psc symposium, Oxford

[Guest guest]

This is an edited transcript of a PSC Symposium at Oxford, UK. 8th June, 2007. I wanted to send this much earlier but illness and pressure of work has delayed it. I think there are some interesting points here. It’s not fully edited and there may be some errors and spelling mistakes. I hope you get it in one piece. A better edited version will appear in our newsletter which should be sent soon to subscribers.

Ivor (PSC-Support UK)

Ref: PAGE 2 YOUR REF: F1 - F31A SYMPOSIUM AT ST. ANNE’S COLLEGE, OXFORD, ON THE8th JUNE, 2007: ORGANISED BY DR. CHAPMAN ANDSUPPORTED BY DR. FALK PHARMA U.K. LTD.

The aim of this conference was to “bring togetherhepatologists, luminal gastroenterologists andendoscopists to discuss the important association ofP.S.C. and I.B.D.â€

This was a day-long symposium: the first speaker was DR.JERRY KINGHAM (Singleton Hospital, Swansea)“P.S.C./I.B.D. EPIDEMIOLOGY/NATURAL HISTORYâ€

He said that this is a disease which was hardly known whenhe was a medical student. It was only really in the 1970s withthe advent of ERCP that it became clearer. And then therewere two seminal papers by doctors Wiesner & Chapmanwhich told us much of what we now know about the clinicalpresentation of the disease. We had to wait another 15 yearsbefore the first epidemiological studies came out.(epidemiology = the study of the distribution of diseaseamong the population). The first Swedish studies,particularly Broome et. al. were large scale and involved 10%of the whole Swedish population. They looked at P.S.C.through U.C. (ulcerative colitis), over a 25 year period. 1,300were found to have U.C. 10% of these had raised LFTs ofthese 48% had P.S.C. Other studies also showed that around4% of those with U.C. had P.S.C. Boberg’s Norwegian studycovered a 10 year period, looking only at P.S.C.(Scandinavian J. of Gastro. 1998).

There was a Mayo study in 2003, where they usually examinethe local population in Minnesota. Our local ~Swansea studyexamined a population of 250,000 over 20 years. Theresults were similar to those of the Mayo. The figures thatcome out suggest that up to 10 out of every 100,000 of thepopulation will have P.S.C. (In which case the P.S.C.population in the U.K. (60million population) should bearound 6,000). With PBC it’s usually found to be double that.In the Swansea study there was also a higher incidence ofPBC, but not very much more than P.S.C.In terms of the natural history of the disease, the cholestasisis usually progressive but has a terribly slow progression.There are commonly strictures in the bile ducts, bouts ofcholangitis, bacterial cholangitis, orcholangitis as part of the disease. Hepatitis (AutoimmuneHepatitis) may also develop, especially in children ~ overlapsyndrome. Gallstones are present in about 25% of P.S.C.patients. As the liver becomes increasingly fibrotic morecomplications can develop. Cancer of the bile ducts andother cancers are a risk including cancer of the pancreas.Prognosis of P.S.C. is very difficult ~ it does shorten life.Those who are asymptomatic have the best diagnosis. In thebrief discussion which followed Dr. Chapman confirmed that75% of asymptomatic patients will be alive and well 15 yearsafter P.S.C. was first diagnosed. P.S.C. will develop in up to10% of those with long-term U.C.~ The outlook is very different amongstpatients. We have seen patients who are asymptomatic 20years after diagnosis and some patients in their 20s dying ofC.C. (Cholaniocarcinoma). With small-duct P.S.C. theprognosis is better and I haven’t seen any reports of C.C.There is a good degree of unanimity in the studies, Onaverage P.S.C. patients who are symptomatic whendiagnosed - Dr. Chapman says 50% of these will not survive or willgo to transplantation in 10 - 12 years. But studies ignore thefact that the age of those diagnosed has gone up by at least10 years.Dr. Chapman - About male dominance in P.S.C. (2 out of 3patients are male) ~ normally in auto-immune diseasesthere’s a predominance of female patients).There are biliary diseases which predispose toC.C. and are male dominant ~ Caroli’s Disease, SecondarySclerosing Cholangitis, Liver Fluke (Thailand) ~ all of whichpredispose to C.C. ~ are male dominant. This doesn’tanswer the question but there is some factor operating in thebiliary system which leads to male predominance. There’sauto-immune pancreatitis, clearly auto-immune by anydefinition, and strongly male dominant ~ this is a clue tosomething.We (at the Radcliffe) look for P.S.C. and we find a lot of it.We find that it is more common than the figures show. We’vebeen doing MRCPs on people who have total U.C., who arecompletely well and have (apparently) no liver disease at all~ normal LFTs ~ BUT ONE IN FIVE OF THESE PATIENTS HAVECHANGES CONSISTENT WITH P.S.C. This has majorconnotations for their natural history. It (P.S.C.), may be avery under-diagnosed condition in IBD.

Dr. Chapman; Although you’ve given us a median prognosis of10 years after diagnosis for symptomatic patients, mostpeople’s work suggests that those who are asymptomaticwhen first diagnosed ~ their life expectancy (or time totransplant) is longer.Dr. Kingham; I think you need to see that patient for some years :::PRIMARY SCLEROSINGCHOLANGITIS ANDINFLAMMATORY BOWEL DISEASE

Ref: PAGE 2a YOUR REF: F1 - F31CONTINUED FROM PREVIOUS PAGEDr. KinghamIYou can’t really put a prognosis on it because I’ve seenpatients who are asymptomatic and who are dead ortransplanted within five years and also patients who remainwell 20 years down the line. And I think you have to have atime-frame to access the progression of cholestasis.But it’s often not mentioned that theasymptomatic patient is about 5 years younger thanaverage. In addition age at diagnosis has increased by abouta decade to people in their 50s.

The Swedish data relating to cholangiocarcinoma ~(bile duct cancer). This is now a 10 year follow-up. The goodnews for the patient is that it is worthwhile finding out whetherthey have got small-duct or not because they have a muchbetter prognosis.It does make you wonder if it is the samedisease.What is the effect of colectomy? (removal of thecolon).It does have an importance but not necessarilyin terms of life expectancy. It’s important after transplant. (Itmay reduce the likelihood of a return of P.S.C. But it doesn’tseem to modify the disease: it may modify the transplant.IBD with P.S.C. is usually milder than IBD alone. There is rectalsparing, (the rectum may not be affected) and backwashileitis. (Inflammation of the ileum, when the contents of thecolon flow backwards into the last segment of the smallintestine). With P.S.C. and IBD many more have pouchitis(after colectomy). In terms of dysplasia (abnormalities incells ~ sometime pre-cancerous) P.S.C. has been seen as arisk factor. In IBD without P.S.C. about 5% have dysplasia. Butin the Broome study well over 30% of those with P.S.C. andIBD had dysplasia. Although the study in “Gastroenterologyâ€last year did not find P.S.C. as a risk factor for dysplasia ~most people are fairly certain that is.

This is an area of particular interest in Scotland where there isa large amount of early onset IBD. Clearly there is aconnection between environment and genetics. Theweather is different, the food is different … … genome-wideresearch has narrowed down the genes involved insusceptible patients. Genetic research should clarify therelationship between P.S.C. and IBD.

Dr. Chapman: The figure for Scandinavia, which we agreewith ~ 50% of symptomatic patients would need atransplant after 10 years post-diagnosis. 75% ofasymptomatic patients will be alive 15 years (plus) afterdiagnosis. Some will have unpredictable progression. Butonce they get the first symptoms, then they are on theslippery slope.::NONE OF THOSE WITHsmall-duct P.S.C. developed C.C.::Genome-wide research hasalready been successful in Crohn’s Disease.The journal “Nature†in June 2007 gives full treatment to thisresearch. We can now apply this type of study to P.S.C. and otherauto-immune diseases. For genome-wide studies thetechnology and the expertise are available. We need accessto adequate wide cohorts which may be an issue. This will bethe next crest of the wave for IBD studies.

On Cancer and IBD

There was an Oxford paper suggesting thatinflammation in IBD was not a risk factor for cancer. To mymind the animal data, and now the human data, indicate thatuntreated inflammation IS a risk factor for the developmentof colon cancer in U.C.I first became interested in P.S.C. in 1976 at Southampton. Ithen went to the Royal Free Hospital (London) to see DameSheila Sherlock (renowned British hepatologist). She calledme into her office: she didn’t look very interested: she wasmarking exam papers at the time. We discussed what Iwanted to do. I said I wanted to find the cause of P.S.C. Shesaid, “You are doing ironâ€. And that was that! I did iron.I continued my interest in P.S.C. It’s been a bit of a nightmarereally. That’s where it all began. We developed the ideaalmost 25 years ago that P.S.C. may be an auto-immunedisease.The bacteria in the colon, some form of colonic toxicity ~toxic bile acid (the liver reacts to this in an auto-immunefashion) ~ it may be an auto-immune disease or at leastimmune-mediated.

SMOKING was discussed ( and which we havedealt with before in a previous newsletter). Something in the tobacco smoke doessomething in the mucus lining ~ but trials with nicotinepatches had no effect).PBC is a smoker’s disease. The ladies smoke. In P.S.C. men(mostly) don’t. There is a strong effect of smoking in IBD.

There is an increased incidence of other auto-immunediseases in those who have P.S.C. and IBD (25% of patients)compared to patients who have IBD alone ~ (9%). There is astrong association with DR3 (HLA-DR3 Antigen) ~ amultigene haplotype and an important factor in a number ofprominent autoimmune diseases).This can develop in both adults and children ~ an overlapcondition P.S.C. to AIH, but rarely the other way round. Atleast half the patients will have bile duct changes. Morerecently in adult studies from Canada they looked at MRCP ofadults with AIH. Half of these patients had abnormalcholangiograms. These diseases may be different ends ofthe same disease spectrum.

PANCREATITIS

The pancreas is a strange sausage shape. The disease maypresent with jaundice, weight loss, with obstruction in thebile ducts. Half the patients are diabetic. The pancreas isinflamed. If you take biopsies it’s full of IG4 lymphosites.

Ref: PAGE 2b YOUR REF: F1 - F31CONTINUED FROM PREVIOUS PAGE“P.S.C. Medical Treatmentâ€

PANCREATIC DISEASE IS a multiple condition affectingthe lungs, kidneys and there are problems with the bileducts. The important thing is the ICG4 which is almost adiagnosis for the condition. There are strictures and it’salmost indistinguishable from P.S.C. Patients should besupported by steroids. Complete normality can be returnedafter the use of corticosteroids. If you find these changesearly enough you can do something about it. How does thisrelate? It is very difficult. Is it a form of P.S.C.? I think it is adifferent condition but the genetics haven’t been done yet.90% of P.S.C. is HLA associated. This may be co-incidental orchance. We don’t know at the moment. A lot of non-specificantibodies are found in P.S.C. raising the concept of immunedysfunction. There is a lot of circumstantial evidence, atleast, that the disease is immune regulated.You have to ask the question ~ how does IBD drive thedevelopment of P.S.C.? Lymphocytes travel between gut andliver and this may explain the cause of infiltration but itdoesn’t explain the trigger and we still don’t know that.In terms of pathogenesis, (Professor Neuberger) haspointed out that in terms of r.P.S.C. (recurrent P.S.C. aftertransplant) if you have your colon still there ~ this wasfound in Birmingham ~ there’s a higher risk of getting P.S.C. in the newliver. This has been reproduced in the Norwegian cohortbut it has not been in the Edinburgh cohort, though it may be be agood idea to remove the colon before transplantation, notleast because of P.S.C. but also because of the risk of cancerin the colon.The hypothesis of Vierling is very interesting: that youhave a (genetically) susceptible host: typically a male nonsmoker.HLA-DR3 antigens are present. Various bacteria arise fromthe gut and activate a variety of cells, developing a form ofsecretion. This attracts neutrophils and other lymphocytesand fibroblasts. He says that these cause concentric fibrosisaround the bile ducts. This causes ischemia ~ the bile ductslose their blood supply. They atrophy leading to cholangitisand the consequent cycle of fibrosis and biliary cirrhosis.

In conclusion there is good evidence that P.S.C. is immune- mediated,only circumstantial evidence of bacterialinvolvement, no evidence for viral infection and, as we’veheard, lymphocytes provide the link between the gut and theliver. But I think that the Holy Grail, which I set out, 30 yearsago is elusive and I think it very unlikely that any singleinfective factor will be found.

Dr. Sue Cullen

was Dr. Chapman’s Research Assistant for 3 years and isnow a Consultant at High Wycombe. She gave us a talk lastyear and on previous occasions so we’re familiar with herwork on the High-Dose Urso Trial, which is to be publishedshortly. the following is a summary of her presentation:The causation of P.S.C. is still very unclear. C.C.(cholangiocarcinoma) is still very much beyond our understanding. It’s very difficult to determine the onset of P.S.C.This means that in P.S.C. trials we are studyingpatients at all stages of the disease. (and we may not bestudying like with like). Most drug trials with P.S.C. patientsare too small and short and therefore underpowered. (Thismay mean that trial results are unreliable). The low profile ofthe disease makes it difficult to get funding. More than adozen drugs have been tested in trials. Those trials haveshown little success. A 2003 trial showed that there may be a smallsub-group of patients that responds well to immunosuppressants. It would also be interesting togo back and look at the genetic profiling of this sub-group tosee if there is any way in which we can predict which patientsmight do well.Dr. Cullen described trials with nicotine patches, combinationtherapies, immunosuppresants, colchicine etc., none ofwhich showed any benefits. She then looked at the OxfordUrso Trial, soon to be published, in which she was involved: apilot study of 33 patients over 2 years. Only 3 of the patientshad a worsening of their biopsies at that time.The large Scandinavian Urso study by Dr. Broome and othersused 17 - 23mg of Urso per kilo of body weight. 219 patientswere studied over 5 years. Nevertheless it was underpoweredbecause they were unable to reach their aim of 346patients. This survey did not find any substantial benefits forUrso apart from the fact that the data can be interpreted toshow that the Urso group had half the rate of C.C. comparedto the placebo group. (An important enough benefit). And 2years into this study the Urso group appeared to stabilise.There is consensus that with the Urso studies so far Ursocertainly improves LFTs, it doesn’t make much difference tosymptoms.Does it improve histology? The jury is still out on that. (Thereis clinical evidence that those liver units which have beenprescribing high-dose Urso for some years have lower ratesof C.C. and colon cancer).Overall, progress in understanding and treating P.S.C. is slow.Our understanding of auto-immune pancreatitis andAIH/P.S.C. crossover has been helpful in prescribing patientswith steroids (and immunosuppresants for AIH). We havebeen able to genetically profile patients and determine whichtreatments are most successful and this may be the wayforward.She added that in terms of the dose of Urso there isa biliary enrichment with increasing doses up to 25mg perkilo of body weight (per day). There’s a plateau that comes inafter that. My feeling is that it comes in at around 20-25mg ~which is what is meant by high-dose. There’s a lot ofevidence that you shouldn’t push it much higher than that. Inthe treatment of cystic fibrosis it’s pushed up to 30-40mg.(There isn’t any benefit in pushing it up to this in P.S.C.) Thelarge Mayo study on high-dose Urso has about 2 years to run.I think that that trial may be very helpful. The problem is thattrials have a mixed group of patients. If we had patients withonly early P.S.C. the results might be more impressive. Theproblem is knowing who these patients are and finding a bigenough group of early patients to have a worthwhile trial.

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PROFESSOR ADOLF STIEHL“P.S.C. - ENDOSCOPIC TREATMENTâ€The next speaker is well-knownfor his approach in emphasising the importance ofclearing dominant bile-duct strictures in patients withcholestatic disease by balloon endoscopy.

Dr. Chapman introduced him by saying that Professor Stiehlhas done great studies on bile acids and contributed to thescience of bile acids in cholestasis and has developedendoscopic therapy with or without high-dose Urso.

My topic is endoscopic treatment ~ the problem in P.S.C. isthe fibrosis which develops around the bile ducts. Thefibrosis tends to shrink and we get the development ofdominant strictures (narrowing), or stenosis. The problem isthat firstly we have to detect dominant strictures, (which isoften difficult), and we have to make a judgement as towhether the patient has or has not got a dominant stricture. Iwant to stress that the specificity and sensitivity of MRCP isbetween 85-95%. This means we can miss strictures. This isa real problem. In many cases it’s easy but we CAN missdominant strictures. The technique involves dilating thestrictures. We have found that stenting these strictures is notas good as dilating them by balloon endoscopy. With stents,,in a relatively short time, the bacteria enters the bile ducts.This can create a major problem. We get much better resultsif we open the strictures by balloon. (Slides are then shownon the screen in the lecture hall). This is from one of our firstpatients who was deeply jaundiced.It’s very difficult to judge if this is a DS (dominant stricture).The ERCP was repeated and then we realised he had a largesegment of DS which we hadn’t seen. What I want to showyou here (on the screen) is that if you can get a guide wire tothe DS and dilate it … …This is the situation after one year. You can open these longsegments of stenosis. Here you can see the bile ducts after12 years - you canget a normal CBD (Common Bile Duct). This should delay theneed for a transplant (and/or increase survival).. There are a number ofdilatations over the years. What I’ve shown you is that weCAN open long segments of DS.At the same time it’s very important that all endoscopicprocedures are performed with prophylactic antibiotics.Bacteria play a major role in P.S.C. Perhaps this is one reasonwhy the use of immunosuppresants is associated with somany problems and are not successful. They may even beharmful. These bacteria may be associated with DSs. i.e.when you find a DS the likelihood is that you will find bacterialgrowth.When we started out on this procedure we thought that onlyshort segments of DSs could be treated but we are now ableto treat long segments. What is the functional result? Pruritis(itching) is successfully treated. And we believe that survivaltime (or time to transplantation) is extended.There is significant improvement in survival if you have such a process ofREPEATING THIS DILATION EVERY YEAR.BUT IT’S NOTSUFFICIENT TO DO THIS ONCECompared with those who don’t have their DSsopened we gain a certain time if the patient has to go on totransplantation. It is not sufficient to open a DS once. Evenafter 9 or 10 years where a patient has (apparently) been freeof DS, repeat dilatation may be necessary. (Evidence isshown on the screen of perfect bile ducts after severaldilations).After 10 years 50% of our patients are free of livertransplantation. This is what you achieve if you treat DSactively by endoscopic means. Pruritis (itching) is alsosuccessfully treated this way.The problem with P.S.C. is the natural presence of bacteria. Irefer here to the paper by Ohlsson, (Swedish hepatologist).60% of patients who did not receive anti-biotics at the time ofexploration of the liver and the bile ducts had bacteria in thebile ducts as opposed to 30-40% who did have antibioticswhen we treat DSs. The incidence of DS in P.S.C. is, in ouropinion underestimated. We follow our patients very closely.20% of them came to us specifically because of their DSs inP.S.C. because we have become a referral centre for thiscondition. Over time half our patients develop DSs and needtreatment. We have been doing this for 20 years.Naturally there are others who have contributed to this area.This is a study from the Mayo clinic (on the screen). Theycompared endoscopic dilation with and without stents andhave shown that if you put in stents you get complications.The method of choice is to open the stenosis with balloonendoscopy. Two studies have compared survival (or time totransplant) where DS is treated in PSC. and in our own study, and found significant improvement in survival overpredicted survival. Nevertheless when we compare ourpatients who have DSs with those who don’t there is asignificant difference. Even though our patients with DSs aretreated as described their overall survival is worse than thosewho have no DSs at all.

In conclusion, I think the number of DSs is underestimated.You have to look for it otherwise you may not see it. ERCPand/or MRCP should be performed in cholestasis. If you don’tsee anything with MRCP I still think you should go on to ERCPbecause it is better and a more accurate procedure.

A brief discussion which followed said ~ Question: Iknow you treat your patients with high-dose Urso, as well …… …All the studies have shown that the toxic effects of bile acidscan be prevented by use of Urso … … …

Dr. Chapman wondered whether repeat balloon-endoscopiesand the (laborious) treatment of DSs could be followed withinthe confines of the N.H.S.

Prof. Stiehl: We use 20 - 25mg per kilo Urso. We have a low rate of C.C., at3%.

For a critique of Professor Stiehl’s approach see PSC-Newsnumber 34, August 2006. P.S.C. Conference, Pittsburgh.~ strictures, Page 9. (Dr. Adam Slivka.)

PROFESSOR JAMES NEUBERGER: Q.E.H., BIRMINGHAM

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“WHO TO TRANSPLANT, WHEN TO TRANSPLANT?â€

The whole problem with transplantation, particularly in theUK, is the number of patients who would benefit fromtransplantation (tx) and the number of organs available andthis is what I want to deal with. The number of donors is evendecreasing slightly. For every person you put into the systemone person has got to come out of it. Rationing has to occurbecause there aren’t enough organs to go round and wemust use selection criteria. This has to be an open processbased on equity. Everybody has an equal right. We mustconsider what is the best use of the organ. We are movingtowards a more open system in the UK, which just meansthere’s another layer of obfuscation beneath that. Ourselection criteria are based mainly on the risk of deathwithout tx (transplantation). Secondarily you’re also talkingabout the quality of life.In 1999 we had a consensus meeting and it was agreed thata tx patient should have a greater than 50% chance of beingalive 5 years after tx with a quality of life acceptable to thepatient. This is nice and very helpful until you start applying itto individuals because a lot of sentiments are difficult toquantify.A very small proportion of txs are live donor txs in the U.K.And despite the publicity it’s also extremely low in the U.S.There’s more in continental Europe and a lot in the Far East. Itshouldn’t be forgotten that with adult Live Donor LiverTransplants there’s a mortality rate of about 1%, mostlyamongst the donors.Looking at survival and how you select patients there are twomodels:1. MELD System2. U.K. ModelWe should note that a model is just a model. They’re usuallyvery good when applied to populations but when youextrapolate them to the individual that’s when they start tofail.The Meld model (Model for End Stage Liver Disease) wasdeveloped at the Mayo clinic, mainly for short-term survivalin patients undergoing the TIPS procedure ~ based on acombination of bilibrubin, creantinine and INR. This givessome cause for concern. It’s well recognised that there arelab variations. The same sample measured in different labscan vary by 10 - 15%. If you’re enthusiastic about diureticsyou can increase warfarin. So if you want to get your patient ahigher MELD score, you can make their prognosis worse. Ithas been done.The Child-Pugh classification is very subjective: it’s based onencephalopathy, ascites etc. You wouldn’t get consensus onthis: if they’re sick they’re Child-C, if they’re well they’reChild-B. It’s a very useful shorthand but if I ask you to writedown what you think of the Child-Pugh score we’ll see a lot ofvariation. And even if you look at textbooks you’ll seevariation. The correlation between Child-Pugh and MELD isnot great. With MELD you put in the numbers and you get ascore that’s roughly between 7 and 40 and you would seethe correlation as to mortality over 3 months. A score of 40would give you an 8% probability of mortality at 3 months. Ascore of 10 would give you a 5% mortality. People talk aboutMELD but they don’t usually correlate it with survival. It is amarker for short-term rather than long-term survival. I wasinterested in the discussion on the value of prognosis. I’mnever sure how valuable it is. You can’t influence it and youdon’t know what the confidence intervals of that prognosisare.As you can see (from the screen) there’s quite a goodcorrelation between MELD and 3 months probability ofsurvival. Meldology is really becoming a science withinhepatology. Here are some new US data (on the screen) onprobability of survival on the waiting list after tx. And theimportant two points to notice is that tx only gives yousurvival benefit when your MELD approaches 17. Secondly ifyou look at survival after tx MELD correlates very poorly withpost-tx survival. It’s often said that patients who are sick arelikely to do less well: the evidence is against you althoughquite clearly it is intuitive. The reason is that surgeons arequite good at matching donors to recipients. (The papercontinued with reference to data presented on the screen andwithout that some of the meaning is lost here). Using theU.K. data base of about 6,000 transplanted liver patients(data derived from ston). Some of these patientswere relatively well and some quite ill. Does this matter interms of outcome? Those who have a high U.K. score at tx ~their condition does affect outcome (data shown on screen).The U.K. model applies better to patients in the U.K. thanMELD and is more important in predicting outcome. You wantto tx U.K. patients when their score is about 50 on the U.K.model and before 64. This just shows the model is valid.Using data for tx P.S.C. patients which goes back 10 years ~survival is pretty good although there’s an initial highmortality, there’s 65% survival after 10 years. Not bad but it’sclearly not good enough. Results have been improving overtime. When do you not tx? As I said, prognostic models areuseful guides but they are subject to problems when appliedto individuals. We haven’t mentioned symptoms. Clinicaljudgement clearly plays a role. Intractable pruritis is clearly anindication to tx (when none of the usual drugs have anyeffect). Also intractable encephalopathy, liver cell cancer,diuretic ascites etc. are all indications for tx which are notcovered by MELD or the U.K. model because you’re not likelyto die. Lethargy is not an indication for tx. It may not improveafter tx. The best data comes from a small study done by theNewcastle group. They had a score for PBC patients and theyfound there was not great differenced in levels of lethargybefore and after tx. Our own retrospective study atBirmingham found that if you’re (relatively) well with a lot oflethargy before tx, you’ll be well but also with a lot of lethargyafter tx. Whether people have a low threshold or whetherthere’s something more important here we don’t reallyknow.

Ref: PAGE 2e YOUR REF: F1 - F31CONTINUED FROM PREVIOUS PAGEThe other indication ~ or in fact a contra-indication is C.C.This is because patients with C.C. do extremely badly. Youcannot approach the 50% 5-year survival that we wouldrequire. The reason is that C.C. spreads through thelymphatic and nervous systems at an early stage. By thetime you’re diagnosed it is probably too late. Mainly, as withhepatoma, it (C.C.) occurs in the allograft, but notentirely. In my view most of the (tumor) markers used arevery good at producing papers but next to useless whenapplied to patients. I do have to stress that a very smallnumber of people with C.C. can do very well after tx. Thesepatients have a rigorous work out with surgery, chemo- andradiotherapy. the small numbers they’ve done have donevery well after tx at the Mayo Clinic. But in the majority ofpatients I don’t believe there is any effective treatment forC.C.Certainly age is another factor in considering tx. It’s anindependent predictive factor for post-transplant survival.Depressingly it starts to creep in as a factor from the age of40. After 60 it’s a significant factor. But there are some verygood survivors and one has to make a judgement of thepatient.Nutrition is a factor. Many of these patients are malnourished(as a consequence of advanced liver disease). But in spite ofsurgeons going on about this there are no data showing thatwell-nourished patients do better; it’s inappropriate towithhold patients from tx because of malnutrition. Thedifficulty is with those who have a past history of cancer,especially colon cancer. How long do you leave them beforeyou’re convinced it won’t recur? Previous abdominal surgery,morbidity, add somewhat to the mortality post-tx ~ the samewith biliary and gastric surgery. For those with activeUlcerative Colitis there is no problem in doing a colectomy atthe same time as the tx.Tx is a very good procedure but it does shorten your life. Thisis some data we produced (at Birmingham) and published in2006.Life expectancy ~ and this is for men ~ is very good in P.S.C.patients after tx. Much better than those who have livercancer, Hepatitis C and alcoholic liver disease. At 20-years oldyou can expect to live 45 years. 65-year-olds may have 10years. It is a very good prognosis for tx P.S.C. patients.Recurrence (rP.S.C.) does affect survival. Those withoutrP.S.C. do significantly better. Recurrence can be detected inthe presence of normal LFTs. We look for it radiologically andhistologically and (as shown on the screen) there is increasingrecurrence over time. We don’t know why and it doesn’tnecessarily translate into graft loss.Those who have had a colectomy either before or at the timeof tx had a lot less recurrence than those with an intact colon.It has been controversial, the Scandinavians have beenunable to repeat their findings in large studies and look for it more actively.What this tells you about tx and P.S.C. is anybody’s guess.Again we disagreed with the Scandinavians about post-txColitis. Those with Ulcerative Colitis and tx for P.S.C. ~ about athird had improvements in their Ulcerative Colitis, one thirdstayed the same and one third became worse. TheScandinavians found that the type of immunosuppressionmakes a difference. We weren’t able to show that. All patientspost-tx have an increased risk of cancer, especially coloncancer. This isn’t true of breast and cervical cancer in womenPSCers. Therefore more surveillance and monitoring of thecolon is necessary.

In summary P.S.C. is an excellentindication for a transplant. The models are a guide but not areplacement for clinical judgement. It’s important to stressthat C.C. and lethargy are not indications for a transplant.We tell patients that tx is not a cure, it’s a swap. Swopping onedisease for another. When the MELD score starts to reach 12or 13, that is the time to start thinking of a tx, but it may beearlier, it may be later. Too early doesn’t matter, too late ~ andthe problem is waiting for an organ because of the shortage.Please write to your M.P.s, raise the alcohol limit, no safetybelts in cars, no crash helmets!We tend to use immunosuppressants ~ Azathioprin alongwith tacrolimus, as our major agents but we don’t put themon routine Azathioprin because of the Colitis.

Further details came out at the meeting fromU.C.L., London (â€Hepatobiliary Cancer and P.S.C.â€).

Amongstoutpatients, those with AIH responded well to immunosuppressantsand there was 50% relapse. In the case of C.C.this tended mostly to occur early after the diagnosis afterwhich the rate tended to be around 1-2% p.a. There is asignificant increase in pancreatic cancer and this needs to beconfirmed. The symptoms of this are known but not the riskfactors.On C.C. Prof.Stiehl said that all his patients who havehad C.C. had dominant strictures.( There is evidence that those who have P.S.C.have increased risk of colon cancer. This risk is highest inthose with extensive P.S.C. and long duration).In Sweden it was found that those with C.C. had anincreased risk of colon cancer. 8 studies have shown such anincreased risk but 3 studies have shown no increased risk.Patients with U.C. are commonly treated with 5-aminosalicylic acid (5-ASA) ~ Mesalazine (Asacol, Pentasaetc), steroids, probiotics, aspirin, 2, calcium + Vit. D & folic acid may be beneficial although we don’t know the rightdose. (1)

Dr. J. Jankowski (Oxford)

“Chemoprevention in IBD & P.S.C./IBDâ€

Talked in detail about the problems of surveillanceendoscopy. 1% of the population have IBD. About 5% of thosewith colitis get colon cancer. The risk increased with theduration of the disease and the extent of damage in the colon.If only the lower colon and rectum are involved, the risk ofcancer is no higher than normal.

60% of those with colitis get high-grade dysplasia in the colon.50% of those with low-grade dysplasia will eventually get high-gradedysplasia (pre-cancerous changes in the cell lining). There is alack of agreement about what is high-grade and low-grade.Generally this is an area of medicine where it is very difficult tofind funding for research.His young son thinks that we should alleat raisons which is a natural source of salicylates!

Dr. S. Pereira,

“Hepayobiliary cancer and P.S.C.â€

“We (U.C.L., London) are now leading the world incancer trialsâ€. (1) See “Folic Acid for the prevention of Colorectal Adenomas,†JAMA,2007; 297: 2351-59, 2408-9. And: ~“Folic Acid Suppls. do not appear to reduce the risk of colorectaltumoursâ€. R. Peek & K. R. Reddy. Gastroenterology, Vol. 133, issue 2,P.S.C. 379. August 2007.With regard to Aspirin use in treatment of colon cancer ~ Duke, C. et. al.“Aspirin Chemoprevention for Colorectal Cancer; Helpful, Harmful or StillToo Soon To Tellâ€. Gastroenterology. 2007; 133: 717-723.

End.

[Guest guest]

Dear Ivor,Thank you so much for sending this. I am sorry to hear that you were ill !! I hope it was nothing serious and that you are hale and hearty now !LeeThis is an edited transcript of a PSC Symposium at Oxford, UK. 8th June, 2007. I wanted to send this much earlier but illness and pressure of work has delayed it. I think there are some interesting points here. It’s not fully edited and there may be some errors and spelling mistakes. I hope you get it in one piece. A better edited version will appear in our newsletter which should be sent soon to subscribers.                                                                           Ivor (PSC-Support UK)