Question & Answer Panel Session II - Drs. Slivka, Horwitz and Bergquist

(Note that some questions were tabled for afternoon breakout sessions which explicitly address the questions. The responses are not direct quotes but summaries of discussions).

Summaries prepared by Arne Myrabo.

For Dr. Slivka – How often do you do blood tests and lab tests for screening?  At what levels of tumor markers CA-19-9, CEA do you become concerned? 
In my practice, I draw tumor markers every six months for the first 3-4 years and then I do them yearly.  I look for levels of CEA over 5, and CA-19-9 over 180. If I’m following a patient and it skyrockets, that raises a red flag.  If it starts to rise, we start doing more imaging. We’ll always start with an MRI (liver) and MRCP (ducts).  We’ll use a specific protocol, as tumors tend to hold on to contrast a little longer.  We’ll have a lower threshold for doing ERCPs and brushing.

For Dr. Horwitz – Can you provide brief criteria for PSC patients?  When should they be getting a bone scan, what factors should influence them to ask their doctors for a bone scan – age, symptoms, timing of disease?   
There’s not really a clear-cut answer on this.  Certainly anybody over the age of 50 should have a baseline bone scan; anyone who has had a symptomatic fracture (a fracture without trauma) or atraumatic fracture (fall from less than standing height).  Anybody who is on glucocorticoids for more than three months.  Bone scans should be done about every two years for severe disease.  It’s not that sensitive of a test, so doing it sooner will not provide reliable data.

For  Dr. Bergquist – How low should Alkaline Phosphatase (ALP) go?  If my ALP is low, is it masking the disease due to the effect of Urso? In your opinion, are the AASLD guidelines a little premature on Urso?  
How low?  The lower the better.  We did look at the amount ALP was lowered in our study, and the group that totally normalized levels did even better. It is difficult to say whether lowered ALP masks disease, but I don’t think so.  The AASLD guideline on Urso has resulted in a big discussion.  I would not have agreed on that statement – we really don’t know.  Urso is quite a harmless drug, and there may be some who benefit.

For Dr. Slivka – Can you use the confocal technology in pediatric patients?  How do you propose to screen out the false positives?
I want to be clear with everyone that this is an experimental technology.  It is FDA approved for use, but we need more data to build an effective algorithm.  You can use it on children and adults.  It is fairly expensive, and the probes are expensive.  We are doing it as research.  What do we do if we have a positive?  Our clinical index of suspicion guides what we do next.  Usually, patients that have a positive pCLE have other symptoms.  We don’t know they are false positives until we have something definitive, which may take a year. pCLE is pretty effective for non-PSC patients, and we’re just beginning to apply this to PSC patients.  It’s way too early to answer the question on false positives.

For Dr. Horwitz – How long can you take bisphosphonates – is there a time limit? What are the dangers of Fosamax®?  My insurance disallowed Forteo®, but allowed Reclast®. Should I be pushing for Forteo?
How long you should be on Fosamax is an area of controversy.  There is some indication of problems with long-term use (5-10 years) of bisphosphonates, but the occurrence rate is very low.  If bone density has recovered and completely stabilized, we may give the patient a one-year “drug holiday”.  Most patients will maintain good bone density for a year, but it starts to decrease after that.  If you are on high-dose steroids for a long time, that complicates things and the answer is not so straightforward.  Some patients only need bisphosphonates while on steroids.  Once they are taken off of them, they can usually stop the bisphosphonates.  Ultimately, it is a decision that must be made on a patient by patient basis.  Forteo and Reclast are very different drugs and not interchangeable, in my opinion.  Generally, we start with bisphosphonates and only use Forteo in special circumstances.  We avoid the use of bisphosphonates in children or those in their childbearing years.

For Dr. Bergquist – How do you define high-dose Urso?  Is there a relationship between high-dose Urso and bile duct cancer?  What about the relationship between Urso and colorectal cancer? 
Low-dose is 13-15 mg/kg, around 20 mg/kg for moderate and 28-30 mg/kg for high dose.  There is an increased risk for dysplasia in the colon using high-dose Urso.  There are some studies indicating low-dose Urso could protect against colorectal cancer. For cholangiocarcinoma I think there is good evidence for chemo-protective effect.

For Dr. Slivka – Could you speculate why the risk of bile duct cancer is increased in the first three years after diagnosis?
The only thing I could suggest is that developing cancer is multifactorial.  So the patient has a genetic propensity to cancer and then gets an inflammatory trigger, or two, or three – one too many strikes.  The other group of patients acquires mutations over time on a more linear rate.  That’s just my thought as to why we’re making most of the diagnoses early on and the risk levels out to 5-10% per year.

For Dr. Horwitz – For someone with PSC and UC who has to take 50,000 units of vitamin D off and on, and seems to be lower after UC flare, would you recommend a daily supplement instead?
No, I don’t recommend a daily supplement if you need that high a dose.  I have some patients that get a weekly injection of 50,000 units, and some that need it two-three times a week.  It’s the easiest, most direct way. Vitamin D toxicity is a very infrequent problem – we just don’t have patients that get vitamin D toxicity.  If you know you need more vitamin D during a flare, get the injection.  Once the flare is resolved, get a vitamin D test and supplement per the test.  It’s a fat-soluble vitamin, so it is stored in fat and does not vary a lot on a day-to-day basis.

For Dr. Bergquist – Could you discuss the potential of the new nor-Urso vs Urso?
Nor-Urso is a chemical related to Urso (homologue).  It is more hydrophilic (has an affinity for water) and has been shown to have properties that reduce scarring in animal models.  It has been tested on healthy people, and now is being tested on patients in a phase II, 3-month trial for safety.  The trial is currently enrolling in many centers in Europe.

For Dr. Slivka – If you have had a Roux-en-Y and anastomosis, does that eliminate the risk of bile duct cancer? 
In liver transplant, there are two ways you can hook up the new liver.  There’s always a stump, but I’ve never seen bile duct cancer in the stump.  The part where bile duct cancer normally forms is removed.

For Dr. Horwitz – Can the effects of corticosteroids in pediatric patients be reversed?  Once you stop prednisone, how long does it take for bone density to return to normal? 
I don’t study the pediatric literature, as I never see patients under the age of 18.  But you’re stuck between a rock and a hard place.  If you have active disease and steroids are the only treatment that works, treating the disease is the priority.  When you stop steroids you can see bone density return to normal but not often.  Once you break enough connections of the bone scaffold, you cannot rebuild them.  Once your bone density is really low, it is unlikely that you can recover to what it was.  The longer you’re off steroids, the better chance you have to improve bone density.

For Dr. Bergquist – Is anyone studying the genetics of Urso responders vs non-responders in people who have normalized their ALP?  Should patients who are asymptomatic be taking Urso? 
This has not been on the agenda for genetics.  I would recommend Urso if you have normalized, if you are asymptomatic or not.