PSC Symposium; Oxford, 8th June, 2007

[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 - F31

A SYMPOSIUM AT ST. ANNE’S COLLEGE, OXFORD, ON THE

8th JUNE, 2007: ORGANISED BY DR.

CHAPMAN AND

SUPPORTED BY DR. FALK PHARMA U.K. LTD.

The aim of this conference was to “bring together

hepatologists, luminal gastroenterologists and

endoscopists to discuss the important association of

P.S.C. and I.B.D.”

This was a day-long symposium: the first speaker was DR.

JERRY KINGHAM (Singleton Hospital, Swansea)

“P.S.C./I.B.D. EPIDEMIOLOGY/NATURAL HISTORY”

He said that this is a disease which was hardly known when

he was a medical student. It was only really in the 1970s with

the advent of ERCP that it became clearer. And then there

were two seminal papers by doctors Wiesner & Chapman

which told us much of what we now know about the clinical

presentation of the disease. We had to wait another 15 years

before the first epidemiological studies came out.

(epidemiology = the study of the distribution of disease

among 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. 1,300

were found to have U.C. 10% of these had raised LFTs of

these 48% had P.S.C. Other studies also showed that around

4% of those with U.C. had P.S.C. Boberg’s Norwegian study

covered 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 examine

the local population in Minnesota. Our local ~Swansea study

examined a population of 250,000 over 20 years. The

results were similar to those of the Mayo. The figures that

come out suggest that up to 10 out of every 100,000 of the

population will have P.S.C. (In which case the P.S.C.

population in the U.K. (60million population) should be

around 6,000). With PBC it’s usually found to be double that.

In the Swansea study there was also a higher incidence of

PBC, but not very much more than P.S.C.

In terms of the natural history of the disease, the cholestasis

is usually progressive but has a terribly slow progression.

There are commonly strictures in the bile ducts, bouts of

cholangitis, bacterial cholangitis, or

cholangitis as part of the disease. Hepatitis (Autoimmune

Hepatitis) may also develop, especially in children ~ overlap

syndrome. Gallstones are present in about 25% of P.S.C.

patients. As the liver becomes increasingly fibrotic more

complications can develop. Cancer of the bile ducts and

other 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 the

brief discussion which followed Dr. Chapman confirmed that

75% of asymptomatic patients will be alive and well 15 years

after P.S.C. was first diagnosed. P.S.C. will develop in up to

10% of those with long-term U.C.

~ The outlook is very different amongst

patients. We have seen patients who are asymptomatic 20

years after diagnosis and some patients in their 20s dying of

C.C. (Cholaniocarcinoma). With small-duct P.S.C. the

prognosis is better and I haven’t seen any reports of C.C.

There is a good degree of unanimity in the studies, On

average P.S.C. patients who are symptomatic when

diagnosed - Dr. Chapman says 50% of these will not survive or will

go to transplantation in 10 - 12 years. But studies ignore the

fact that the age of those diagnosed has gone up by at least

10 years.

Dr. Chapman - About male dominance in P.S.C. (2 out of 3

patients are male) ~ normally in auto-immune diseases

there’s a predominance of female patients).

There are biliary diseases which predispose to

C.C. and are male dominant ~ Caroli’s Disease, Secondary

Sclerosing Cholangitis, Liver Fluke (Thailand) ~ all of which

predispose to C.C. ~ are male dominant. This doesn’t

answer the question but there is some factor operating in the

biliary system which leads to male predominance. There’s

auto-immune pancreatitis, clearly auto-immune by any

definition, and strongly male dominant ~ this is a clue to

something.

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’ve

been doing MRCPs on people who have total U.C., who are

completely well and have (apparently) no liver disease at all

~ normal LFTs ~ BUT ONE IN FIVE OF THESE PATIENTS HAVE

CHANGES CONSISTENT WITH P.S.C. This has major

connotations for their natural history. It (P.S.C.), may be a

very under-diagnosed condition in IBD.

Dr. Chapman; Although you’ve given

us a median prognosis of

10 years after diagnosis for symptomatic patients, most

people’s work suggests that those who are asymptomatic

when first diagnosed ~ their life expectancy (or time to

transplant) is longer.

Dr. Kingham; I think you need to see that patient for some years

:

:

:

PRIMARY SCLEROSING

CHOLANGITIS AND

INFLAMMATORY BOWEL DISEASE

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CONTINUED FROM PREVIOUS PAGE

Dr. Kingham

IYou can’t really put a prognosis on it because I’ve seen

patients who are asymptomatic and who are dead or

transplanted within five years and also patients who remain

well 20 years down the line. And I think you have to have a

time-frame to access the progression of cholestasis.

But it’s often not mentioned that the

asymptomatic patient is about 5 years younger than

average. In addition age at diagnosis has increased by about

a decade to people in their 50s.

The Swedish data relating to cholangiocarcinoma ~

(bile duct cancer). This is now a 10 year follow-up. The good

news for the patient is that it is worthwhile finding out whether

they have got small-duct or not because they have a much

better prognosis.

It does make you wonder if it is the same

disease.

What is the effect of colectomy? (removal of the

colon).

It does have an importance but not necessarily

in terms of life expectancy. It’s important after transplant. (It

may reduce the likelihood of a return of P.S.C. But it doesn’t

seem to modify the disease: it may modify the transplant.

IBD with P.S.C. is usually milder than IBD alone. There is rectal

sparing, (the rectum may not be affected) and backwash

ileitis. (Inflammation of the ileum, when the contents of the

colon flow backwards into the last segment of the small

intestine). With P.S.C. and IBD many more have pouchitis

(after colectomy). In terms of dysplasia (abnormalities in

cells ~ sometime pre-cancerous) P.S.C. has been seen as a

risk factor. In IBD without P.S.C. about 5% have dysplasia. But

in the Broome study well over 30% of those with P.S.C. and

IBD had dysplasia. Although the study in “Gastroenterology”

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 is

a large amount of early onset IBD. Clearly there is a

connection between environment and genetics. The

weather is different, the food is different … … genome-wide

research has narrowed down the genes involved in

susceptible patients. Genetic research should clarify the

relationship between P.S.C. and IBD.

Dr. Chapman: The figure for Scandinavia, which we agree

with ~ 50% of symptomatic patients would need a

transplant after 10 years post-diagnosis. 75% of

asymptomatic patients will be alive 15 years (plus) after

diagnosis. Some will have unpredictable progression. But

once they get the first symptoms, then they are on the

slippery slope.

:

:

NONE OF THOSE WITH

small-duct P.S.C. developed C.C.

:

:

Genome-wide research has

already been successful in Crohn’s Disease.

The journal “Nature” in June 2007 gives full treatment to this

research. We can now apply this type of study to P.S.C. and other

auto-immune diseases. For genome-wide studies the

technology and the expertise are available. We need access

to adequate wide cohorts which may be an issue. This will be

the next crest of the wave for IBD studies.

On Cancer and IBD

There was an Oxford paper suggesting that

inflammation in IBD was not a risk factor for cancer. To my

mind the animal data, and now the human data, indicate that

untreated inflammation IS a risk factor for the development

of colon cancer in U.C.

I first became interested in P.S.C. in 1976 at Southampton. I

then went to the Royal Free Hospital (London) to see Dame

Sheila Sherlock (renowned British hepatologist). She called

me into her office: she didn’t look very interested: she was

marking exam papers at the time. We discussed what I

wanted to do. I said I wanted to find the cause of P.S.C. She

said, “You are doing iron”. And that was that! I did iron.

I continued my interest in P.S.C. It’s been a bit of a nightmare

really. That’s where it all began. We developed the idea

almost 25 years ago that P.S.C. may be an auto-immune

disease.

The bacteria in the colon, some form of colonic toxicity ~

toxic bile acid (the liver reacts to this in an auto-immune

fashion) ~ it may be an auto-immune disease or at least

immune-mediated.

SMOKING was discussed ( and which we have

dealt with before in a previous newsletter). Something in the tobacco smoke

does

something in the mucus lining ~ but trials with nicotine

patches 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-immune

diseases in those who have P.S.C. and IBD (25% of patients)

compared to patients who have IBD alone ~ (9%). There is a

strong association with DR3 (HLA-DR3 Antigen) ~ a

multigene haplotype and an important factor in a number of

prominent autoimmune diseases).

This can develop in both adults and children ~ an overlap

condition P.S.C. to AIH, but rarely the other way round. At

least half the patients will have bile duct changes. More

recently in adult studies from Canada they looked at MRCP of

adults with AIH. Half of these patients had abnormal

cholangiograms. These diseases may be different ends of

the same disease spectrum.

PANCREATITIS

The pancreas is a strange sausage shape.

The disease may

present with jaundice, weight loss, with obstruction in the

bile ducts. Half the patients are diabetic. The pancreas is

inflamed. If you take biopsies it’s full of IG4 lymphosites.

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CONTINUED FROM PREVIOUS PAGE

“P.S.C. Medical Treatment”

PANCREATIC DISEASE IS a multiple condition affecting

the lungs, kidneys and there are problems with the bile

ducts. The important thing is the ICG4 which is almost a

diagnosis for the condition. There are strictures and it’s

almost indistinguishable from P.S.C. Patients should be

supported by steroids. Complete normality can be returned

after the use of corticosteroids. If you find these changes

early enough you can do something about it. How does this

relate? It is very difficult. Is it a form of P.S.C.? I think it is a

different condition but the genetics haven’t been done yet.

90% of P.S.C. is HLA associated. This may be co-incidental or

chance. We don’t know at the moment. A lot of non-specific

antibodies are found in P.S.C. raising the concept of immune

dysfunction. There is a lot of circumstantial evidence, at

least, that the disease is immune regulated.

You have to ask the question ~ how does IBD drive the

development of P.S.C.? Lymphocytes travel between gut and

liver and this may explain the cause of infiltration but it

doesn’t explain the trigger and we still don’t know that.

In terms of pathogenesis, (Professor Neuberger) has

pointed out that in terms of r.P.S.C. (recurrent P.S.C. after

transplant) if you have your colon still there ~ this was

found in Birmingham ~ there’s a higher risk of getting P.S.C. in the new

liver. This has been reproduced in the Norwegian cohort

but it has not been in the Edinburgh cohort, though it may be be a

good idea to remove the colon before transplantation, not

least because of P.S.C. but also because of the risk of cancer

in the colon.

The hypothesis of Vierling is very interesting: that you

have a (genetically) susceptible host: typically a male nonsmoker.

HLA-DR3 antigens are present. Various bacteria arise from

the gut and activate a variety of cells, developing a form of

secretion. This attracts neutrophils and other lymphocytes

and fibroblasts. He says that these cause concentric fibrosis

around the bile ducts. This causes ischemia ~ the bile ducts

lose their blood supply. They atrophy leading to cholangitis

and 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 bacterial

involvement, no evidence for viral infection and, as we’ve

heard, lymphocytes provide the link between the gut and the

liver. But I think that the Holy Grail, which I set out, 30 years

ago is elusive and I think it very unlikely that any single

infective factor will be found.

Dr. Sue Cullen

was Dr. Chapman’s Research Assistant for 3 years and is

now a Consultant at High Wycombe. She gave us a talk last

year and on previous occasions so we’re familiar with her

work on the High-Dose Urso Trial, which is to be published

shortly. 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 studying

patients at all stages of the disease. (and we may not be

studying like with like). Most drug trials with P.S.C. patients

are too small and short and therefore underpowered. (This

may mean that trial results are unreliable). The low profile of

the disease makes it difficult to get funding. More than a

dozen drugs have been tested in trials. Those trials have

shown little success. A 2003 trial showed that there may be a small

sub-group of patients that responds well to immunosuppressants. It would also

be interesting to

go back and look at the genetic profiling of this sub-group to

see if there is any way in which we can predict which patients

might do well.

Dr. Cullen described trials with nicotine patches, combination

therapies, immunosuppresants, colchicine etc., none of

which showed any benefits. She then looked at the Oxford

Urso Trial, soon to be published, in which she was involved: a

pilot study of 33 patients over 2 years. Only 3 of the patients

had a worsening of their biopsies at that time.

The large Scandinavian Urso study by Dr. Broome and others

used 17 - 23mg of Urso per kilo of body weight. 219 patients

were studied over 5 years. Nevertheless it was underpowered

because they were unable to reach their aim of 346

patients. This survey did not find any substantial benefits for

Urso apart from the fact that the data can be interpreted to

show that the Urso group had half the rate of C.C. compared

to the placebo group. (An important enough benefit). And 2

years into this study the Urso group appeared to stabilise.

There is consensus that with the Urso studies so far Urso

certainly improves LFTs, it doesn’t make much difference to

symptoms.

Does it improve histology? The jury is still out on that. (There

is clinical evidence that those liver units which have been

prescribing high-dose Urso for some years have lower rates

of C.C. and colon cancer).

Overall, progress in understanding and treating P.S.C. is slow.

Our understanding of auto-immune pancreatitis and

AIH/P.S.C. crossover has been helpful in prescribing patients

with steroids (and immunosuppresants for AIH). We have

been able to genetically profile patients and determine which

treatments are most successful and this may be the way

forward.

She added that in terms of the dose of Urso there is

a biliary enrichment with increasing doses up to 25mg per

kilo of body weight (per day). There’s a plateau that comes in

after that. My feeling is that it comes in at around 20-25mg ~

which is what is meant by high-dose. There’s a lot of

evidence that you shouldn’t push it much higher than that. In

the 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.) The

large Mayo study on high-dose Urso has about 2 years to run.

I think that that trial may be very helpful. The problem is that

trials have a mixed group of patients. If we had patients with

only early P.S.C. the results might be more impressive. The

problem is knowing who these patients are and finding a big

enough group of early patients to have a worthwhile trial.

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CONTINUED FROM PREVIOUS PAGE

PROFESSOR ADOLF STIEHL

“P.S.C. - ENDOSCOPIC TREATMENT”

The next speaker is well-known

for his approach in emphasising the importance of

clearing dominant bile-duct strictures in patients with

cholestatic disease by balloon endoscopy.

Dr. Chapman introduced him by saying that

Professor Stiehl

has done great studies on bile acids and contributed to the

science of bile acids in cholestasis and has developed

endoscopic therapy with or without high-dose Urso.

My topic is endoscopic treatment ~ the

problem in P.S.C. is

the fibrosis which develops around the bile ducts. The

fibrosis tends to shrink and we get the development of

dominant strictures (narrowing), or stenosis. The problem is

that firstly we have to detect dominant strictures, (which is

often difficult), and we have to make a judgement as to

whether the patient has or has not got a dominant stricture. I

want to stress that the specificity and sensitivity of MRCP is

between 85-95%. This means we can miss strictures. This is

a real problem. In many cases it’s easy but we CAN miss

dominant strictures. The technique involves dilating the

strictures. We have found that stenting these strictures is not

as 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 results

if we open the strictures by balloon. (Slides are then shown

on the screen in the lecture hall). This is from one of our first

patients 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 large

segment of DS which we hadn’t seen. What I want to show

you here (on the screen) is that if you can get a guide wire to

the DS and dilate it … …

This is the situation after one year. You can open these long

segments of stenosis. Here you can see the bile ducts after

12 years - you can

get a normal CBD (Common Bile Duct). This should delay the

need for a transplant (and/or increase survival).

.. There are a number of

dilatations over the years. What I’ve shown you is that we

CAN open long segments of DS.

At the same time it’s very important that all endoscopic

procedures are performed with prophylactic antibiotics.

Bacteria play a major role in P.S.C. Perhaps this is one reason

why the use of immunosuppresants is associated with so

many problems and are not successful. They may even be

harmful. These bacteria may be associated with DSs. i.e.

when you find a DS the likelihood is that you will find bacterial

growth.

When we started out on this procedure we thought that only

short segments of DSs could be treated but we are now able

to treat long segments. What is the functional result? Pruritis

(itching) is successfully treated. And we believe that survival

time (or time to transplantation) is extended.

There is significant improvement in survival if you have such a process of

REPEATING THIS DILATION EVERY YEAR.

BUT IT’S NOT

SUFFICIENT TO DO THIS ONCE

Compared with those who don’t have their DSs

opened we gain a certain time if the patient has to go on to

transplantation. It is not sufficient to open a DS once. Even

after 9 or 10 years where a patient has (apparently) been free

of DS, repeat dilatation may be necessary. (Evidence is

shown on the screen of perfect bile ducts after several

dilations).

After 10 years 50% of our patients are free of liver

transplantation. This is what you achieve if you treat DS

actively by endoscopic means. Pruritis (itching) is also

successfully treated this way.

The problem with P.S.C. is the natural presence of bacteria. I

refer here to the paper by Ohlsson, (Swedish hepatologist).

60% of patients who did not receive anti-biotics at the time of

exploration of the liver and the bile ducts had bacteria in the

bile ducts as opposed to 30-40% who did have antibiotics

when we treat DSs. The incidence of DS in P.S.C. is, in our

opinion underestimated. We follow our patients very closely.

20% of them came to us specifically because of their DSs in

P.S.C. because we have become a referral centre for this

condition. Over time half our patients develop DSs and need

treatment. 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). They

compared endoscopic dilation with and without stents and

have shown that if you put in stents you get complications.

The method of choice is to open the stenosis with balloon

endoscopy. Two studies have compared survival (or time to

transplant) where DS is treated in PSC. and in our own study, and found

significant improvement in survival over

predicted survival. Nevertheless when we compare our

patients who have DSs with those who don’t there is a

significant difference. Even though our patients with DSs are

treated as described their overall survival is worse than those

who 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. ERCP

and/or MRCP should be performed in cholestasis. If you don’t

see anything with MRCP I still think you should go on to ERCP

because it is better and a more accurate procedure.

A brief discussion which followed said ~

Question: I

know you treat your patients with high-dose Urso, as well …

… …

All the studies have shown that the toxic effects of bile acids

can be prevented by use of Urso … … …

Dr. Chapman wondered whether repeat

balloon-endoscopies

and the (laborious) treatment of DSs could be followed within

the confines of the N.H.S.

Prof. Stiehl: We use 20 - 25mg per kilo Urso.

We have a low rate of C.C., at

3%.

For a critique of Professor Stiehl’s

approach see PSC-News

number 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?”

The whole problem with transplantation,

particularly in the

UK, is

the number of patients who would benefit from

transplantation (tx) and the number of organs available and

this is what I want to deal with. The number of donors is even

decreasing slightly. For every person you put into the system

one person has got to come out of it. Rationing has to occur

because there aren’t enough organs to go round and we

must use selection criteria. This has to be an open process

based on equity. Everybody has an equal right. We must

consider what is the best use of the organ. We are moving

towards a more open system in the UK, which just means

there’s another layer of obfuscation beneath that. Our

selection criteria are based mainly on the risk of death

without tx (transplantation). Secondarily you’re also talking

about the quality of life.

In 1999 we had a consensus meeting and it was agreed that

a tx patient should have a greater than 50% chance of being

alive 5 years after tx with a quality of life acceptable to the

patient. This is nice and very helpful until you start applying it

to individuals because a lot of sentiments are difficult to

quantify.

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. It

shouldn’t be forgotten that with adult Live Donor Liver

Transplants there’s a mortality rate of about 1%, mostly

amongst the donors.

Looking at survival and how you select patients there are two

models:

1. MELD System

2. U.K. Model

We should note that a model is just a model. They’re usually

very good when applied to populations but when you

extrapolate them to the individual that’s when they start to

fail.

The Meld model (Model for End Stage Liver Disease) was

developed at the Mayo clinic, mainly for short-term survival

in patients undergoing the TIPS procedure ~ based on a

combination of bilibrubin, creantinine and INR. This gives

some cause for concern. It’s well recognised that there are

lab variations. The same sample measured in different labs

can vary by 10 - 15%. If you’re enthusiastic about diuretics

you can increase warfarin. So if you want to get your patient a

higher MELD score, you can make their prognosis worse. It

has been done.

The Child-Pugh classification is very subjective: it’s based on

encephalopathy, ascites etc. You wouldn’t get consensus on

this: if they’re sick they’re Child-C, if they’re well

they’re

Child-B. It’s a very useful shorthand but if I ask you to write

down what you think of the Child-Pugh score we’ll see a lot of

variation. And even if you look at textbooks you’ll see

variation. The correlation between Child-Pugh and MELD is

not great. With MELD you put in the numbers and you get a

score that’s roughly between 7 and 40 and you would see

the correlation as to mortality over 3 months. A score of 40

would give you an 8% probability of mortality at 3 months. A

score of 10 would give you a 5% mortality. People talk about

MELD but they don’t usually correlate it with survival. It is a

marker for short-term rather than long-term survival. I was

interested in the discussion on the value of prognosis. I’m

never sure how valuable it is. You can’t influence it and you

don’t know what the confidence intervals of that prognosis

are.

As you can see (from the screen) there’s quite a good

correlation between MELD and 3 months probability of

survival. Meldology is really becoming a science within

hepatology. Here are some new US data (on the screen) on

probability of survival on the waiting list after tx. And the

important two points to notice is that tx only gives you

survival benefit when your MELD approaches 17. Secondly if

you look at survival after tx MELD correlates very poorly with

post-tx survival. It’s often said that patients who are sick are

likely to do less well: the evidence is against you although

quite clearly it is intuitive. The reason is that surgeons are

quite good at matching donors to recipients. (The paper

continued with reference to data presented on the screen and

without that some of the meaning is lost here). Using the

U.K. data

base of about 6,000 transplanted liver patients

(data derived from ston). Some of these patients

were relatively well and some quite ill. Does this matter in

terms 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. than

MELD and is more important in predicting outcome. You want

to 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 high

mortality, there’s 65% survival after 10 years. Not bad but it’s

clearly not good enough. Results have been improving over

time. When do you not tx? As I said, prognostic models are

useful guides but they are subject to problems when applied

to individuals. We haven’t mentioned symptoms. Clinical

judgement clearly plays a role. Intractable pruritis is clearly an

indication to tx (when none of the usual drugs have any

effect). Also intractable encephalopathy, liver cell cancer,

diuretic ascites etc. are all indications for tx which are not

covered by MELD or the U.K. model because you’re not likely

to die. Lethargy is not an indication for tx. It may not improve

after tx. The best data comes from a small study done by the

Newcastle group. They had a score for PBC patients and they

found there was not great differenced in levels of lethargy

before and after tx. Our own retrospective study at

Birmingham found that if you’re (relatively) well with a lot of

lethargy before tx, you’ll be well but also with a lot of lethargy

after tx. Whether people have a low threshold or whether

there’s something more important here we don’t really

know.

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CONTINUED FROM PREVIOUS PAGE

The other indication ~ or in fact a contra-indication is C.C.

This is because patients with C.C. do extremely badly. You

cannot approach the 50% 5-year survival that we would

require. The reason is that C.C. spreads through the

lymphatic and nervous systems at an early stage. By the

time you’re diagnosed it is probably too late. Mainly, as with

hepatoma, it (C.C.) occurs in the allograft, but not

entirely. In my view most of the (tumor) markers used are

very good at producing papers but next to useless when

applied to patients. I do have to stress that a very small

number of people with C.C. can do very well after tx. These

patients have a rigorous work out with surgery, chemo- and

radiotherapy. the small numbers they’ve done have done

very well after tx at the Mayo Clinic. But in the majority of

patients I don’t believe there is any effective treatment for

C.C.

Certainly age is another factor in considering tx. It’s an

independent predictive factor for post-transplant survival.

Depressingly it starts to creep in as a factor from the age of

40. After 60 it’s a significant factor. But there are some very

good survivors and one has to make a judgement of the

patient.

Nutrition is a factor. Many of these patients are malnourished

(as a consequence of advanced liver disease). But in spite of

surgeons going on about this there are no data showing that

well-nourished patients do better; it’s inappropriate to

withhold patients from tx because of malnutrition. The

difficulty is with those who have a past history of cancer,

especially colon cancer. How long do you leave them before

you’re convinced it won’t recur? Previous abdominal surgery,

morbidity, add somewhat to the mortality post-tx ~ the same

with biliary and gastric surgery. For those with active

Ulcerative Colitis there is no problem in doing a colectomy at

the same time as the tx.

Tx is a very good procedure but it does shorten your life. This

is some data we produced (at Birmingham) and published in

2006.

Life expectancy ~ and this is for men ~ is very good in P.S.C.

patients after tx. Much better than those who have liver

cancer, Hepatitis C and alcoholic liver disease. At 20-years old

you can expect to live 45 years. 65-year-olds may have 10

years. It is a very good prognosis for tx P.S.C. patients.

Recurrence (rP.S.C.) does affect survival. Those without

rP.S.C. do significantly better. Recurrence can be detected in

the presence of normal LFTs. We look for it radiologically and

histologically and (as shown on the screen) there is increasing

recurrence over time. We don’t know why and it doesn’t

necessarily translate into graft loss.

Those who have had a colectomy either before or at the time

of tx had a lot less recurrence than those with an intact colon.

It has been controversial, the Scandinavians have been

unable 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-tx

Colitis. Those with Ulcerative Colitis and tx for P.S.C. ~ about a

third had improvements in their Ulcerative Colitis, one third

stayed the same and one third became worse. The

Scandinavians found that the type of immunosuppression

makes a difference. We weren’t able to show that. All patients

post-tx have an increased risk of cancer, especially colon

cancer. This isn’t true of breast and cervical cancer in women

PSCers. Therefore more surveillance and monitoring of the

colon is necessary.

In summary P.S.C. is an excellent

indication for a transplant. The models are a guide but not a

replacement for clinical judgement. It’s important to stress

that C.C. and lethargy are not indications for a transplant.

We tell patients that tx is not a cure, it’s a swap. Swopping one

disease for another. When the MELD score starts to reach 12

or 13, that is the time to start thinking of a tx, but it may be

earlier, it may be later. Too early doesn’t matter, too late ~ and

the problem is waiting for an organ because of the shortage.

Please write to your M.P.s, raise the alcohol limit, no safety

belts in cars, no crash helmets!

We tend to use immunosuppressants ~ Azathioprin along

with tacrolimus, as our major agents but we don’t put them

on routine Azathioprin because of the Colitis.

Further details came out at the meeting

from

U.C.L., London (”Hepatobiliary Cancer and P.S.C.”).

Amongst

outpatients, those with AIH responded well to immunosuppressants

and there was 50% relapse. In the case of C.C.

this tended mostly to occur early after the diagnosis after

which the rate tended to be around 1-2% p.a. There is a

significant increase in pancreatic cancer and this needs to be

confirmed. The symptoms of this are known but not the risk

factors.

On C.C. Prof.Stiehl said that all his patients who have

had 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 in

those with extensive P.S.C. and long duration).

In Sweden it was found that those with C.C. had an

increased risk of colon cancer. 8 studies have shown such an

increased risk but 3 studies have shown no increased risk.

Patients with U.C. are commonly treated with 5-

aminosalicylic acid (5-ASA) ~ Mesalazine (Asacol, Pentasa

etc), steroids, probiotics, aspirin, 2, calcium + Vit. D &

folic acid may be beneficial although we don’t know the right

dose. (1)

Dr. J. Jankowski (Oxford)

“Chemoprevention in IBD &

P.S.C./IBD”

Talked in detail about the problems of

surveillance

endoscopy. 1% of the population have IBD. About 5% of those

with colitis get colon cancer. The risk increased with the

duration of the disease and the extent of damage in the colon.

If only the lower colon and rectum are involved, the risk of

cancer 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-grade

dysplasia (pre-cancerous changes in the cell lining). There is a

lack of agreement about what is high-grade and low-grade.

Generally this is an area of medicine where it is very difficult to

find funding for research.

His young son thinks that we should all

eat raisons which is a natural source of salicylates!

Dr. S. Pereira,

“Hepayobiliary cancer and P.S.C.”

“We (U.C.L., London) are now leading the world in

cancer trials”.

(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 colorectal

tumours”. 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 Still

Too Soon To Tell”. Gastroenterology. 2007; 133: 717-723.

End.

[Guest guest]

This is a pretty good transcript. Thanks!

Jarad

>

> 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 - F31

> A SYMPOSIUM AT ST. ANNE'S COLLEGE, OXFORD, ON THE

> 8th JUNE, 2007: ORGANISED BY DR. CHAPMAN AND

> SUPPORTED BY DR. FALK PHARMA U.K. LTD.

>

>

> The aim of this conference was to " bring together

> hepatologists, luminal gastroenterologists and

> endoscopists to discuss the important association of

> P.S.C. and I.B.D. "

>

>

> This was a day-long symposium: the first speaker was DR.

> JERRY KINGHAM (Singleton Hospital, Swansea)

> " P.S.C./I.B.D. EPIDEMIOLOGY/NATURAL HISTORY "

>

>

> He said that this is a disease which was hardly known when

> he was a medical student. It was only really in the 1970s with

> the advent of ERCP that it became clearer. And then there

> were two seminal papers by doctors Wiesner & Chapman

> which told us much of what we now know about the clinical

> presentation of the disease. We had to wait another 15 years

> before the first epidemiological studies came out.

> (epidemiology = the study of the distribution of disease

> among 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. 1,300

> were found to have U.C. 10% of these had raised LFTs of

> these 48% had P.S.C. Other studies also showed that around

> 4% of those with U.C. had P.S.C. Boberg's Norwegian study

> covered 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 examine

> the local population in Minnesota. Our local ~Swansea study

> examined a population of 250,000 over 20 years. The

> results were similar to those of the Mayo. The figures that

> come out suggest that up to 10 out of every 100,000 of the

> population will have P.S.C. (In which case the P.S.C.

> population in the U.K. (60million population) should be

> around 6,000). With PBC it's usually found to be double that.

> In the Swansea study there was also a higher incidence of

> PBC, but not very much more than P.S.C.

> In terms of the natural history of the disease, the cholestasis

> is usually progressive but has a terribly slow progression.

> There are commonly strictures in the bile ducts, bouts of

> cholangitis, bacterial cholangitis, or

> cholangitis as part of the disease. Hepatitis (Autoimmune

> Hepatitis) may also develop, especially in children ~ overlap

> syndrome. Gallstones are present in about 25% of P.S.C.

> patients. As the liver becomes increasingly fibrotic more

> complications can develop. Cancer of the bile ducts and

> other 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 the

> brief discussion which followed Dr. Chapman confirmed that

> 75% of asymptomatic patients will be alive and well 15 years

> after P.S.C. was first diagnosed. P.S.C. will develop in up to

> 10% of those with long-term U.C.

> ~ The outlook is very different amongst

> patients. We have seen patients who are asymptomatic 20

> years after diagnosis and some patients in their 20s dying of

> C.C. (Cholaniocarcinoma). With small-duct P.S.C. the

> prognosis is better and I haven't seen any reports of C.C.

> There is a good degree of unanimity in the studies, On

> average P.S.C. patients who are symptomatic when

> diagnosed - Dr. Chapman says 50% of these will not survive or will

> go to transplantation in 10 - 12 years. But studies ignore the

> fact that the age of those diagnosed has gone up by at least

> 10 years.

> Dr. Chapman - About male dominance in P.S.C. (2 out of 3

> patients are male) ~ normally in auto-immune diseases

> there's a predominance of female patients).

> There are biliary diseases which predispose to

> C.C. and are male dominant ~ Caroli's Disease, Secondary

> Sclerosing Cholangitis, Liver Fluke (Thailand) ~ all of which

> predispose to C.C. ~ are male dominant. This doesn't

> answer the question but there is some factor operating in the

> biliary system which leads to male predominance. There's

> auto-immune pancreatitis, clearly auto-immune by any

> definition, and strongly male dominant ~ this is a clue to

> something.

> 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've

> been doing MRCPs on people who have total U.C., who are

> completely well and have (apparently) no liver disease at all

> ~ normal LFTs ~ BUT ONE IN FIVE OF THESE PATIENTS HAVE

> CHANGES CONSISTENT WITH P.S.C. This has major

> connotations for their natural history. It (P.S.C.), may be a

> very under-diagnosed condition in IBD.

>

>

>

> Dr. Chapman; Although you've given us a median prognosis of

> 10 years after diagnosis for symptomatic patients, most

> people's work suggests that those who are asymptomatic

> when first diagnosed ~ their life expectancy (or time to

> transplant) is longer.

> Dr. Kingham; I think you need to see that patient for some years

>

> :

> :

> :

> PRIMARY SCLEROSING

> CHOLANGITIS AND

> INFLAMMATORY BOWEL DISEASE

>

>

>

> Ref: PAGE 2a YOUR REF: F1 - F31

> CONTINUED FROM PREVIOUS PAGE

> Dr. Kingham

> IYou can't really put a prognosis on it because I've seen

> patients who are asymptomatic and who are dead or

> transplanted within five years and also patients who remain

> well 20 years down the line. And I think you have to have a

> time-frame to access the progression of cholestasis.

> But it's often not mentioned that the

> asymptomatic patient is about 5 years younger than

> average. In addition age at diagnosis has increased by about

> a decade to people in their 50s.

>

>

>

>

> The Swedish data relating to cholangiocarcinoma ~

> (bile duct cancer). This is now a 10 year follow-up. The good

> news for the patient is that it is worthwhile finding out whether

> they have got small-duct or not because they have a much

> better prognosis.

> It does make you wonder if it is the same

> disease.

> What is the effect of colectomy? (removal of the

> colon).

> It does have an importance but not necessarily

> in terms of life expectancy. It's important after transplant. (It

> may reduce the likelihood of a return of P.S.C. But it doesn't

> seem to modify the disease: it may modify the transplant.

> IBD with P.S.C. is usually milder than IBD alone. There is rectal

> sparing, (the rectum may not be affected) and backwash

> ileitis. (Inflammation of the ileum, when the contents of the

> colon flow backwards into the last segment of the small

> intestine). With P.S.C. and IBD many more have pouchitis

> (after colectomy). In terms of dysplasia (abnormalities in

> cells ~ sometime pre-cancerous) P.S.C. has been seen as a

> risk factor. In IBD without P.S.C. about 5% have dysplasia. But

> in the Broome study well over 30% of those with P.S.C. and

> IBD had dysplasia. Although the study in " Gastroenterology "

> 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 is

> a large amount of early onset IBD. Clearly there is a

> connection between environment and genetics. The

> weather is different, the food is different . . genome-wide

> research has narrowed down the genes involved in

> susceptible patients. Genetic research should clarify the

> relationship between P.S.C. and IBD.

>

>

> Dr. Chapman: The figure for Scandinavia, which we agree

> with ~ 50% of symptomatic patients would need a

> transplant after 10 years post-diagnosis. 75% of

> asymptomatic patients will be alive 15 years (plus) after

> diagnosis. Some will have unpredictable progression. But

> once they get the first symptoms, then they are on the

> slippery slope.

> :

> :

> NONE OF THOSE WITH

> small-duct P.S.C. developed C.C.

> :

> :

> Genome-wide research has

> already been successful in Crohn's Disease.

> The journal " Nature " in June 2007 gives full treatment to this

> research. We can now apply this type of study to P.S.C. and other

> auto-immune diseases. For genome-wide studies the

> technology and the expertise are available. We need access

> to adequate wide cohorts which may be an issue. This will be

> the next crest of the wave for IBD studies.

>

>

>

> On Cancer and IBD

>

>

> There was an Oxford paper suggesting that

> inflammation in IBD was not a risk factor for cancer. To my

> mind the animal data, and now the human data, indicate that

> untreated inflammation IS a risk factor for the development

> of colon cancer in U.C.

> I first became interested in P.S.C. in 1976 at Southampton. I

> then went to the Royal Free Hospital (London) to see Dame

> Sheila Sherlock (renowned British hepatologist). She called

> me into her office: she didn't look very interested: she was

> marking exam papers at the time. We discussed what I

> wanted to do. I said I wanted to find the cause of P.S.C. She

> said, " You are doing iron " . And that was that! I did iron.

> I continued my interest in P.S.C. It's been a bit of a nightmare

> really. That's where it all began. We developed the idea

> almost 25 years ago that P.S.C. may be an auto-immune

> disease.

> The bacteria in the colon, some form of colonic toxicity ~

> toxic bile acid (the liver reacts to this in an auto-immune

> fashion) ~ it may be an auto-immune disease or at least

> immune-mediated.

>

>

> SMOKING was discussed ( and which we have

> dealt with before in a previous newsletter). Something in the

tobacco smoke

> does

> something in the mucus lining ~ but trials with nicotine

> patches 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-immune

> diseases in those who have P.S.C. and IBD (25% of patients)

> compared to patients who have IBD alone ~ (9%). There is a

> strong association with DR3 (HLA-DR3 Antigen) ~ a

> multigene haplotype and an important factor in a number of

> prominent autoimmune diseases).

> This can develop in both adults and children ~ an overlap

> condition P.S.C. to AIH, but rarely the other way round. At

> least half the patients will have bile duct changes. More

> recently in adult studies from Canada they looked at MRCP of

> adults with AIH. Half of these patients had abnormal

> cholangiograms. These diseases may be different ends of

> the same disease spectrum.

>

>

>

> PANCREATITIS

>

> The pancreas is a strange sausage shape. The disease may

> present with jaundice, weight loss, with obstruction in the

> bile ducts. Half the patients are diabetic. The pancreas is

> inflamed. If you take biopsies it's full of IG4 lymphosites.

>

>

>

>

> Ref: PAGE 2b YOUR REF: F1 - F31

> CONTINUED FROM PREVIOUS PAGE

> " P.S.C. Medical Treatment "

>

>

>

>

> PANCREATIC DISEASE IS a multiple condition affecting

> the lungs, kidneys and there are problems with the bile

> ducts. The important thing is the ICG4 which is almost a

> diagnosis for the condition. There are strictures and it's

> almost indistinguishable from P.S.C. Patients should be

> supported by steroids. Complete normality can be returned

> after the use of corticosteroids. If you find these changes

> early enough you can do something about it. How does this

> relate? It is very difficult. Is it a form of P.S.C.? I think it is

a

> different condition but the genetics haven't been done yet.

> 90% of P.S.C. is HLA associated. This may be co-incidental or

> chance. We don't know at the moment. A lot of non-specific

> antibodies are found in P.S.C. raising the concept of immune

> dysfunction. There is a lot of circumstantial evidence, at

> least, that the disease is immune regulated.

> You have to ask the question ~ how does IBD drive the

> development of P.S.C.? Lymphocytes travel between gut and

> liver and this may explain the cause of infiltration but it

> doesn't explain the trigger and we still don't know that.

> In terms of pathogenesis, (Professor Neuberger) has

> pointed out that in terms of r.P.S.C. (recurrent P.S.C. after

> transplant) if you have your colon still there ~ this was

> found in Birmingham ~ there's a higher risk of getting P.S.C. in

the new

> liver. This has been reproduced in the Norwegian cohort

> but it has not been in the Edinburgh cohort, though it may be be a

> good idea to remove the colon before transplantation, not

> least because of P.S.C. but also because of the risk of cancer

> in the colon.

> The hypothesis of Vierling is very interesting: that you

> have a (genetically) susceptible host: typically a male nonsmoker.

> HLA-DR3 antigens are present. Various bacteria arise from

> the gut and activate a variety of cells, developing a form of

> secretion. This attracts neutrophils and other lymphocytes

> and fibroblasts. He says that these cause concentric fibrosis

> around the bile ducts. This causes ischemia ~ the bile ducts

> lose their blood supply. They atrophy leading to cholangitis

> and 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 bacterial

> involvement, no evidence for viral infection and, as we've

> heard, lymphocytes provide the link between the gut and the

> liver. But I think that the Holy Grail, which I set out, 30 years

> ago is elusive and I think it very unlikely that any single

> infective factor will be found.

>

>

>

> Dr. Sue Cullen

>

>

> was Dr. Chapman's Research Assistant for 3 years and is

> now a Consultant at High Wycombe. She gave us a talk last

> year and on previous occasions so we're familiar with her

> work on the High-Dose Urso Trial, which is to be published

> shortly. 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 studying

> patients at all stages of the disease. (and we may not be

> studying like with like). Most drug trials with P.S.C. patients

> are too small and short and therefore underpowered. (This

> may mean that trial results are unreliable). The low profile of

> the disease makes it difficult to get funding. More than a

> dozen drugs have been tested in trials. Those trials have

> shown little success. A 2003 trial showed that there may be a small

> sub-group of patients that responds well to immunosuppressants. It

would

> also be interesting to

> go back and look at the genetic profiling of this sub-group to

> see if there is any way in which we can predict which patients

> might do well.

> Dr. Cullen described trials with nicotine patches, combination

> therapies, immunosuppresants, colchicine etc., none of

> which showed any benefits. She then looked at the Oxford

> Urso Trial, soon to be published, in which she was involved: a

> pilot study of 33 patients over 2 years. Only 3 of the patients

> had a worsening of their biopsies at that time.

> The large Scandinavian Urso study by Dr. Broome and others

> used 17 - 23mg of Urso per kilo of body weight. 219 patients

> were studied over 5 years. Nevertheless it was underpowered

> because they were unable to reach their aim of 346

> patients. This survey did not find any substantial benefits for

> Urso apart from the fact that the data can be interpreted to

> show that the Urso group had half the rate of C.C. compared

> to the placebo group. (An important enough benefit). And 2

> years into this study the Urso group appeared to stabilise.

> There is consensus that with the Urso studies so far Urso

> certainly improves LFTs, it doesn't make much difference to

> symptoms.

> Does it improve histology? The jury is still out on that. (There

> is clinical evidence that those liver units which have been

> prescribing high-dose Urso for some years have lower rates

> of C.C. and colon cancer).

> Overall, progress in understanding and treating P.S.C. is slow.

> Our understanding of auto-immune pancreatitis and

> AIH/P.S.C. crossover has been helpful in prescribing patients

> with steroids (and immunosuppresants for AIH). We have

> been able to genetically profile patients and determine which

> treatments are most successful and this may be the way

> forward.

> She added that in terms of the dose of Urso there is

> a biliary enrichment with increasing doses up to 25mg per

> kilo of body weight (per day). There's a plateau that comes in

> after that. My feeling is that it comes in at around 20-25mg ~

> which is what is meant by high-dose. There's a lot of

> evidence that you shouldn't push it much higher than that. In

> the 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.) The

> large Mayo study on high-dose Urso has about 2 years to run.

> I think that that trial may be very helpful. The problem is that

> trials have a mixed group of patients. If we had patients with

> only early P.S.C. the results might be more impressive. The

> problem is knowing who these patients are and finding a big

> enough group of early patients to have a worthwhile trial.

>

>

>

>

>

> Ref: PAGE 2c YOUR REF: F1 - F31

> CONTINUED FROM PREVIOUS PAGE

>

>

>

> PROFESSOR ADOLF STIEHL

> " P.S.C. - ENDOSCOPIC TREATMENT "

> The next speaker is well-known

> for his approach in emphasising the importance of

> clearing dominant bile-duct strictures in patients with

> cholestatic disease by balloon endoscopy.

>

>

>

> Dr. Chapman introduced him by saying that Professor Stiehl

> has done great studies on bile acids and contributed to the

> science of bile acids in cholestasis and has developed

> endoscopic therapy with or without high-dose Urso.

>

>

>

> My topic is endoscopic treatment ~ the problem in P.S.C. is

> the fibrosis which develops around the bile ducts. The

> fibrosis tends to shrink and we get the development of

> dominant strictures (narrowing), or stenosis. The problem is

> that firstly we have to detect dominant strictures, (which is

> often difficult), and we have to make a judgement as to

> whether the patient has or has not got a dominant stricture. I

> want to stress that the specificity and sensitivity of MRCP is

> between 85-95%. This means we can miss strictures. This is

> a real problem. In many cases it's easy but we CAN miss

> dominant strictures. The technique involves dilating the

> strictures. We have found that stenting these strictures is not

> as 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 results

> if we open the strictures by balloon. (Slides are then shown

> on the screen in the lecture hall). This is from one of our first

> patients 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 large

> segment of DS which we hadn't seen. What I want to show

> you here (on the screen) is that if you can get a guide wire to

> the DS and dilate it . .

> This is the situation after one year. You can open these long

> segments of stenosis. Here you can see the bile ducts after

> 12 years - you can

> get a normal CBD (Common Bile Duct). This should delay the

> need for a transplant (and/or increase survival).

> . There are a number of

> dilatations over the years. What I've shown you is that we

> CAN open long segments of DS.

> At the same time it's very important that all endoscopic

> procedures are performed with prophylactic antibiotics.

> Bacteria play a major role in P.S.C. Perhaps this is one reason

> why the use of immunosuppresants is associated with so

> many problems and are not successful. They may even be

> harmful. These bacteria may be associated with DSs. i.e.

> when you find a DS the likelihood is that you will find bacterial

> growth.

> When we started out on this procedure we thought that only

> short segments of DSs could be treated but we are now able

> to treat long segments. What is the functional result? Pruritis

> (itching) is successfully treated. And we believe that survival

> time (or time to transplantation) is extended.

> There is significant improvement in survival if you have such a

process of

> REPEATING THIS DILATION EVERY YEAR.

> BUT IT'S NOT

> SUFFICIENT TO DO THIS ONCE

> Compared with those who don't have their DSs

> opened we gain a certain time if the patient has to go on to

> transplantation. It is not sufficient to open a DS once. Even

> after 9 or 10 years where a patient has (apparently) been free

> of DS, repeat dilatation may be necessary. (Evidence is

> shown on the screen of perfect bile ducts after several

> dilations).

> After 10 years 50% of our patients are free of liver

> transplantation. This is what you achieve if you treat DS

> actively by endoscopic means. Pruritis (itching) is also

> successfully treated this way.

> The problem with P.S.C. is the natural presence of bacteria. I

> refer here to the paper by Ohlsson, (Swedish hepatologist).

> 60% of patients who did not receive anti-biotics at the time of

> exploration of the liver and the bile ducts had bacteria in the

> bile ducts as opposed to 30-40% who did have antibiotics

> when we treat DSs. The incidence of DS in P.S.C. is, in our

> opinion underestimated. We follow our patients very closely.

> 20% of them came to us specifically because of their DSs in

> P.S.C. because we have become a referral centre for this

> condition. Over time half our patients develop DSs and need

> treatment. 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). They

> compared endoscopic dilation with and without stents and

> have shown that if you put in stents you get complications.

> The method of choice is to open the stenosis with balloon

> endoscopy. Two studies have compared survival (or time to

> transplant) where DS is treated in PSC. and in our own study, and

found

> significant improvement in survival over

> predicted survival. Nevertheless when we compare our

> patients who have DSs with those who don't there is a

> significant difference. Even though our patients with DSs are

> treated as described their overall survival is worse than those

> who 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. ERCP

> and/or MRCP should be performed in cholestasis. If you don't

> see anything with MRCP I still think you should go on to ERCP

> because it is better and a more accurate procedure.

>

>

>

> A brief discussion which followed said ~ Question: I

> know you treat your patients with high-dose Urso, as well .

> . .

> All the studies have shown that the toxic effects of bile acids

> can be prevented by use of Urso . . .

>

>

>

> Dr. Chapman wondered whether repeat balloon-endoscopies

> and the (laborious) treatment of DSs could be followed within

> the confines of the N.H.S.

>

>

>

> Prof. Stiehl: We use 20 - 25mg per kilo Urso. We have a low rate

of C.C.,

> at

> 3%.

>

>

>

> For a critique of Professor Stiehl's approach see PSC-News

> number 34, August 2006. P.S.C. Conference, Pittsburgh.

> ~ strictures, Page 9. (Dr. Adam Slivka.)

>

>

>

>

>

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

>

>

>

>

>

> Ref: PAGE 2d YOUR REF: F1 - F31

> CONTINUED FROM PREVIOUS PAGE

>

>

>

> " WHO TO TRANSPLANT, WHEN TO TRANSPLANT? "

>

>

>

> The whole problem with transplantation, particularly in the

> UK, is the number of patients who would benefit from

> transplantation (tx) and the number of organs available and

> this is what I want to deal with. The number of donors is even

> decreasing slightly. For every person you put into the system

> one person has got to come out of it. Rationing has to occur

> because there aren't enough organs to go round and we

> must use selection criteria. This has to be an open process

> based on equity. Everybody has an equal right. We must

> consider what is the best use of the organ. We are moving

> towards a more open system in the UK, which just means

> there's another layer of obfuscation beneath that. Our

> selection criteria are based mainly on the risk of death

> without tx (transplantation). Secondarily you're also talking

> about the quality of life.

> In 1999 we had a consensus meeting and it was agreed that

> a tx patient should have a greater than 50% chance of being

> alive 5 years after tx with a quality of life acceptable to the

> patient. This is nice and very helpful until you start applying it

> to individuals because a lot of sentiments are difficult to

> quantify.

> 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. It

> shouldn't be forgotten that with adult Live Donor Liver

> Transplants there's a mortality rate of about 1%, mostly

> amongst the donors.

> Looking at survival and how you select patients there are two

> models:

> 1. MELD System

> 2. U.K. Model

> We should note that a model is just a model. They're usually

> very good when applied to populations but when you

> extrapolate them to the individual that's when they start to

> fail.

> The Meld model (Model for End Stage Liver Disease) was

> developed at the Mayo clinic, mainly for short-term survival

> in patients undergoing the TIPS procedure ~ based on a

> combination of bilibrubin, creantinine and INR. This gives

> some cause for concern. It's well recognised that there are

> lab variations. The same sample measured in different labs

> can vary by 10 - 15%. If you're enthusiastic about diuretics

> you can increase warfarin. So if you want to get your patient a

> higher MELD score, you can make their prognosis worse. It

> has been done.

> The Child-Pugh classification is very subjective: it's based on

> encephalopathy, ascites etc. You wouldn't get consensus on

> this: if they're sick they're Child-C, if they're well they're

> Child-B. It's a very useful shorthand but if I ask you to write

> down what you think of the Child-Pugh score we'll see a lot of

> variation. And even if you look at textbooks you'll see

> variation. The correlation between Child-Pugh and MELD is

> not great. With MELD you put in the numbers and you get a

> score that's roughly between 7 and 40 and you would see

> the correlation as to mortality over 3 months. A score of 40

> would give you an 8% probability of mortality at 3 months. A

> score of 10 would give you a 5% mortality. People talk about

> MELD but they don't usually correlate it with survival. It is a

> marker for short-term rather than long-term survival. I was

> interested in the discussion on the value of prognosis. I'm

> never sure how valuable it is. You can't influence it and you

> don't know what the confidence intervals of that prognosis

> are.

> As you can see (from the screen) there's quite a good

> correlation between MELD and 3 months probability of

> survival. Meldology is really becoming a science within

> hepatology. Here are some new US data (on the screen) on

> probability of survival on the waiting list after tx. And the

> important two points to notice is that tx only gives you

> survival benefit when your MELD approaches 17. Secondly if

> you look at survival after tx MELD correlates very poorly with

> post-tx survival. It's often said that patients who are sick are

> likely to do less well: the evidence is against you although

> quite clearly it is intuitive. The reason is that surgeons are

> quite good at matching donors to recipients. (The paper

> continued with reference to data presented on the screen and

> without that some of the meaning is lost here). Using the

> U.K. data base of about 6,000 transplanted liver patients

> (data derived from ston). Some of these patients

> were relatively well and some quite ill. Does this matter in

> terms 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. than

> MELD and is more important in predicting outcome. You want

> to 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 high

> mortality, there's 65% survival after 10 years. Not bad but it's

> clearly not good enough. Results have been improving over

> time. When do you not tx? As I said, prognostic models are

> useful guides but they are subject to problems when applied

> to individuals. We haven't mentioned symptoms. Clinical

> judgement clearly plays a role. Intractable pruritis is clearly an

> indication to tx (when none of the usual drugs have any

> effect). Also intractable encephalopathy, liver cell cancer,

> diuretic ascites etc. are all indications for tx which are not

> covered by MELD or the U.K. model because you're not likely

> to die. Lethargy is not an indication for tx. It may not improve

> after tx. The best data comes from a small study done by the

> Newcastle group. They had a score for PBC patients and they

> found there was not great differenced in levels of lethargy

> before and after tx. Our own retrospective study at

> Birmingham found that if you're (relatively) well with a lot of

> lethargy before tx, you'll be well but also with a lot of lethargy

> after tx. Whether people have a low threshold or whether

> there's something more important here we don't really

> know.

>

>

>

> Ref: PAGE 2e YOUR REF: F1 - F31

> CONTINUED FROM PREVIOUS PAGE

> The other indication ~ or in fact a contra-indication is C.C.

> This is because patients with C.C. do extremely badly. You

> cannot approach the 50% 5-year survival that we would

> require. The reason is that C.C. spreads through the

> lymphatic and nervous systems at an early stage. By the

> time you're diagnosed it is probably too late. Mainly, as with

> hepatoma, it (C.C.) occurs in the allograft, but not

> entirely. In my view most of the (tumor) markers used are

> very good at producing papers but next to useless when

> applied to patients. I do have to stress that a very small

> number of people with C.C. can do very well after tx. These

> patients have a rigorous work out with surgery, chemo- and

> radiotherapy. the small numbers they've done have done

> very well after tx at the Mayo Clinic. But in the majority of

> patients I don't believe there is any effective treatment for

> C.C.

> Certainly age is another factor in considering tx. It's an

> independent predictive factor for post-transplant survival.

> Depressingly it starts to creep in as a factor from the age of

> 40. After 60 it's a significant factor. But there are some very

> good survivors and one has to make a judgement of the

> patient.

> Nutrition is a factor. Many of these patients are malnourished

> (as a consequence of advanced liver disease). But in spite of

> surgeons going on about this there are no data showing that

> well-nourished patients do better; it's inappropriate to

> withhold patients from tx because of malnutrition. The

> difficulty is with those who have a past history of cancer,

> especially colon cancer. How long do you leave them before

> you're convinced it won't recur? Previous abdominal surgery,

> morbidity, add somewhat to the mortality post-tx ~ the same

> with biliary and gastric surgery. For those with active

> Ulcerative Colitis there is no problem in doing a colectomy at

> the same time as the tx.

> Tx is a very good procedure but it does shorten your life. This

> is some data we produced (at Birmingham) and published in

> 2006.

> Life expectancy ~ and this is for men ~ is very good in P.S.C.

> patients after tx. Much better than those who have liver

> cancer, Hepatitis C and alcoholic liver disease. At 20-years old

> you can expect to live 45 years. 65-year-olds may have 10

> years. It is a very good prognosis for tx P.S.C. patients.

> Recurrence (rP.S.C.) does affect survival. Those without

> rP.S.C. do significantly better. Recurrence can be detected in

> the presence of normal LFTs. We look for it radiologically and

> histologically and (as shown on the screen) there is increasing

> recurrence over time. We don't know why and it doesn't

> necessarily translate into graft loss.

> Those who have had a colectomy either before or at the time

> of tx had a lot less recurrence than those with an intact colon.

> It has been controversial, the Scandinavians have been

> unable 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-tx

> Colitis. Those with Ulcerative Colitis and tx for P.S.C. ~ about a

> third had improvements in their Ulcerative Colitis, one third

> stayed the same and one third became worse. The

> Scandinavians found that the type of immunosuppression

> makes a difference. We weren't able to show that. All patients

> post-tx have an increased risk of cancer, especially colon

> cancer. This isn't true of breast and cervical cancer in women

> PSCers. Therefore more surveillance and monitoring of the

> colon is necessary.

>

>

>

> In summary P.S.C. is an excellent

> indication for a transplant. The models are a guide but not a

> replacement for clinical judgement. It's important to stress

> that C.C. and lethargy are not indications for a transplant.

> We tell patients that tx is not a cure, it's a swap. Swopping one

> disease for another. When the MELD score starts to reach 12

> or 13, that is the time to start thinking of a tx, but it may be

> earlier, it may be later. Too early doesn't matter, too late ~ and

> the problem is waiting for an organ because of the shortage.

> Please write to your M.P.s, raise the alcohol limit, no safety

> belts in cars, no crash helmets!

> We tend to use immunosuppressants ~ Azathioprin along

> with tacrolimus, as our major agents but we don't put them

> on routine Azathioprin because of the Colitis.

>

>

>

> Further details came out at the meeting from

> U.C.L., London ( " Hepatobiliary Cancer and P.S.C. " ).

>

> Amongst

> outpatients, those with AIH responded well to immunosuppressants

> and there was 50% relapse. In the case of C.C.

> this tended mostly to occur early after the diagnosis after

> which the rate tended to be around 1-2% p.a. There is a

> significant increase in pancreatic cancer and this needs to be

> confirmed. The symptoms of this are known but not the risk

> factors.

> On C.C. Prof.Stiehl said that all his patients who have

> had 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 in

> those with extensive P.S.C. and long duration).

> In Sweden it was found that those with C.C. had an

> increased risk of colon cancer. 8 studies have shown such an

> increased risk but 3 studies have shown no increased risk.

> Patients with U.C. are commonly treated with 5-

> aminosalicylic acid (5-ASA) ~ Mesalazine (Asacol, Pentasa

> etc), steroids, probiotics, aspirin, 2, calcium + Vit. D &

> folic acid may be beneficial although we don't know the right

> dose. (1)

>

>

>

>

>

> Dr. J. Jankowski (Oxford)

>

>

>

> " Chemoprevention in IBD & P.S.C./IBD "

>

>

>

> Talked in detail about the problems of surveillance

> endoscopy. 1% of the population have IBD. About 5% of those

> with colitis get colon cancer. The risk increased with the

> duration of the disease and the extent of damage in the colon.

> If only the lower colon and rectum are involved, the risk of

> cancer 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-grade

> dysplasia (pre-cancerous changes in the cell lining). There is a

> lack of agreement about what is high-grade and low-grade.

> Generally this is an area of medicine where it is very difficult to

> find funding for research.

> His young son thinks that we should all

> eat raisons which is a natural source of salicylates!

>

>

>

> Dr. S. Pereira,

>

>

>

> " Hepayobiliary cancer and P.S.C. "

>

>

> " We (U.C.L., London) are now leading the world in

> cancer trials " .

>

>

> (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 colorectal

> tumours " . 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

Still

> Too Soon To Tell " . Gastroenterology. 2007; 133: 717-723.

>

>

>

>

>

> End.

>