease. Asymp-tomatic patients are usually younger and have fewerbiochemical abnormalities than symptomatic patients.Ultimately, asymptomatic patients usually develop symp-toms.Small duct PSC has been reported to be less rapidlyprogressivethanlargeductPSC.8,9,24Thispatternisprob-ably not due to lead time bias, in that only 12% to 16% ofpatientswithsmallductPSCprogresstolargeductdisease(in 5- to 6-year follow up). Furthermore, some patientsdevelopcirrhosiswithoutobviouslargeductinvolvement.Thus, small duct PSC may present a distinct clinical en-tity.Several prognostic models for PSC have been developed(Table 2).2,25-29Most models include age and serum biliru-bin, but not symptoms. A revised Mayo Model has beendeveloped based upon the course of disease in 468 patientsseenatthreelargereferralcentersinthelast20years.Theriskscore is calculated as follows: 0.30 age (years)0.54 logebilirubin (mg/dL) 0.54 logeAST (U/L) 1.24 history ofvariceal bleeding (0no, 1 yes) – 0.84 albumin (g/dL)(web-based calculator available at http://www.mayoclinic.org/gi-rst/ mayomodel3.html). The advantage of the revisedmodel over the Child-Pugh-Turcotte (CPT) score or Math-ematical Model for End-stage Liver Disease (MELD) is incapturing earlier stages of PSC before onset of cirrhosis.30,31Once decompensated cirrhosis is present, the MELD scoremore accurately predicts survival and is more appropriatelyused in listing for liver transplantation.Dr. Kirsten Muri Boberg (Rikshospitalet, Oslo, Nor-way) described the epidemiology of PSC. With betterFig. 2. Survival in PSC, as measured by time to death or time to eitherdeath or liver transplantation. Modified with permission from Dr. W. RayKim.Table 1. Five Published Case Series on PSC in ChildrenAuthorRef(year)No. ofPatientsPercentMaleMean Age(years)PercentWithIBDPercentWith AIHfeaturesJaundiceElevatedAlk PDebray18(1994)1953%7.137%11%32%84%Wilschanski19(1995)3272%11.253%28%25%53%Gregorio11(2001)2744%11.844%100%56%NAFeldstein20(2003)5265%13.881%27%19%75%Floreani21(2005)30%15.333%100%NANAAbbreviations: IBD, inflammatory bowel disease; AIH, autoimmune hepatitis-like features; Alk P, serum alkaline phosphatase levels; NA, not available.748LARUSSO ET AL.HEPATOLOGY, September 2006Page 4diagnostic tests, PSC has been found to be more commonthan previously believed. In Scandinavian countries, PSCis the single leading cause for liver transplantation.10There have been few population-based epidemiologi-cal studies of PSC (Table 3). The incidence is 0.9 to 1.3per 100,000 in Northern Europe10,32,33and the UnitedStates6but less than 0.1 per 100,000 in Southern Eu-rope34and Asia.35Patients with PSC survive for an aver-age of 12 to 17 years, so that the prevalence of this diseasein these same surveys ranges from 8 to 14 per 100,000persons in Northern Europe and the United States, but is1.3 or less in Southern Europe and Asia. The frequency ofPSC in Africa is unknown and there have been no largestudies of PSC in minority U.S. populations (Asians andAfrican Americans). PSC appears to be rare among NativeAlaskans.36TheincidenceandprevalenceofPSC(1.3and8.5 per 100,000 in Oslo, Norway) is somewhat less thanthat for primary biliary cirrhosis (1.6 and 14.6 per100,000) and autoimmune hepatitis (1.9 and 16.9 per100,000).32PSC is frequently associated with IBD. In NorthernEurope and the United States, 70% to 80% of patientswith PSC have or will develop IBD. In contrast, IBD isfound in 54% or less of patients with PSC in Spain,34Italy,28and India37and in only 20% of PSC patients inAsian countries.38In Western countries, 2.4% to 4% ofpatients with IBD have PSC.39-41Of course, the fre-quency of these associations depends on diagnostic rigor.Thus, in some studies, patients with IBD are routinelyevaluated for liver disease (serum enzymes) or biliary ab-normalities [ERCP or magnetic resonance cholangiopan-creatography (MRCP)]. Furthermore, patients with PSCin these series are frequently screened for IBD usingcolonoscopy with biopsies. Thus, the epidemiology ofPSC is not well defined. Better studies are needed inlarger, more representative populations, using standard-ized means of screening and diagnosis.Session Two. Diagnosis and Assessment ofPrimary Sclerosing CholangitisDr. Angulo (Mayo Clinic, Rochester, MN) dis-cussed the differential diagnosis of PSC in adults. Themajor criteria for diagnosis are (1) cholangiographic find-ings of multifocal strictures and beading of the intra-and/or extra-hepatic bile ducts with (2) compatible bio-chemical abnormalities and (3) exclusion of secondarycauses.1,3,42Secondary causes of bile duct abnormalitiesthat should be excluded in adults include strictures due tosurgery, trauma, ischemia, tumors and infections, such ascryptosporidiosis and cytomegalovirus (particularly in pa-tients with immunodeficiency).PSC can be suspected from typical biochemical abnor-malities such as elevations in serum alkaline phosphataseand GGT with lesser increases in ALT and AST levels.The mainstay of diagnosis is ERCP demonstrating mul-tiple strictures and focal dilatation of bile ducts.1Mostdiagnostic are changes found in the extra-hepatic biliarytree, because focal narrowing and a “pruned tree†appear-ance can occur advanced cirrhosis without PSC. Recently,MRCP has been increasingly used for imaging of the bil-Table 2. Prognostic Models in PSC: FactorsReference (year)Factor 1Factor 2Factor 3Factor 4Factor 5Wiesner2(1989)AgeBilirubinHistologyHemoglobinIBDFarrant25(1991)AgeAlkaline PhosphataseHistologySplenomegalyHepatomegalyDickson26(1992)AgeBilirubinHistologySplenomegalyBroome27(1996)AgeBilirubinHistologyOkolicanyi28(1996)CholesterolALTKim29(2000)AgeBilirubinASTAlbuminVariceal BleedingAbbreviations: Alk Phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IBD, inflammatory bowel disease.Table 3. Epidemiology of PSCRegion(reference)TimePopulationNo. Casesof PSCIncidence(per 100,000/year)Prevalence(per 100,000)Norway321986-1995130,000171.38.5Wales, U.K.331984-2003NA460.912.7Minnesota, U.S.61976-2000NA220.913.6Spain34*1984-198819,200,000430.070.22Singapore35†1989-1998750,00010NA1.3Alaska, U.S.361983-2000100,312000Abbreviation: NA, not available.*Based on a questionnaire sent to gastroenterologists in parts of the country. †10 cases diagnosed over a 10-year period, giving a maximum prevalence of 1.3.HEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.749Page 5iary tree.43,44Liver biopsy is usually not needed for diag-nosis, although it may help in excluding other diseases.45There are no standardized and widely accepted diag-nostic criteria for the different forms of PSC. Small-ductPSC is diagnosed on the basis of cholangiography, butexcellent technique is needed to exclude mild extra-hepatic biliary involvement. Autoimmune features arecommon in patients with PSC, antinuclear antibody be-ing present in up to 50% and perinuclear antineutrophilcytoplasmic antibody (pANCA) in 80% of cases.46Auto-immune cholangitis is a term used to describe patientswith ERCP changes consistent with PSC who have sero-logical and histologic features of autoimmune hepati-tis.11,47Thus, the diagnosis of PSC relies on excellentcholangiography and the exclusion of other diseases, au-toimmune hepatitis being the most challenging.Dr. Giorgina Mieli-Vergani (King’s College Hospi-tal, London, UK) discussed the special challenges to diag-nosis of PSC in children. The diagnostic criteria for PSCare similar in children as adults, although a differentgroup of secondary causes need to be excluded, includingneonatal sclerosing cholangitis, Langerhans cell histiocy-tosis, primary and secondary immunodeficiences, andcysticfibrosis.13,19,22Amajordifferentialdiagnosisinchil-dren is between autoimmune hepatitis and autoimmunecholangitis (Table 4). At issue is whether these are differ-ent diseases; whether one evolves into the other; whetherthe prognosis and natural history of each are different;and whether different approaches to therapy should beused in these different clinical patterns of disease.Dr. Ann S. Fulcher (Virginia Commonwealth Uni-versity, Richmond, VA) reviewed the current role of im-aging tests in PSC. The gold standard for diagnosis hasbeen ERCP,1,2,48which in experienced hands is successfulin demonstrating the intra- and extra-hepatic biliary treein 95% of cases. Shortcomings of ERCP include its dis-comforts and risks, including pancreatitis, cholangitis, in-testinal or bile duct perforation, and bleeding. The risksare probably greater in patients with PSC than those withother diagnoses, and instances of life-threatening andeven fatal cholangitis have been reported. In recent years,MR techniques have been developed and improved suchthat MRCP has replaced ERCP for diagnosis of PSC inmany centers43,44,49,50(Fig. 3). MRCP is done withoutthe need for endoscopy, catheterization of the biliary tree,contrast material, sedation, or radiation exposure. MRCPhas the advantage of depicting ducts proximal to high-grade strictures and allowing visualization in patients withbiliary-enteric anastamoses and gastric bypass procedures.In addition, MR provides imaging of the rest of the ab-domen, which may yield important information. Theshortcomings of MRCP are that it is purely diagnostic,not allowing intervention. In addition, in some instances,MRCP may be less sensitive in demonstrating bile ductabnormalities and provide equivocal results that wouldcall for follow up ERCP. Overall, in routine cases, MRCPis probably the best initial approach to diagnosis of PSC51and can be used for screening, such as in patients withIBD or patients with new onset autoimmune hepatitis torule out PSC. ERCP and percutaneous transhepaticcholangiographywillremainusefuladjunctiveprocedureswhen MRCP is nondiagnostic or when acquisition of tis-sue samples or intervention is necessary.Dr. Swan N. Thung (Mount Sinai School of Medi-cine, New York, NY) discussed the role of liver biopsy inthe diagnosis and staging of PSC. The primary injury inPSC is not to hepatocytes but rather to medium- andlarge-sized bile ducts ( 100 m in diameter) which arenot captured in a typical percutaneous liver biopsy. Thesmaller bile ducts ( 100 m) are affected by the resultantobstruction and gradually disappear (“ductopeniaâ€). Thecharacteristic pathologic features of PSC are concentricTable 4. Autoimmune Cholangitis Versus Autoimmune Hepatitis Versus Primary Sclerosing Cholangitis in Children.11Clinicaland Laboratory Features at PresentationFeaturePSC n9AC n27AIH n28Male Sex67%45%25%Age at Onset (years)*6.6 (2-14.5)11.8 (2.3-16)10.5 (2.2-14)Jaundice at Onset13%56%68%Bilirubin (mg%)*0.9 (0.3-1.5)1.2 (0.3-10.5)2.1 (0.3-18.0)AST (U/L)*90 (26-760)102 (18-1215)333 (24-4830)Alk Phos (U/L)*474 (23-688)303 (104-1710)356 (131-878)GGT (U/L)*141 (23-688)129 (13-948)76 (29-383)Alk Phos/AST ratio*5.5 (1.4-9.9)4.0 (0.2-14.2)1.14 (0.1-14.8)pANCA44%74%36%Response to CorticosteroidsUncommon89%94%Presence of IBD33%44%18%Abbreviations: PSC, primary sclerosing cholangitis; AC, autoimmune cholangitis; AIH, autoimmune hepatitis; AST, aspartate aminotransferase; Alk Phos, alkalinephosphatase; GGT, gamma-glutamyl transpeptidase; pANCA, perinuclear antineutrophil cytoplasmic antibody; IBD, inflammatory bowel disease. *Median (range).750LARUSSO ET AL.HEPATOLOGY, September 2006Page 6periductal fibrosis (“onion-skinningâ€) that progresses to anarrowing and then obliteration of the small bile ductsleaving a bile duct scar (Fig. 4).52-54The bile duct epithe-lium may exhibit degeneration and atrophy. Chroniccholestasis leads to bile stasis, pseudoxanthomatouschanges, Mallory bodies, and copper accumulation, mosttypically in the periportal region. These changes are notpathognomic of PSC and can occur with chronic extra-hepatic bile duct obstruction from any cause.55The dif-ferential diagnosis should include primary biliarycirrhosis (PBC), biliary atresia, autoimmune hepatitis andgraft-versus-host disease.56Systems for grading and staging PSC have not beenrigorously tested for reliability. Stage 1 disease is markedby bile duct injury and portal inflammation with minimalfibrosis; Stage 2 by expansion of portal tracts, periportalfibrosis and further inflammation; Stage 3 by fibroussepta, bridging fibrosis, and progressive ductopenia; Stage4 by cirrhosis.53Systems that separate grade (activity)from stage (fibrosis) have not been developed and bettersystems for use in clinical trials are needed.The primary injury in PSC is to the major bile ducts,which are rarely available except at the time of autopsy orliver transplantation. The bile ducts are thickened andsclerotic and demonstrate alternating areas of stricturesand dilatation.57Dysplasia and malignant transformationmay be found in advanced cases.Sessions Three and Four. PathogenesisDr. LaRusso (Mayo Clinic Foundation,Rochester, MN) provided an overview of cholangiocytepathobiology. PSC is a cholangiopathy, belonging to aspectrum of diseases characterized by injury to and oblit-eration of cholangiocytes.58Cholangiocytes are epithelialcells and have several physiologic functions, the best char-acterized being transport of water, ions, and solutes intobile.59Cholangiocytes represent only 3% to 5% of cells inthe liver, but produce 40% of the volume of bile. Cholan-giocytes probably also function as sensors and modulatorsof bile flow and can reabsorb bile salts and other compo-nents. Cholangiocytes are heterogeneous; those fromsmall bile ducts have different morphology, gene expres-sion and response to injury than those from larger bileducts. Cholangiocytes proliferate in response to injuryand can assume an activated phenotype with de novo ex-pression of receptors, cytokines and chemokines. Cholan-giocytes interact with other cells in the liver includingmacrophages and immunocytes as well as with matrixproteins, microbes and xenobiotics.The cholangiopathies include genetic conditions(Alagille syndrome, cystic fibrosis, fibropolycytic dis-eases), immune-mediated disorders (PSC, PBC, autoim-mune cholangitis, allograft rejection, graft-versus-hostdisease), infections (cholangitis due to bacteria, fungi,parasites or viruses), drug-induced injury (floxuridine),ischemic damage (hepatic artery thrombosis), malignan-cies (cholangiocarcinoma) and diseases of unknown etiol-ogy (biliary atresia, sarcoidosis, idiopathic vanishing bileduct syndromes).58These diseases are associated with bileduct injury which can lead to loss of bile ducts, bile stasis,and secondary hepatocellular injury.Recent advances in techniques in isolation and study ofcholangiocytes have allowed for better understanding oftheir biology. Cholangiocytes have multiple receptors,transporters, ion channels, and exchangers.59Strikingly,cholangiocyteshaveasingleprimarycilium,alongtubularFig. 3. Magnetic resonance (left panel) compared to endoscopicretrograde cholangiography (right panel) in a patient with extra- andintrahepatic PSC. Reprinted from: Fulcher AS, MA, lin KJ,Shiffman M, Sterling RK, Luketic VA, Sanyal AJ. Primary sclerosingcholangitis: Evaluation with MR cholangiography—a case control study.Radiology 200-;215:71-80,49with permission from the RadiologicalSociety of North America.Fig. 4. Histology of PSC showing a typical bile duct scar with resultantductopenia in PSC. Masson trichrome stain, original magnification100. Provided with permission by Dr. Swann Thung.HEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.751Page 7organellethatarisesfromthecentrosomeandextendsintothe duct lumen. Cilia act as mechanical, chemical, andosmotic sensors, and disorders in their structure and func-tion may underlie the pathology of polycystic liver diseaseand cystic fibrosis.Cholangiocytes also interact with immune cells andproduce as well as respond to cytokines, growth factorsand signaling molecules, which are no doubt important inthe pathogenesis of immune-related cholangiopathies.The cellular crosstalk between the immune system, mac-rophages, hepatic stellate cells, and cholangiocytes in-cludes production of and/or response to cytokines,growth factors, endothelin-1, and nitric oxide. The reac-tive cholangiocyte is likely to play an important role inliver damage and repair (Fig. 5).Dr. son (University of Newcastle-Upon-Tyne, UK) discussed the genetics of PSC. The ge-netic predisposition to PSC is shown by the 100-foldincreased risk of this disease among siblings.60,61Inheri-tance of PSC, however, does not follow classical Mende-lian genetics, but appears to be complex; one or moregenes act alone or in concert to increase or decreaserisk.60,62Difficulties in genetic studies of PSC are its rarityand delayed expression, factors that preclude traditionallinkage analysis.The major genetic associations described in PSC arewith specific alleles of the human MHC, a large region ofchromosome 6p21.3, which includes 252 expressedgenes, 56 of which are polymorphic. To date, 10 of these56 have been evaluated in PSC including the human leu-kocyteantigen(HLA)classIA,B,andCwgenes;theHLAclass II DRB, DQA, DQB, and DPB genes; and two genesfrom the MHC class III region, MICA and TNFA.60,62,63Six different MHC haplotypes have been associated withPSC (Table 5), 3 with an increased and 3 with a reducedrisk of disease. Some haplotypes appear to carry severalrisk alleles (B8-TNFA*2-MICA*008-DRB1*0301 haplo-type), while others carry only one (MICA*002). To date,no common shared risk allele or peptide sequence hasbeen identified.The biological bases for the genetic associations be-tween the MHC and PSC are not well understood. HLAclass I and II molecules are important in T cell immunity,whereas, the MHC class III MIC- molecule is importantin innate immunity, particularly in the regulation of nat-ural killer (NK) cells.63Further understanding of the role of MHC genes insusceptibility and resistance await better knowledge ofspecific autoantigen(s) and/or infectious agents in PSC.Importantly, MHC genes alone are unlikely to accountfor all of the genetic risk in PSC. Non-MHC risk genes ofinterest include CARD4, CARD15, as well as BSEP,MDR3, and CFTR.60,64-66Dr. M. Vierling (Baylor College of Medicine,Houston, TX) described the current status of animalmodels of PSC. The rarity of PSC and the difficulties inassessing cholangiocyte injury in humans stress the needfor a reliable animal model to study pathogenesis andevaluate potential therapies. Unfortunately, no currentanimal model fully recapitulates the clinical and patho-logical features of PSC.67,68Cholangiocyteinjuryandbileductlosscanbeinducedbyseveral toxins, and pathologic features resembling sclerosingcholangitis can be induced by infusions of formalin, 2,4,5-trinitrobenzenesulfonicacid,alpha-naphthylisothiocyanate,or steroidal sapongenins into the biliary tree of rodents.While immune signals are activated by these toxic injuries,the conditions do not mimic the human disease. A specificmurine model of graft-versus-host disease develops featuresof PSC but with involvement of smaller rather than largerbile ducts.69Infection of immunodeficient mice with Cryptospo-ridium and of rodents and cats with Helicobacter speciesFig. 5. Proposed pathogenesis and cause of progression in PSC.Modified and reprinted from: Lazaridis KN, Strazzabosco M, LaRusso NF.Cholangiopathies: Disorders of biliary epithelia. Gastroenterology 2004;127:1565-1577,58with permission from the American Gastroenterologi-cal Association.Table 5. Haplotypes Associated With PSC Disease RiskHaplotypeOdds RatioIncreased RiskB8-DRB1*03012.69DRB1*13013.80DRB1*15011.52Decreased RiskDRB1*04010.26DRB1*07010.15MICA*0020.12752LARUSSO ET AL.HEPATOLOGY, September 2006Page 8produce secondary forms of sclerosing cholangitis, whichcan be used to study pathogen and immune-mediatedcholangiocyte injury. A potentially valuable model ofPSC was produced in genetically susceptible rats withsmall bowel bacterial overgrowth after portal infusionwith bacterial peptidoglycanpolysaccharides, ligands forinnate immune receptors on Kupffer cells.70These ani-mals develop histologic and cholangiographic features ofPSC. Submucosal colonic injections of the bacterial cellwall product, muramyl dipeptide, results in colitis,peribiliary inflammation, and fibrosis, which resemblesPSC. Finally, a proinflammatory, chemotactic peptide se-creted by Escherichia coli is cleared from portal venousblood by hepatocytes and secreted into bile, where it actsas a chemoattractant for both neutrophils and macro-phages, causing peribiliary inflammation and injury.71Thus, several animal models exist that exhibit immuno-logical and genetic susceptibility similar to PSC, but nonefully recapitulates the human disease.Dr. Trauner (Medical University, Graz, Aus-tria) discussed the potential role of hepatobiliary trans-porters in PSC. Normal bile secretion is dependent onand regulated by a large number of hepatic and biliarytransporters, defects in which can lead to severe liver dis-ease.72The Mdr2 gene, the murine analog of humanMDR3/ABCB4, encodes a canalicular phospholipid flip-pase responsible for transport of phospholipids into bile.Humans with MDR3 mutations develop progressive fa-milial intrahepatic cholestasis, type 3 (PFIC-3) a severeform of chronic cholestasis.72In mice, knockout of theMdr2 gene results in a spontaneous sclerosing cholangitiswith serum biochemical as well as histologic features re-sembling human PSC.73,74Preliminary data indicate thatthese mice also develop autoantibodies includingpANCA. The bile duct injury may be due to defectivebiliary phospholipid secretion which results in produc-tion of “toxic bile,†causing cholangiocyte injury.74TheMdr2 knockout mice do not develop IBD or cholangio-carcinoma but can develop hepatocellular carcinoma.The possibility that mutations in the MDR3 gene inhumans are linked to PSC has been investigated in tworecent studies (a total of 80 patients), neither of whichfound an increase in MDR3 haplotype distribution.75,76However, the hypothesis that injury in PSC is due todefective bile acid or lipid secretion with formation oftoxic bile is attractive and deserves further study. Indeed,patients with cystic fibrosis with mutations in their chlo-ride transmembrane conductance regulator gene (CFTR)can develop ductopenia with focal biliary cirrhosis as aresult of inspissated bile which injures cholangiocytes.The role of CFTR mutations in PSC is controversial,some studies demonstrating an association66,77and othersnot.78,79Other candidate transporters that could play arole in PSC include the canalicular bile salt export pump(BSEP), the cholesterol transporter (ABCG5/G8), andthe glutathione transporter (conjugate export pumpMRP2).75,76,80Chronic inflammation and injury maylead to downregulation of cholangiocyte transporters,81,82which may be mediated by proinflammatory cytokines ormediators. These regulatory processes may help to protecthepatocytes from accumulation of toxic biliary constitu-ents.83-86The Mdr2 knockout mouse model has recently beenused to assess therapies of PSC.87Promising results wereobtained with use of the side-chain shortened bile acidnorUDCA, a C23 homolog of ursodeoxycholic acid(UDCA). NorUDCA, unlike UDCA, undergoes littlehepatic conjugation and is reabsorbed by cholangiocytesfrom bile. Such biliary-hepatocyte shunting circumventsthe intestine and may result in improved targeting of thehydrophilic bile acid to injured bile duct epithelium. Inthe Mdr2 knockout mouse, norUDCA, but not UDCA,ameliorated the histological changes of sclerosing cholan-gitis and improved serum liver enzymes. Thus, hepato-biliary transporter defects can cause bile duct injury, andtargeting of transporter changes and bile toxicity may af-ford valuable approaches to therapy of PSC.Dr. W. Chapman (Oxford University MedicalSchool, Oxford, UK) discussed the evidence that autoim-munity plays a role in PSC. Autoimmunity is defined asimmune reactivity against self-molecules that is sufficientto cause cell and tissue injury. Evidence that PSC is anautoimmune disorder include the presence of hyperglob-ulinemia, multiple autoantibodies, activated immuno-cytes88,89and the association with specific “autoimmuneâ€MHChaplotypes.60PSCalsoisassociatedwithotherpos-sible autoimmune conditions such as IBD and, to a lesserextent, autoimmune hepatitis and thyroiditis.PSC is associated with multiple autoantibodies (Table6), but most closely with pANCA.90Although commonin PSC, pANCA is not specific, nor do its levels predictprognosis or response to therapy. While pANCA is rare inTable 6. Prevalence of Autoantibodies in PSCAntibodyReportedPrevalence2Atypical perinuclear antineutrophil cytoplasmic antibody(pANCA)33%-87%Antinuclear antibody (ANA)7%-77%Anti-smooth muscle antibody (SMA)13%-20%Antiendothelial cell antibody35%Anticardiolipin antibody4%-66%Antithyroperoxidase antibody (anti-TPO)7%-16%Antithyroglobulin antibody (anti-TG)4%Rheumatoid factor (RF)15%HEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.753Page 9PBC and extra-hepatic obstruction, identical reactivitycan be found in up to 42% of patients with autoimmunehepatitis, 34% with ulcerative colitis, and 4% withCrohn’s disease. Preliminary results using proteomicssuggest that the auto-antigen of pANCA is the nuclearenvelop protein, myeloid-specific tubulin-beta isotype 5.91The autoantibodies in PSC including pANCA do notappear to play a pathological role. Nevertheless, the bili-ary epithelial cell appears to be the target of immune-mediated injury and dense infiltrations with activated Tcells and high local concentrations of pro-inflammatorycytokines with increased expression of HLA on bile ductsare common.92Thus, PSC appears to be immune-medi-ated, but direct evidence that it is an autoimmune diseaseis lacking.Dr. Podolsky (Harvard Medical School, Bos-ton, MA) discussed the pathogenesis of IBD as it relates toPSC. Recent findings point to the role of the innate im-mune response in the pathogenesis of ulcerative colitisand Crohn’s disease,93and similar studies are now beingextended to PSC.Unlike adaptive immunity, innate immunity is rapidand immediate (rather than delayed), hardwired (not re-quiring priming), dependent upon pattern molecule rec-ognition (rather than specific antigens), and mediated bymacrophages, NK cells and other antigen-presenting cells(rather than B and T cells). Innate immune responses areoften triggered by engagement of toll-like receptors(TLRs), a system of transmembrane receptors, the bestknown of which are TLR4 (the receptor for lipopolysac-charide), TLR3 (dsRNA), TLR5 (flagellin), TLR7/8 (ss-RNA), and TLR9 (CpG DNA). The signaling pathwaysare complex and interactive and many activate nuclearfactor kappa B (NF resulting in production of multi-ple downstream inflammatory mediators. TLRs arehighly expressed in gastrointestinal tract epithelial cellsincluding cholangiocytes.94,95Activation of the TLRs canmodulate transepithelial resistance and decrease epithelialbarrier function which may be important in the etiologyof PSC.Genome-wide scans for susceptibility to IBD haveidentified mutations in the gene NOD2 (or CARD15) ina proportion of familial cases. NOD1 and NOD2 are keyintracellular receptors which activate innate immune re-sponses.96Thus, a unifying hypothesis is that IBD iscaused by abnormalities in the innate immune responsewhich results in heightened immune reactivity to intesti-nal bacteria. Similarly, activation of TLRs and engagementof the innate immune response has recently been demon-strated in PSC, PBC, and other biliary diseases,97-100sug-gesting that alterations in TLR pathways and NODs mayplay a role in these diseases as well.Dr. H. (University of BirminghamMedical School, Birmingham, UK) discussed the role ofT cell activation in PSC. Recent findings suggest that theunderlying injury in PSC associated with IBD is due toinappropriate recruitment of mucosal lymphocytes to ex-tra-intestinal tissue.101,102Effector cells activated by gutinflammation exhibit increased adhesion to endothelia inother organs mediated by nonspecific adhesion mole-cules.103In PSC, there is aberrant hepatic expression ofthe gut addressin MADCAM-1 and the gut-specific che-mokine CCL25, which are normally restricted to the gutwhere they regulate recruitment of mucosal lympho-cytes.92,104-106InPSC,theliverisinfiltratedwithactivatedmucosal T cells.107These T cells are long-lived memorycells capable of being activated to secrete pro-inflamma-tory cytokines.105The activated T cells can bind to biliaryepithelial cells via specific adhesion pathways.108Becausememory cells, unlike effector cells, are long lived, thismechanism can explain the clinical findings of discrepan-cies between periods of activity of IBD and that ofPSC.101However, until the signals responsible for theinduction of gut-specific homing receptors in the liver inPSC are determined, it is uncertain whether these pro-cesses are primary instigators of the biliary disease or sec-ondary players that amplify liver damage.Session Five: Therapy of PSCDr. Marshall Kaplan (Tufts-New England MedicalCenter, Boston, MA) provided an overview of medicalmanagement of PSC. No therapy has yet been proven toprolong survival or improve outcome of PSC.41,42,109Clinical trials of new treatments for PSC are challengingbecause of its rarity, the lack of understanding of itspathogenesis, the difficulty in identifying the diseaseearly, and the lack of surrogate endpoints for definingbenefit. Most therapies that are used are directed at thecomplications rather than the underlying cause of PSC.Ursodeoxycholic acid (UDCA), the hydrophilic bileacid, is conventionally recommended for patients withPSC. UDCA therapy can lead to improvements in serumbilirubin, alkaline phosphatase, and ALT, but has notbeen shown to slow the course of illness or prolong sur-vival. Furthermore, the data on the effects of UDCA onsymptoms and quality of life are controversial.109In alarge, prospective, randomized controlled trial from theUnited States, UDCA therapy (12-15 mg/kg daily) wasassociated with improvements in serum liver enzyme ab-normalities, but had no effect on liver histology or livertransplant-free survival.110Subsequently, small pilot trialssuggested that higher doses of UDCA (25-30 mg/kg/day)might be more effective than standard doses.111,112A re-cent report of a randomized controlled trial in 198 pa-754LARUSSO ET AL.HEPATOLOGY, September 2006Page 10tients from Europe, however, demonstrated no effect ofhigher UDCA doses on symptoms, serum biochemicalabnormalities, quality of life, or transplant-free surviv-al.113Death or liver transplantation occurred in 7% ofUDCA-treated compared to 11% of placebo-treated pa-tients (P.37). A similar but larger trial of high-doseUDCA therapy in PSC is currently underway in theUnited States.114In patients with an autoimmune cholangitis, use ofcorticosteroids has been associated with a high rate ofclinical response, in symptoms as well as in serum biliru-bin and ALT levels.115Whether corticosteroids alter thenatural history of this form of PSC has not been estab-lished. Certainly, corticosteroids are not beneficial in typ-ical PSC and have considerable risks in this population(osteoporosis, increased susceptibility to infections).Other agents that failed to show efficacy in PSC in con-trolled trials include methotrexate, colchicine, D-penicil-lamine, pentoxifyliline, and tacrolimus.109,116The use ofstandard doses of UDCA, although widely recom-mended, has scant evidence for either short-term or long-term benefit and is unlikely to have an effect on theunderlying pathogenesis of PSC. Clearly, new therapiesare needed.Dr. Shneider (Mount Sinai School ofMedicine, New York, NY) discussed management of PSCin children. There have been no prospective, randomizedcontrolled trials of therapy of PSC in children, and rec-ommendations are based on studies in adults and anec-dotal findings from cases series in children.11,18-22UDCA(15-30 mg/kg/day) leads to improvements in liver testabnormalities, particularly in children with early disease.Children with autoimmune cholangitis usually have amarked clinical response to corticosteroids with or with-out azathioprine. Ultimately, however, these agents maynot control the disease, and features of chronic cholestasisarise. Because of the known adverse effects of corticoste-roids on linear growth and bone mineral density, theseagents should be closely monitored and the lowest dosethat maintains biochemical remission used. Trials ofother approaches to therapy are greatly needed in chil-dren, but are unlikely to be initiated without a nationwideor an international initiative.Dr. Adolph Stiehl (University of Heidelberg, Heidel-berg, Germany) provided an overview of the complica-tions of PSC. Nonspecific complications include fatigue,pruritus, metabolic bone disease, steatorrhea, and fat-sol-uble vitamin deficiencies.5,11,109The fatigue of PSC issimilar to that of other liver diseases, is rarely disablingand is sometimes, but not reliably, improved with UDCAtreatment. In contrast, pruritus in PSC can be severe andinterfere with activities of everyday life. Pruritus rarelyresponds to typical antipruritic medications such as anti-histamines, but may respond to resin-binding agents suchas cholestyramine. In controlled trials, UDCA has notbeen associated with improvements in pruritus.110,113Ri-fampin has been used to treat pruritus in patients withliver disease, but its mechanism of action is unclear.117,118ThebonedensityandvitamindeficiencycomplicationsofPSC should be monitored and treated appropriately. Sup-plementation with calcium and fat-soluble vitamins isappropriate, particularly in patients with advanced dis-ease.109Specific complications of PSC include bacterialcholangitis, biliary strictures, biliary duct stones and chol-angiocarcinoma as well as complications of IBD. Bacterialcholangitis is common in patients with PSC particularlyafter biliary interventions and may accelerate the progres-sion of the liver injury. Prophylaxis with antibiotics hasnot been proven to be of benefit, but patients with recur-rent cholangitis should be advised to seek medical atten-tion rapidly and start antibiotics at the first sign of biliaryinfection.109Patients with PSC and IBD are at increased risk ofcolon cancer. Preliminary reports suggest that UDCAtherapy decreases the risk of colon cancer,119,120perhapsby changing the intestinal milieu by decreasing concen-trations of hydrophobic bile acids in favor of UDCA.121Cross-sectional studies indicate a lower rate of colonicepithelial dysplasia among patients receiving UDCA.120However, UDCA therapy has not been associated with alower rate of colon or other cancers in patients withPBC,122,123and this effect in PSC awaits further prospec-tive assessment.Dr. Kalloo (s Hopkins School of Med-icine, Baltimore, MD) discussed endoscopic therapy ofPSC. Between 10% and 15% of patients with PSC willexperience high-grade obstruction from a discrete area ofnarrowing within the extra-hepatic biliary tree (dominantstricture).1,2,41These strictures can cause sudden worsen-ing of jaundice and cholangitis. In the past, dominantstrictures were managed surgically. With advanced endo-scopic techniques, they can be managed using ERCP withballoon or coaxial dilatation.124-130Clinical response canbe achieved in 80% of patients without cirrhosis. Endo-prostheses can be placed across strictures, but stent occlu-sion and cholangitis are frequent, and prospective studiesfailed to show their benefit.131-135Endoscopic dilation of dominant strictures is currentlywidely practiced despite the lack of prospective random-ized controlled trials demonstrating its benefit.136,137Ret-rospective analyses using the Mayo Risk Score to modeloutcome, however, have suggested that endoscopic dila-tation of dominant strictures does improve survival.130HEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.755Page 11Therapeutic endoscopy has risks, and complications oc-cur in 10% of patients, the most common being pancre-atitis, acute cholangitis, biliary tract perforation andhemorrhage.138These complications usually respond toconservative management. Thus, interventional endo-scopic therapy may improve outcome in patients withdominant strictures due to PSC, but should only be doneby endoscopists with extensive experience in managementof biliary strictures.Dr. Lindor (Mayo Clinic Foundation, Roches-ter, MN) discussed future innovative approaches to ther-apy of PSC. To date, available animal models and in vitrostudies have suggested autoimmunity, cytokines, infec-tions, and bile acid transporter or ion channel abnormal-ities as underlying causes of PSC.5,41,114,139Accordingly,immunosuppressive agents, anticytokines, antibiotics,and modulators of ion channels or bile acid transportershave been tried in small pilot trials, largely without evi-dence of success. The agents found to have little effectinclude corticosteroids, budesonide,140tacrolimus,141methotrexate,116,142,143mycophenolate mofetil,144pen-toxyfylline,145silymarin,146and etanercept.147Trials ofantibiotics such as metronidazole148and minocyclinehave been promising but inconclusive. A small study ofdocosahexaenoic acid which improves CFTR function iscurrently underway. Antifibrotic agents such as pirfeni-done which inhibit fibrogenesis have also been testedwithout obvious benefit.149Most promising for the nearfuture are inhibitors of TNF action, antifibrotic agents,and inhibitors of formation of toxic bile.87Session Six. Liver Transplantation for PSCDr. Merion (University of Michigan, Ann Ar-bor, MI) reviewed the current status of liver transplanta-tion for PSC. Liver transplantation is the only therapythat can reverse or correct end-stage liver disease fromPSC.150-152In the United States, approximately 250 livertransplants are done yearly in adults for PSC, representing5% of all liver transplants (Scientific Registry of Trans-plant Recipients, 2005). Males account for 70% of can-didates, and the median age is 50 years. In relation toother diagnoses, candidates with PSC are more likely tobe younger, male, and African American.The MELD system is currently used for liver organallocation in the United States, regardless of cause of end-stage liver disease.31,150-153At any time, 800 to 900 adultpatients with PSC are on the national waiting list, repre-senting 5% to 6% of candidates.In 2004, there were only10 deaths per 100 patient-years among PSC transplantcandidates compared to 17 per 100 among non-PSC can-didates. PSC candidates had the lowest death rate of anydiagnostic subgroup.Survival after transplantation is also excellent for can-didates with PSC, being 90% at 1 and 84% at 2 years,rates that are higher than any other patient subgroup (Fig.6).154-156Retransplantation rates are higher for patientswith PSC than other diagnoses (9.6% vs. 4.9% within 2years).The survival benefit of liver transplantation can be cal-culated by the ratio of death rates on the waiting listcompared to that after liver transplantation adjusting forother factors that affect survival.154For PSC, the adjustedmortality rate ratio for transplantation is 0.31, which is69% lower compared to remaining on the waiting list.These features demonstrate the very real benefit of livertransplantation for PSC.Dr. Estella Alonso (Children’s Memorial Hospital,Chicago, IL) addressed the special issues surroundingliver transplantation for children with PSC. PSC is anuncommon indication for liver transplantation in chil-dren,19,20being the cause for only 73 of 2219 (3.5%)children listed in the Studies of Pediatric Liver Transplan-tation (SPLIT) registry between 1995 and 2004.157Com-paredtochildrenwithotherdiagnoses,childrenwithPSCwere more likely to be male (64% vs. 47%: P.004),Caucasian and older in age (median 12.7 vs. 1.4 years),and were less likely to be hospitalized. Probably as a con-sequence, waiting time for transplant was longer for chil-dren listed for PSC than other diagnoses. Nevertheless,survival on the waiting list was excellent, with only oneFig. 6. Patient survival after liver transplantation for PSC with com-parisons to acute hepatic necrosis, other cholestatic liver diseases,malignancies, and cirrhosis not due to cholestatic diseases. Adjusted forrecipient age, gender, race, body mass index, MELD score at the time oftransplant, medical condition, dialysis, diabetes, life support, surgery,and portal vein thrombosis, donor age, gender, race, cause of death,donation after cardiac death of donor, partial/split liver, and coldischemia time. Analysis of the Scientific Registry of Transplant Recipientscarried out by Goodrich, MS. Supported by contract number231-00-0116 from the Health Resources and Services Administration(HRSA), U.S. Department of Health and Human Services.756LARUSSO ET AL.HEPATOLOGY, September 2006Page 12death being recorded. At the time of transplant, childrenwith PSC tended to have milder disease than childrenwith other diagnoses both in terms of clinical status andPediatric End-Stage Liver Disease (PELD) scores. In ad-dition, posttransplant survival in children with PSC wasexcellent,with1-yearsurvivalof98%comparedto87.5%for all other diagnoses (P.04).Drs. and Neuberger (Univer-sity of Birmingham Medical School, Birmingham,UK) reviewed the issue of PSC recurrence and latecomplications after transplantation. Transplantationfor PSC generally involves resection of the extra-he-patic biliary tree and use of a Roux-en-Y loop.150Re-currence of PSC in the transplanted graft bile ducts hasbeen reported, but its frequency, natural history, andoptimal management are not well defined. The diagno-sis of recurrent PSC is a challenge, in that many fea-tures can be mimicked by liver injury caused byischemia, infection, chronic rejection, biliary obstruc-tion, and medications.158-161The reported frequency ofrecurrent PSC ranged from 1% to 33%, the variationrelated in part to differences in diagnostic criteria, du-ration of follow up, and rigor with which thediagnosis is sought.150,162-166Factors associated withrecurrence were steroid-resistant rejection, OKT3 use,preservation injury, ABO incompatibility, cytomega-lovirus infection, lack of history of colectomy, malesex, and donor-recipient gender mismatch, but notspecific calcineurin inhibitor use or frequency of rejec-tion.162-167A critical issue is whether recurrence of PSC ad-versely affects outcome. Instances of graft failure due torecurrent PSC are rare and often confounded by thepresence of other forms of liver injury. Overall, thelong-term outcome of liver transplantation for PSC hasbeen excellent, with 10-year survival in Europe being ashigh as 79% (www.eltr.org). Also important in long-term follow up of transplantation for PSC is the ac-companying IBD and complications of colon cancer.Overall, the cumulative rate of de novo appearance ofcolitis after liver transplantation has been 6% at 1 and20% at 5 years.168Among persons with preexistingIBD, flares occur in approximately 39%. Instances ofcholangiocarcinoma due to recurrent PSC have beenpublished.169More important has been colon cancer,which is common, particularly in patients with preex-isting ulcerative colitis.167,170The cumulative risk forcolon cancer is 14% at 5 years and 17% at 10 years.Routine surveillance colonoscopy is recommended,and UDCA is commonly used as means of decreasingthe risk of colon cancer, although neither practice hasbeen proven to be effective in this situation.Session Seven. CholangiocarcinomaDr. Hashem El-Serag (Baylor College of Medicine,Houston, TX) described the epidemiology of cholangio-carcinoma. Cholangiocarcinoma is typically separatedinto intra- and extra-hepatic forms and categorized sepa-rately from gall bladder cancer. Unfortunately, manycancer registries do not separate these forms, and catego-rization of hilar tumors (Klatskin tumors) as intra- versusextra-hepatic is inconsistent. Data from the U.S. Surveil-lance, Epidemiology and End Results (SEER) databaseindicate that the incidence of intrahepatic cholangiocar-cinoma (including Klatskin tumors) has risen from 0.32in 1975-1979 to 0.66 per 100,000 population between1975 and 2002, while rates of extra-hepatic cholangiocar-cinoma have decreased.171-173It is not clear whether thesearetrueincreasesorwhethertheincreasesareduetobetterdiagnosis and changes in classification. Nevertheless, sim-ilar patterns have been reported from England and Japan.The incidence of cholangiocarcinoma increases withage with highest rates in the 8th and 9th decade of life.The identifiable risk factors include PSC, IBD, chronicliver disease, cirrhosis, alcohol use, smoking and diabe-tes.174,175Interestingly, in these databases no more than10% of cholangiocarcinoma are attributed to PSC.Among cohorts of patients with PSC, the risk of develop-ing cholangiocarcinoma ranges from 0.6% to 1.5% peryear, leading to a 20% lifetime risk.176,177Risk factors arenot well defined. This cancer is not associated as closelywith cirrhosis as is hepatocellular carcinoma. The risk alsoappears to be independent of the duration of PSC or IBD.In some studies, UDCA therapy has been associated witha decreased risk of cholangiocarcinoma,120,178but not inothers.113,150Dr. Naga Chalasani (Indiana University School ofMedicine, Indianapolis, IN) discussed the clinical fea-tures, diagnosis and natural history of cholangiocarci-noma associated with PSC. Cholangiocarcinoma hasseveral typical presentations.150,177Most typically patientswith long-standing PSC present with abdominal pain andworsening jaundice, marked elevations in alkaline phos-phatase and CA 19-9 levels, and strictures of the extra-hepatic biliary tree which upon brushings or biopsy showcholangiocarcinoma. However, cholangiocarcinoma canalso present without symptoms, with extra-hepatic man-ifestations (thrombophlebitis), or as an incidental findingduring surveillance or at the time of liver transplantation.Regardless of presentation, the outcome of cholangio-carcinoma is poor, with survival rare beyond 1 year. If anytherapy is to be curative, early diagnosis should be impor-tant.179However, in prospective studies, the risk was sim-ilar at different stages of disease. Among serum tumorHEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.757Page 13markers for cholangiocarcinoma, the most promising isCA 19-9.179-181High CA 19-9 levels ( 129 U/L) have ahigh specificity, but low sensitivity, particularly forsmall cancers. Addition of testing for carcinoembry-onic antigen and serial testing for tumor markers mayimprove accuracy,181but the reliability for early detec-tion has not been defined and the increase in sensitivity islikely to come with an increase in false positive reactions.Brush cytology and pinch biopsies have been used forsurveillance of cholangiocarcinoma in patients withPSC.182However, ERCP is not without risk and theadded benefit of cytology and biopsy are unproven. Pro-spective studies using brushing for cytology and biopsieswith combinations of specialized tests (such as analysis ofp53, K-ras mutations, fluorescent in situ hybridization forchromosomal abnormalities) have not materially in-creased the sensitivity of such screening. Specialized im-aging using MR and positron emission tomographyscanning have not been systematically studied and tend tohave poor sensitivity and specificity. Thus, there is scantevidence that current approaches to surveillance for chol-angiocarcinoma are effective in prolonging patient surviv-al.179Dr. Greg Gores (Mayo Clinic Foundation, Rochester,MN) discussed the pathogenesis of cholangiocarcinoma.Cholangiocarcinoma arising during the course of PSCrepresents a classic example of the role of chronic inflam-mation in carcinogenesis.176,179Studies of cholangiocytesfrom PSC patients showed that chronic inflammationstimulates expression of nitric oxide synthase which cancontribute to carcinogenesis by inducing DNA injury,inhibiting DNA repair, causing increased expression ofdevelopmental cell receptors, silencing of tumor suppres-sor genes, and inhibiting apoptosis.183-188Aneuploidy is acommon feature of cholangiocarcinoma and may play arole in carcinogenesis in PSC. Aneuploidy detected incholangiocytes from biliary brushings may appear beforethe development of cholangiocarcinoma. Furthermore,trisomy-7 may be an early marker possibly due to effectsof epidermal growth factor on chromosome 7 in cholan-giocarcinoma cells. Understanding the mechanisms ofcarcinogenesis in PSC may point to specific targets fornoncytolytic chemotherapy.Dr. Massimo Malagó (University of Essen, Germany)provided an overview of the role of surgery and liver trans-plantation for cholangiocarcinoma. Cholangiocarcinomais often detected late, when it is no longer resectable or hasalready spread to other organs.176,179Medical manage-ment with stenting, radiation therapy, or conventionalchemotherapy is largely ineffective, with 1-year survivalbeing rare. Surgical resection of cholangiocarcinoma isalso rarely successful; reported 5-year survival rates rangefrom 9% to 28%, although somewhat higher with extra-hepatic tumors.189-191In view of these results, liver trans-plantation has been tried, for both resectable andunresectable tumors.192In 3 large, single-center series,which included a total of 60 patients, survival was 22% to77% at 1 year and 0% to 39% at 3 years.193-196Because ofpoor outcomes, many centers will no longer perform livertransplantation for patients with cholangiocarcinoma andwill terminate surgery if a patient is found to have anincidental cancer during exploration. On the other hand,innovative approaches using a combination of neoadju-vant chemotherapy, irradiation and transplantation holdsome promise.197-200Use of these approaches should belimited to centers engaged in prospective studies of de-fined chemotherapeutic and surgical regimens.Summary Recommendations for FutureResearchResearch on PSC would be aided by standardization ofnomenclature and diagnostic criteria including defini-tions of endpoints for clinical trials. Currently, there islittle agreement on diagnostic criteria for subgroups ofPSC, and terms used to describe PSC are not well defined.Similarly, there are no widely agreed upon staging andgrading systems for PSC, based upon clinical features,histology or cholangiographic changes and, consequently,no standard endpoints for clinical trials other than livertransplantation and/or death. Surrogate endpoints wouldbe much more appropriate for evaluation of therapiesaimed at the etiology of PSC or directed at early stages ofdisease. Better definitions would also allow for compari-son of results of studies from different areas of the worldand would allow for phenotype-genotype comparisons ingenetic studies.Epidemiologic studies of PSC are needed to better de-fine the prevalence and incidence of this disease particu-larly in special cohorts of patients, such as minorityindividuals, persons with IBD and persons from areas ofthe world where PSC is uncommon. These studies shouldusecommoncriteriafordiagnosisandcommonmeansforscreeningoridentifyingcases.Truevariationingeograph-ical and racial frequency of PSC may provide insights intoits pathogenesis. Risk factors in populations deservingfurther study include smoking, socioeconomic class, clin-ical and genetic features of associated IBD, modifyinggenes,familialassociations,andenvironmentalexposures.NaturalhistorystudiesofPSCcurrentlypaintapictureof a variable course of disease with an average survival of12 to 17 years. Further, more rigorous studies are neededto help define the full spectrum of disease, factors thatcontribute to progression, and means of grading and stag-ing disease severity. A cohort study or registry of a large758LARUSSO ET AL.HEPATOLOGY, September 2006Page 14number of patients with PSC drawn from various referralcenters would be helpful in better defining natural historyand providing patients for clinical trials. Such cohortstudies should include children and appropriate numbersof minority individuals. A special focus should be on au-toimmune cholangitis.The pathogenesis of PSC remains unclear but promis-ing inroads have been made in elucidating genetic andimmunologic mechanisms. The basic cell biology of thebiliary epithelial cell deserves more attention particularlythe response of cholangiocytes to inflammatory signalsand injury. An animal model of PSC that adequately re-flected the disease course and outcome would be of greatbenefit, not only in helping to define pathogenesis, butalso in developing approaches to prevention and treat-ment. In this regard, the Mdr2 knock-out mouse andmurine models generated by altering the immune systemdeserve further study. Ultimately, hypotheses and path-ways elucidated in animal models need to be investigatedin humans with PSC. A natural history cohort study thatprovided well characterized serum, tissue and DNA sam-ples would be an invaluable resource for investigation ofinnovative concepts regarding pathogenesis.Genetic factors are important in PSC, and further in-vestigation of MHC genes as well as bile transporter andbiliary epithelial function genes are justified. Cohort stud-ies would help to provide clinical material and shouldinclude arrangements for obtaining informed consent forgenetic studies, privacy protection and resources for stor-ing adequate amounts of carefully isolated DNA samplesfrom patients who are fully characterized clinically. Stud-ies of the genetics of IBD should be expanded to includeanalyses of patients who also have PSC.Cholangiocarcinoma is the most dreaded outcome ofPSC and there are currently no reliable noninvasive mark-ers for early identification nor effective means of treat-ment or prevention. Cohort studies on PSC should bedesigned to help identify risk factors for this complica-tion, and stored serum and tissue used to search for andvalidate biomarkers. New means of imaging the biliarytree and discriminating the nonmalignant effects of PSCfrom early cholangiocarcinoma deserve evaluation. Fi-nally, new approaches to therapy and prevention shouldbe pursued, particularly ones using noncytolytic modifi-ers of cell-signaling molecules, growth factors or tumorsuppressor genes.Currently with the exception of endoscopic dilation ofdominant strictures, there are no treatments that haveproven benefit in PSC. New therapeutic approaches areneeded, and standard treatments deserve objective re-evaluation for efficacy. Several types of clinical trials areappropriate. Simple, randomized controlled trials ofsymptomatic therapy of PSC might focus upon clinicalendpoints such as symptoms and quality of life. Small,short-term, clinical trials are also appropriate to evaluateinnovative therapies using endpoints based on clinical,biochemical, serological, imaging, and possibly histolog-ical findings. Examples of agents that might be studied insuch trials include bile acid therapies, novel immunosup-pressive agents, TNF inhibitors, potent antioxidants, pro-biotics, and antifibrotic agents. Also important areendoscopic approaches to therapy. Agents found to bepromising in small trials should be rapidly evaluated inmore rigorous randomized, controlled trials in whichlarger numbers of patients are enrolled and treated for 2 to5 years with the major endpoint outcomes being hepaticdecompensation, liver transplantation and/or death.These clinical trials would be greatly aided by definitionand standardization of terminology and concurrent as-sessment of surrogate endpoints.Liver transplantation has provided an effective al-though expensive and challenging means of treatment forend-stage liver disease due to PSC. Continued monitor-ing of the frequency, complications and outcome of livertransplantation for PSC will be provided by national da-tabases. Prospective studies of optimal surgical proce-dures, peritransplant management, and long-termtherapy for patients (including children) undergoingtransplantation for PSC are important to optimize out-comes and prevent complications. A more rigorous defi-nition of recurrent PSC after transplantation, assessmentof its clinical significance of recurrence, analysis of riskfactors and development of approaches for preventionand treatment would benefit patients undergoing livertransplantation for this indication.References1. Chapman RW, Arborgh BAM, JM, Summerfield JA, Dick R,Scheuer PJ. Primary sclerosing cholangitis: A review of clinical features,cholangiography and hepatic histology. Gut 1980;21:870-877.2. Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL,Hunter EB, et al. Primary sclerosing cholangitis: Natural history, prog-nostic factors and survival analysis. HEPATOLOGY1989;10:430-436.3. Angulo P, Lindor, KD. Primary sclerosing cholangitis. HEPATOLOGY1999;30:325-332.4. MacFaul GR, Chapman RW. Sclerosing cholangitis. Curr Opin Gastro-enterol 2005;21:348-353.5. TalwalkarJA,LindorKD.Primarysclerosingcholangitis.InflammBowelDis 2005;11:62-72.6. 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Endothelial ligands and homing of mucosal leuko-cytes in extraintestinal manifestations of IBD. Inflamm Bowel Dis 1998;4:149-156.104. Hillan KJ, Hagler KE, MacSween RN, AM, Renz Me, Chiu HH, etal. Expression of the mucosal vascular addressin, MAdCAM-1, in inflam-matory liver disease. Liver 1999;19:509-518.105. Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG, etal. Hepatic endothelial CCL25 mediates the recruitment of CCR9gut-homing lymphocytes to the liver in primary sclerosing cholangitis. JExp Med 2004;200:1511-1517.106. Kunkel EJ, DJ, Butcher EC. Chemokines in lymphocyte traf-ficking and intestinal immunity. Microcirculation 2003;10:313-323.107. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosem-blatt M, et al. Selective imprinting of gut-homing T cells by Peyer’s patchdendritic cells. Nature 2000;424:88-93.108. Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M, DH. CXC chemokine ligand 16 promotes integrin-mediated adhesion ofliver-infiltrating lymphocytes to cholangiocytes and hepatocytes withinthe inflamed human liver. J Immunol 2005;174:1055-1062.109. Lee YM, Kaplan MM, ACG Practice Guidelines Committee. Practiceguidelines for management of primary sclerosing cholangitis. Am J Gas-troenterol 2002;97:528-534.110. Lindor KD, the Mayo PSC/UDCA study group. Urosodiol for the treat-ment of primary sclerosing cholangitis. N Engl J Med 1997;336:691-695.111. SA, Bansi D, Hunt N, Von Bergman K, Fleming KA, ChapmanRW. A preliminary trial of high dose ursodeoxycholic acid in primarysclerosing cholangitis. Gastroenterology 2001;121:900-907.112. Harnois, DM, Angulo P, nsen RA, LaRusso NF, Lindor KD. High-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenter-ology 2001;121:900-907.113. Olsson R, Boberg KM, Schaffalitsky de Muckadell O, Lindgren S, Hult-crantz R, Folvik G, et al. High-dose ursodeoxycholic acid in primarysclerosing cholangitis: A 5-year multicenter, randomized, controlledstudy. Gastroenterology 2005;129:1464-1472.114. Hoofnagle JH. This month from the NIH: Primary sclerosing cholangi-tis. HEPATOLOGY2005;41:955.115. Sekhon JS, Chung RT, Epstein M, Kaplan MM. Steroid-responsive (au-toimmune) sclerosing cholangitis. Dig Dis Sci 2005;50:1839-1843.116. Kaplan MT. Toward better treatment for primary sclerosing cholangitis.N Engl J Med 1997;336:719-721.117. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliarycirrhosis with rifampin. Results of a double-blind, crossover, randomizedcontrolled trial. Gastroenterology 1988;94:488-493.118. Marschall HU, Wagner M, Zollner G, Fickert P, Dicafalusy U, GumholdJ, et al. Complementary stimulation of hepatobiliary transport and de-toxification systems by rifampicin and ursodeoxycholic acid in humans.Gastroenterology 2005;129:476-485.119. Tung BY, Emond MJ, Haggitt RC, Bronner MP, Kimmey MB, KowdleyKV, et al. Ursodiol use is associated with lower prevalence of colonicneoplasia in patients with ulcerative colitis and primary sclerosing cholan-gitis. Ann Intern Med 2001;134:89-95.120. Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxy-cholic acid as a chemoprotective agent in patients with ulcerative colitisand primary sclerosing cholangitis. Gastroenterology 2003;124:889-893.121. Olsson R, Bjornsson E, Backman L, Friman S, Hockerstedt K, Kaijser B,et al. Bile duct bacterial isolates in primary sclerosing cholangitis: a studyof explanted liver. J Hepatol 1988;28:426-432.122. Serfaty L, De Leusse A, Rosmorduc O, Desaint B, Flejou JF, Chazouill-eres O, et al. Ursodeoxycholic acid therapy and the risk of colorectaladenoma in primary biliary cirrhosis: An observational study. HEPATOL-OGY2003;38:203-209.123. Battezzati PM, Zuin M, Crosignani A, Allocca M, Invernizzi P, Selmi C,et al. Ten-year combination treatment with colchicine and ursodeoxy-cholic acid for primary biliary cirrhosis: a double-blind, placebo-con-trolled trial on symptomatic patients. Aliment Pharmacol Ther 2001;15:1427-1434.124. Ahrendt SA, Pitt HA, Kalloo AN, Venbrux AC, Klein AS, Herlong HF,et al. Primary sclerosing cholangitis: Resect, dilate or transplant? AnnSurg 1998;227:412-423.125. May GR, Bender CE, LaRusso NF, Wiesner RH. Nonoperatative dila-tion of dominant strictures in primary sclerosing cholangitis. Am J Roent-genol 1985;145:1061-1064.126. GK, Greenen JE, Venu RP, Schmalz MJ, Hogan WJ. Endo-scopic treatment of biliary tract strictures in sclerosing cholangitis: Alarger series and recommendation for treatment. Gastrointest Endosc1991;37:38-43.127. Gaing AA, Geders JM, Cohen SA, Siege JH. Endoscopic management ofprimary sclerosing cholangitis: review and report of an open series. Gas-troenterology 1993;88:2000-2008.128. Grijm R, Huibregtse K, Bartelsman J, Mathus-Vliegen EM, Dekker W,Tytgat GN. Therapeutic investigations in primary sclerosing cholangitis.Dig Dis Sci 1986;31:792-798.129. Lee JG, Schutz SM, England RE, Leung JW, Cotton PB. Endoscopictherapy of sclerosing cholangitis. HEPATOLOGY1995;21:661-667.130. Baluyut AR, Sherman S, Lehman GA, Hoen H, Chalasani N. Impact ofendoscopic therapy on the survival of patients with primary sclerosingcholangitis. Gastrointest Endosc 2001;53:308-312.131. Huibregtse K, Tytgat GNJ. Palliative treatment of obstructive jaundiceby transpapillary introduction of large bore bile duct endoprosthesis. Gut1982;23:371-375.132. van Milligen de Wit AW, van Bracht J, Rauws AEJ, EA, TytgatGN, Huibregtse K. Endocopic stent therapy for dominant extrahepaticbile duct strictures in primary sclerosing cholangitis. Gastrointest Endosc1996;44:293-299.133. van Milligen de Wit AW, Rauws EA, van Bracht J, Mulder CJ, EA,Tytgat GN, et al. Lack of complications following short term stent ther-apy for extrahepatic bile duct strictures in primary sclerosing cholangitis.Gastrointest Endosc 1997;46:344-347.134. Wagner S, Gebel M, Meier P, Trautwein C, Bleck J, Nashan B, MannsMP. Endoscopic management of biliary tract strictures in primary scle-rosing cholangitis. Endoscopy 1996;7:546-551.135. Ponsioen CY, Lam K, van Milligen de Wit AW, Huibregtse K, TytgatGN. Four years experience with short term stenting in primary sclerosingcholangitis. Am J Gastroenterol 1999;94:2403-2407.762LARUSSO ET AL.HEPATOLOGY, September 2006Page 18136. Linder S, Soderlund C. Endoscopic therapy in primary sclerosing cholan-gitis: outcome of treatment and risk of cancer. Hepato-Gastroenterol2001;48:387-392.137. Lee JG, Schutz SM, England RE, Leung JW, Cotton PB. Endoscopictherapy of sclerosing cholangitis. HEPATOLOGY1995;21:661-667.138. van den Hazel SJ, Wolfhagen EH, van Buuren HR, van de Meeberg PC,Van Leeuwen DJ. Prospective risk assessment of endoscopic retrogradecholangiography in patients with primary sclerosing cholangitis. DutchPSC Study Group. Endoscopy 2000;32:779-782.139. Boyer JL. Nuclear receptor ligands: Rational and effective therapy forchronic cholestatic liver disease? Gastroenterology 2005;129:735-740.140. Angulo P, Batts KP, nsen RA, LaRusso NA, Lindor KD. Oralbudesonide in the treatment of primary sclerosing cholangitis. Am J Gas-troenterol 2000;95:2333-2337.141. Van Thiel DH, Carroll P, Abu-Elmagd K, -Rilo H, Irish W,Mc J, et al. Tacrolimus (FK 506), a treatment for primary scle-rosing cholangitis: results of an open-label preliminary trial. Am J Gas-troenterol 1995;90:455-459.142. Knox TA, Kaplan MM. A double-blind controlled trial of oral-pulsemethotrexate therapy in the treatment of primary sclerosing cholangitis.Gastroenterology 1994;106:494-499.143. Lindor KD, nsen RA, ML, Gores GL, Hofmann AF,LaRusso NF. Ursodeoxycholic acid and methotrexate for primary scle-rosing cholangitis: A pilot study. Am J Gastroenterol 1996;91:511-515.144. Talwalkar JA, Angulo P, Keach JC, Petz JL, nsen RA, Lindor, KD.Mycophenolate mofetil for the treatment of primary sclerosing cholangi-tis. Am J Gastroenterol 2005;100:308-312.145. Bharucha AE, nsen R, Lichtman SN, LaRusso NF, Lindor KD. Apilot study of pentoxifylline for the treatment of primary sclerosingcholangitis. Am J Gastroenterol 2000;95:2338-2342.146. Ball KR, Kowdley KV. A review of silybum marianum (milk thistle) as atreatment of alcoholic liver disease. J Clin Gastroenterol 2005;39:520-528.147. Epstein MP, Kaplan MM. A pilot study of etanercept in the treatment ofprimary sclerosing cholangitis. Dig Dis Sci 2004;49:1-4.148. Farkkila M, Karvonen AL, Nurmi J, Nuutinen H, Taavitsainen M,Pikkarainen P, et al. Metronidazole and ursodeoxycholic acid for primarysclerosing cholangitis: A randomized placebo-controlled trial. HEPATOL-OGY2004;40:1379-1386.149. Angulo P, MacCarty RL, Sylvestre PB, nsen RA, Wiesner RH, La-Russo NA, et al. Pirfenidone in the treatment of primary sclerosingcholangitis. Dig Dis Sci 2002;47:157-161.150. Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, HansenB, et al. Liver transplantation for primary sclerosing cholangitis; predic-tors and consequences of hepatobiliary malignancy. J Hepatol 2004;40:815-822.151. Wiesner RH. Liver transplantation for primary biliary cirrhosis and pri-mary sclerosing cholangitis: predicting outcomes with natural historymodels. Mayo Clin Proc 1978;73:575-588.152. Ricci P, Therneau TM, Malinchoc M, Benson JT, Petz JL, KlintmalmGB, et al. A prognostic model for the outcome of liver transplantation inpatients with cholestatic liver disease. HEPATOLOGY1997;25:672-677.153. Freeman RB, Wiesner RH, E, Harper A, Merion RM, WolfeRA. Results of the first year of the new liver allocation plan. Liver Transpl2004;10:7-15.154. Merion RM, Schaubel DE, Dystra DM, Freeman RB, Port FK, WolfeRA. The survival benefit of liver transplantation. Am J Transplant 2005;5:307-313.155. MS, Angus DC, Bryce CL, Valenta Z, Weissfeld L. Survival afterliver transplantation in the United States: A disease-specific analysis of theUNOS database. Liver Transpl 2004;10:886-897.156. U.S. Organ Procurement and Transplantation Network and the Scien-tific Registry for Transplant Recipients. Annual Report: Transplant Data1994-2003. Department of Health and Human Services, Health Re-sources and Services Administration, Office of Special Programs, Divi-sion of Transplantation, Rockville, MD. United Network for OrganSharing, Richmond, VA; University Renal Research and Education As-sociation, Ann Arbor, MI, 2004.157. McDiarmid SV, Anand R, SPLIT Research Group. Studies of pediatricliver transplantation (SPLIT): A summary of the 2003 annual report.Clin Transpl 2003;119-130.158. on RF, Davies MH, Neuberger JM, Hubscher SG. Fibrous andobliterative cholangitis in liver allografts: Evidence of recurrent primarysclerosing cholangitis? HEPATOLOGY1994;20:356-361.159. Lerut J, Demetris AJ, Stieber AC, Marsh JW, Gordon RD, Esquivel CO,et al. Intrahepatic bile duct strictures after human orthotopic liver trans-plantation. Recurrence of primary sclerosing cholangitis or unusual pre-sentation of allograft rejection? Transpl Int 1988;1:127-130.160. Feller RB, Waugh RC, Selby WS, Dolan PM, Sheil AG, McCaughanGW. Biliary strictures after liver transplantation: Clinical picture, corre-lates and outcomes. J Gastroenterol Hepatol 1996;11:21-25.161. Jeyarajah DR, Netto GJ, Lee SP, Testa G, Abbasoglu O, Husberg BS, etal. Recurrent primary sclerosing cholangitis after orthotopic liver trans-plantation: Is chronic rejection part of the disease process? Transplanta-tion 1998;66:1300-1306.162. Goss JA, Shackleton CR, Farmer DG, Arnaout WS, Seu P, Markowitz JS,et al. Orthotopic liver transplantation for primary sclerosing cholangitis.A 12-year single center experience. Ann Surg 1997;225:472-481.163. Grzaiadei IW. Recurrence of primary sclerosing cholangitis after livertransplantation. Liver Transpl 2002;8:575-581.164. Gopal DV, Corless CL, Rabkin JM, Olyaei AJ, Rosen HR. Graft failurefrom severe recurrent primary sclerosing cholangitis following orthotopicliver transplantation. J Clin Gastroenterol 2003;37:344-347.165. Khettry U, Keaveny A, Goldar-Najafi A, WD, Pomfret EA, Pom-poselli JJ, et al. Liver transplantation for primary sclerosing cholangitis: Along-term clinicopathologic study. Hum Pathol 2003;34:1127-1136.166. Kugelmas M, Spiegelman P, Osgood MJ, Young DA, Trotter JF, Stein-berg T, et al. Different immunosuppressive regimens and recurrence ofprimary sclerosing cholangitis after liver transplantation. Liver Transpl2003;9:727-732.167. Vera A, Gunson BK, Ussatoff V, Nightingale P, Candinas D, Radley S, etal. Colorectal cancer in patients with inflammatory bowel disease afterliver transplantation for primary sclerosing cholangitis. Transplantation2003;75:1983-1988.168. Haagsma EM, Van Den Berg AP, Kleibeuker JH, Slooff MJ, Dijkstra G.Inflammatory bowel disease after liver transplantation: the effect of dif-ferent immunosuppressive regimens. Aliment Pharmacol Ther 2003;18:33-44.169. Heneghan MA, Tuttle-Newhall JE, Suhocki PV, Muir AJ, Morse M,Bornstein JD, et al. De-novo cholangiocarcinoma in the setting of recur-rentprimarysclerosingcholangitisfollowinglivertransplant.AmJTrans-plant 2003;3:634-638.170. Fabia R, Levy MF, Testa G, Obiekwe S, Goldstein RM, Husberg BS, etal. Colon carcinoma in patients undergoing liver transplantation. Am JSurg 1998;176:265-269.171. Patel T. Increasing incidence and mortality of primary intrahepatic chol-angiocarcinoma in the United States. HEPATOLOGY2001;33:1353-1357.172. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence ofintrahepatic cholangiocarinoma in the United States: A true increase?J Hepatol 2004;40:472-477.173. Patel T. Worldwide trends in mortality from biliary tract malignancies.BMC Cancer 2002;2:10.174. Donato F, Gelatti U, Tagger A, Favret M, Ribero ML, Callea F, et al.Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection,alcohol intake, and hepatolithiasis: A case-control study in Italy. CancerCauses Control 2001;12:959-964.175. Shaib YH, El-Serag HB, Davila JA, R, McGlynn KA. Risk fac-tors of intrahepatic cholangiocarcinoma in the United States: A case-control study. Gastroenterology 2005;128:620-626.176. Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, sson A, etal. Hepatic and extrahepatic malignancies in primary sclerosing cholan-gitis. J Hepatol 2002;36:321-327.HEPATOLOGY, Vol. 44, No. 3, 2006LARUSSO ET AL.763Page 19177. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence andrisk factors for cholangiocarcinoma in primary sclerosing cholangitis.Am J Gastroenterol 2004;99:523-526.178. Stiehl A, Rudolph G, Kloters-Plachky P, Sauer P, S. Develop-ment of bile duct stenoses in patients with primary sclerosing cholangitistreated with ursodeoxycholic acid. outcome after endoscopic treatment.J Hepatol 2002;36:151-156.179. Gores GJ. Early detection and treatment of cholangiocarinoma. LiverTranspl 2000;6:S30-S34.180. Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, GoresGJ, et al. Treatment of cholangiocarcinoma complicating primary scle-rosing cholangitis: The Mayo Clinic experience. Am J Gastroenterol2001;96:1164-1169.181. Ramage JK, Donaghy A, Farrant JM, Iorns R, R. Serum tumormarkers of the diagnosis of cholangiocarcinoma in primary sclerosingcholangitis. Gastroenterology 1995;108:856-869.182. Fleming KA, Boberg KM, Glaumann H, Bergquist A, D, ClausenOP. Biliary dysplasia as a marker of cholangiocarcinoma in primary scle-rosing cholangitis. J Hepatol 2001;34:360-365.183. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokinesinduce DNA damage and inhibit DNA repair in cholangiocarcinomacells by an NO-dependent mechanism. Cancer Res 2000;60:184-190.184. Jaiswal M, LaRusso NF, Shapiro RA, Billiar TR, Gores GJ. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage incholangiocytes. Gastroenterology 2001;120:190-199.185. Jaiswal M, LaRusso NF, Nishioka K, Nakabeppu Y, Gores GJ. HumanOgg1, a protein involved in the repair of 8-oxoguanine, is inhibited bynitric oxide. Cancer Res 2001;61:6388-6493.186. Jaiswal M, LaRusso NF, Gores GJ. Cholangiocarcinoma and pro-inflam-matory cytokines. Cancer Res Alert 2000;1:141-143.187. Jaiswal M, LaRusso NF, Gores GJ. Nitric oxide in gastrointestinal epi-thelial cell carcinogenesis: Linking inflammation to oncogenesis. Am JPhysiol 2001;281:G626-G634.188. Ishimura N, Bronk SF, Gores GF. Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogen-esis. Gastroenterology 2005;128:1354-1368.189. Alessiani M, Tzakis A, Todo S, Demetris AJ, Fung JJ, Starzl TE. Assess-ment of five year experience with abdominal organ cluster transplanta-tion. J Am Coll Surg 1995;180:1-9.190. Goldstein RM, Stone M, Tillery GW, Senzer N, Levy M, Husberg BS, etal. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg1993;166:768-771.191. Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I, et al.Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepaticresection or transplantation. J Am Coll Surg 1998;187:358-364.192. Jonas S, Mittler J, Pascher A, Theruvath T, Thelen A, Klupp J, et al.Extended indications in living-donor liver transplantation: bile duct can-cer. Transplantation 2005;80(1 Suppl):S101-S104.193. 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Shimoda M, Farmer DG, Colquhoun SD, Rosove M, Ghobrial RM,Yersiz H, et al. Liver transplantation for cholangiocellular carcinoma:analysis of a single-center experience and review of the literature. LiverTranspl 2001;7:1023-1033.199. Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B, McCashland T,et al. Radiochemotherapy and transplantation allow long-term sur-vival for nonresectable hilar cholangiocarcinoma. Am J Transplant2002;2:774-779.200. De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, HaddockMG, et al. Prolonged disease-free survival after orthotopic liver transplan-tation plus adjuvant chemoirradiation for cholangiocarcinoma. LiverTransplant 2000;6:317-319.764LARUSSO ET AL.HEPATOLOGY, September 2006

[Guest guest]

I went ahead and uploaded the article to the files section of the group

website. Just click on files and go to news articles and you will find

it. You need to log into the Yahoo PSC Group website in order to be

able to do this.

In order to read the article you must have a version of Adobe Acrobat

Reader on your computer. This is a very common program and is

available for free download. If you don't have this program on your

computer it is something you should strongly consider since many

articles are in this format.

I appreciate Ian attaching in HTML but it is kind of hard to read in

that format, so if you have acrobat you will find it much easier to

read. If you still have problems the only other suggestion I can make

is to type the web address into your browser and see if that gets you

there instead of clicking in the link.

In regards to Katy's question about support groups in

Seattle...probably the closest thing you will find are transplant

support groups. I know they have them at the UW Medical Center but

these are generally geared towards all liver ailments and for those

nearing or already post transplant. This is not to say you would not

be welcome but you may find the topics not relevant to where you are in

the early stages of dealing with PSC.

Welcome to Katy, Tevor and #2. There are several others from the

Seattle area as well. I have been part of this group for about 5 years

and it is a wealth of information and support. One comment I would

like to make to the younger crowd based on recent posts and I hope I

don't come across as too judgemental. I was 20 years old when first

diagnosed with Ulcerative Colitis, over 2000 miles away from home at

college and just getting ready to start a major internship in yet

another city, in the middle of finals and going through a major flare.

I lost probably 50 pounds and was quite anemic during that time.

Through all those issues I managed, on my own, to take all my

medications, go to all my doctor appointments, and in general be in

charge of my health and understand what was going on. There are few

reasons that as young adults we should not be able to take charge of

our health. If not now the when? Taking charge now and understanding

the issues will only help you down the road. It will improve

relationships with your family, your current or future partner, medical

professionals and set a great example for your children if you choose

to have any. I want to encourage all newly diagnosed young people to

face these issues. Don't let them run your life but do be educated so

you can make informed and correct decisions about your future.

in Seattle

DX UC 1991

DX PSC 2001

Married w/ two daughters ages 5 & 3

>

> Katy,

>

> After a lot of searching on the internet II ended up getting it a

HTML copy

> of the document, which I have attached.

>

> Ian

>

>