Alfred
L. Baker, M.D.
Division
of Gastroenterology & Hepatology
Northwestern
2000-2001
Question
7. I understand that calcium supplements can bind other meds if
taken together. Should calcium be taken at mealtime with
actigall or should one wait two hours between the
two? Is there a difference between calcium carbonate and calcium citrate
as far as the timing is concerned?
Answer
7
Moderate
doses of calcium supplements do not interfere sufficiently with the absorption
of other nutrients. Large doses might conceivably inhibit the absorption
of some drugs such as Tetracycline. Doses that are ordinarily prescribed
range from 1,000 to 2,000 mg per day and do not interfere with absorption.
There is no clinical difference between calcium carbonate and calcium citrate
in this
regard.
Nathan M. Bass, MD, PhD
Professor of Medicine
Medical Director, Liver Transplantation Program
University of California, San Francisco
11/4/2002
Question 4
a. What is the difference in a PBCER with a negative AMA
versus a positive AMA?
b. Does this change the symptoms or how the disease progresses?
Answer 4
Some experts believe that even AMA negative PBC
is often positive if a sufficiently sensitive and specific test is used,
but at least 5% of patients who appear to clinically have true PBC are AMA
negative. In general opinion is divided whether this represents true PBC
or another autoimmune hepatitis with some features closely similar to PBC.
The disease in these patients usually behaves like AMA positive PBC, and
responds similarly to ursodiol. This has raised
some questions about the actual role of the AMA in causing PBC.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
December 1999
9. Is it possible to be in stage 3
or 4 by the biopsy and have normal LFTs taking
Actigall or URSO? Are the
LFTs actual indicators of the disease progress?
Answer
I always tell the second year medical
students that "liver enzymes are NOT liver function tests
(LFTs)." The term "LFTs"
is a terrible one and really should not be used. [Help me convince your doctors!]
The values of the blood ALT, AST,
alkaline phosphatase and
gamma-glutamyltranspeptidase (GGT) activities do
NOT tell you about the function of the liver. They also do not tell you about
disease progression (i.e. the development of cirrhosis or deteriorating liver
function). The so-called "LFTs" can be normal in
individuals with end-stage liver disease.
In contrast, they can be markedly
elevated in individuals with liver disease but normally functioning liver.
In PBC, ursodiol
(Actigall or URSO) may lower the blood alkaline
phosphatase activity in the setting of significant
liver damage (Stage III or Stage IV histology).
The best biochemical tests of liver
"function" are serum albumin concentration, serum
bilirubin concentration and
prothrombin time. In PBC, the serum
bilirubin concentration (which may also be lowered
by ursodiol) is probably the best biochemical predictor
of disease progression.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
April 2000
Question 40
Part 1 Can a person
have normal labs, but still Have PBC?
Answer (Part 1)
The diagnosis of PBC is based upon
a combination of clinical, laboratory and histological (liver biopsy) criteria.
Virtually all patients with PBC have an elevated serum alkaline
phosphatase activity and more than 90% have detectable
antimitochondrial antibodies.
Without either of these two laboratory
findings, it would be extremely difficult to say that someone has PBC unless
perhaps a liver biopsy was performed for some reason showing the rare diagnostic
lesion (in most cases, liver biopsy is usually consistent with PBC and not
definitively diagnostic for it).
The blood alkaline
phosphatase can become normal in individuals with
PBC who take
ursodiol.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
February 2000
13. I suffer fatigue on an ongoing
daily basis. I have been told that since I am on
Urso and my blood work is good that my PBC is not
the cause of the fatigue. Yet here I am and so are many other PBCers I have
listened too. Please explain fatigue and PBC.
Answer
Some patients with chronic liver diseases,
including PBC, suffer from fatigue. I am not aware of any study that correlates
fatigue with "blood work" (presumably you are referring to laboratory tests
such as alkaline phosphatase activity, etc.). To
my knowledge, there is no direct association between fatigue in liver disease
and any laboratory test results. The cause of fatigue in chronic liver disease
is not clear. And it is often difficult or impossible to determine if "fatigue"
is a result of the underlying liver disease or something else (e.g. depression).
But fatigue can result from chronic liver disease.
There is no single activity that can
relieve fatigue. Medications are probably not helpful. In part, maintaining
a positive attitude may help ("I know I'm tired but I'm not going to let
it get to me."). This is not always possible for individuals with severe
fatigue. Arranging your daily schedule so that you have time to rest may
also help. Similarly, doing most of your activities when you feel the best
(e.g. early morning) may also be beneficial.
Finally, a regular exercise program
may help overcome fatigue. In the near future, my colleague at Columbia Dr.
Nora Bergasa plans to start a study of regular
exercise for fatigue associated with liver disease. Before starting an exercise
program, individuals with PBC should consult their
doctors.
Dr. Hugo E. Vargas
Medical Director,
Transplantation
University of
Pittsburgh Medical Center
November 1999
3.)
What is your
opinion on using Milk Thistle as an adjunct to
Urso as pharmacotherapy for PBC?
Answer
Milk thistle probably will not hurt
PBC patients but the information is very scanty. The problem is compounded
by the fact that one product in the market cannot be compared with the next
and thus it is difficult to endorse any one in
particular.
Dr. Marshall
Kaplan
Chief, Division of Gastroenterology
Dr. Kaplan gives us his thoughts on
the following article
Methotrexate and transplantation
WESTPORT, Aug 30 (Reuters Health)
- In patients with primary biliary cirrhosis, the
risk of death or transplantation is increased nearly threefold with long-term
use of low-dose methotrexate, according to the
results of a 6-year, placebo-controlled study.
Dr. Mark T.
Hendrickse and colleagues at
Patients treated with
methotrexate had significantly lower "...serum
alkaline phosphatase,
gamma-glutamyltransferase,
[IgM], IgG, and (after
24 months) aspartate
aminotransferase and
alanine aminotransferase
levels..." than controls. On the other hand, clinical factors, such as
Knodell inflammatory scores and
pruritus scores, were not significantly different
between the two groups.
Moreover, patients randomized to low-dose
methotrexate actually had an increased risk of
death or liver transplantation, with a relative risk of 2.9, though this
association did reach statistical significance.
The findings, published in the August
issue of Gastroenterology, indicate that use of
methotrexate in patients with primary
biliary cirrhosis should be limited to the clinical
trials setting, Dr. Hendrickse and colleagues conclude.
They point out that higher doses of the drug may have enhanced efficacy in
this population, but this was not tested in the current study.
Elsewhere in the journal, Drs. Paul
Angulo and E. Rolland Dickson of the Mayo Clinic
and Foundation in Rochester, Minnesota, point out the apparent dichotomy
between the effects of low-dose methotrexate on
biologic outcomes and clinically relevant outcomes in the British study.
They suggest that the biologic markers studied may not be accurate predictors
of disease status, a conclusion that is supported by other studies, as well.
The editorialists note that several
promising drugs are currently in development for the treatment of primary
biliary cirrhosis, but that
ursodeoxycholic acid should remain the initial
treatment for this disease until further data are available.
Date: 9/10/99 8:46:01 AM Central Daylight
Time
As you can see, this is a controversial
area. The British investigators used approximately one half of the dose that
I and others have found to be the minimally effective dose. A colleague and
I have published a paper in the same issue of Gastroenterology that indicates
that methotrexate improves blood tests and liver
biopsy findings in patients who respond incompletely or not at all to
ursodiol. I am in the tenth year of a double-blind
trial comparing methotrexate plus
ursodiol to colchine
plus ursodiol but, because of the nature of the
study, do not have any survival results yet. All that I can say is that
methotrexate appears to be effective in my patients,
but that I only use it in patients who have not responded fully to
ursodioal or
colchicine.
Dr. Ira M. Jacobson
Weill Medical College of Cornell University
Chief, Division of Gastroenterology
& Hepatology
New York Presbyterian Hospital-Cornell
Campus
Director, Gastrointestinal & Liver
Service
New York, NY
April
2001
3. What are the chances of reversing
the PBC Disease with the use of Methotrexate and
Ursodol? I have been in a Research Study for 5
years, it is a blind study. So I don't know whether I am getting the
Methotrexate or not. My Doctor says that I am doing
wonderful and the condition, has not progressed, any further. My blood tests
are good and stable. Has there been any studies in the past, that have proven
this drug (Methotrexate) to reverse the disease.
Answer
The use of
methotrexate is controversial. To my knowledge,
there are still no published, rigorously done studies that show the drug
is effective in this disease.
Dr. Marshall
Kaplan
Chief, Division of Gastroenterology
New England Medical Center
Boston, MA
September 9, 1999
10. What are the side effects of low
dose methatrexate when used in conjunction with
Actigall to treat PBC. What are the risks? Has
it been clinically proven to slow down progression of the disease?
Answer
It's well tolerated by most pts. Less
than 5% note nausea or loss of appetite the day they take it. Some complain
of hair loss, but hair loss is very common in PBC and pts on
ursodiol also complain about this. When I began
to use methotrexate, I was worried that it might
damage the liver but this does not happen. Likewise, in low dose it has no
bad effect on the bone marrow. I reported a 15% incidence of
methotrexate induced pneumonia 6 years ago in a
group of PBC patients who were in a research study with MTX.
I have not seen a case since. Dr.
Munoz who is conducting a multicenter study of
methotrexate in PBC presented a paper last year
at the AASLD meeting entitled "Absence of pulmonary toxicity in primary
biliary cirrhosis treated with
methotrexate and
ursodiol". It was based on 266 patients followed
for 4 years. (Hepatology 1998;28:392A.) The use
of methotrexate is controversial and not accepted
by many liver specialists. I introduced MTX to the treatment of liver disease
20 years ago, wrote the first paper about it 13 years ago and probably have
more experience with it than all other physicians, even if their experiences
are combined. In my experience it has not only slowed down the rate of
progression of disease, but has reversed it.(Kaplan et al, Ann
Int Med 1997;126:682).I am quite comfortable that
my positive experience with methotrexate will
eventually be reproduced by others.
Dr. Andrew Mason
Medical Director of Liver Transplantation
Ochsner Clinic
Assistant Professor of Medicine, Tulane
University Medical Center
Assistant Professor of Microbiology,
Immunology, and Parasitology, Louisiana State
University Medical Center
New Orleans, La
August 2000
Question 8
A
metaanlysis published in the Lancet, Volume 354,
Page 1053, 25th September 1999, "Randomized controlled trials of
ursodeoxycholic acid therapy for primary
biliary cirrhoses, concludes that using UDCA as
a standard therapy has to be checked again as the trials did prove a lack
of effectiveness. What is your opinion?
Answer
Most
Hepatologists believe that UDCA has some benefit
for PBC patients but it is no panacea and will not cure the disease. The
Lancet Meta-analysis merely confirmed what most physicians already know.
It is clear that UDCA can contribute to an improvement in liver biopsy and
liver function tests. However, it may not impact that much on delaying the
onset of liver failure. I do not think that we will have to perform any further
studies on UDCA as a single agent as we have a good idea about its utility.
However, there are ongoing studies to assess UDCA as a combination therapy
with other drugs such as methotrexate, I personally
think that UDCA will be a good adjunct therapy with anti-viral
treatment.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
December 1999
10. What are the side effects of low-does
methatrexate? Can
methatrexate harm the liver? If so, how and when?
Can methatrexate harm other organs or hurt the
immune system? How long can PBC patients stay on
Methatrexate? At what stage in PBC, or what
indications, should a patient begin treatment with this drug?
Answer
Methotrexate is NOT an approved drug for the treatment of PBC.
Studies so far have shown conflicting
results regarding it efficacy. The results of a large,
multicenter US trial are not yet available. I refer
you to two different studies published in the same issue of the same journal
that show conflicting results:
Bonis, P. A. L., and Kaplan, M. 1999.
Methotrexate improves biochemical tests in patients
with primary biliary cirrhosis who respond incompletely
to ursodiol. Gastroenterology. 117:395-399.
Hendrickse, M. T., Rigney, E.,
Giaffer, M. H., Soomro,
I., Triger, D. R., Underwood, J. C. E., and Gleeson,
D. 1999. Low-dose methotrexate is ineffective in
primary biliary cirrhosis: long-term results of
a placebo-controlled trial. Gastroenterology. 117:400-497.
Can
methotrexate harm the liver? The answer is yes.
It is associated with liver fibrosis.
Can
methotrexate harm other organs or the immune system.
The answer is yes (I refer you to the Physicians Desk Reference to read about
all of its potential adverse effects).
How long can PBC patients stay on
methotrexate: there are insufficient data to answer
this question.
At what stage in PBC, or what indications,
should a patient begin treatment with this drug
[methotrexate]? Patients with PBC should ONLY take
methotrexate as part of approved, clinical trials.
The results of well-controlled, large clinical trials will help establish
if methotrexate is or isn't a safe and effective
treatment for PBC.
Andrew Mason MBBS MRCPI
Associate Professor of Medicine
Division of Gastroenterology
Department of Medicine, University of Alberta
Edmonton, Canada T6G 2C2
December 2002
Question 2
Why does the itching of PBC seem to come and go? Do doctors know what causes
the itching?
Answer
There are factors in bile that are not adequately removed in PBC patients
that cause the itching. Although Urso is of great
help, when the therapy is started, the itching can get worse as the
Urso starts to increase the bile flow. So we advise
patients to stick with Urso therapy as it usually
is of some benefit.
Dr. Marshall
Kaplan
Chief, Division of Gastroenterology
New England Medical Center
Boston, MA
September 9, 1999
4. Could you please discuss the dizziness many
of us are experiencing - some call it dizziness while others say light
headedness. Is it a PBC symptom or other liver diseases? Cause and treatment
- and what effect taking urso might/will have one
it.
Answer
Dizziness is not usually part of PBC. However,
it is common in hyperventilation syndrome, a kind of anxiety that some of
my patients have had. Your doctor should check this out.
Howard J.
Worman, M. D.
Associate Professor of Medicine and Anatomy and Cell Biology
College of Physicians and Surgeons Columbia University
July 2003
Question 4
What are the symptoms for PBC stage 1? With early diagnosis can the PBC disease
be reversed?
Answer 4
"Stage 1" is a pathological diagnosis (what you see on liver biopsy) and
not a clinical diagnosis. The most common symptom in individuals with PBC
including those with stage 1 pathology is probably itching. Another fairly
common symptom is fatigue. Many individuals with early PBC have no symptoms
and the diagnosis is only suspected when the blood alkaline
phosphatase activity is abnormal on routine laboratory
testing. There is no evidence that PBC can be "reversed." All individuals
with the disease progress. In some studies,
ursodiol has been shown to slow the progression.
Hopefully, future treatment will someday be available that could "reverse"
the disease or stop the progression; this is why more basic research is
needed.
David Bernstein,
M.D.
Chief, Division of
Gastroenterology
North Shore University
Hospital
Manhasset, NY
July 2000
17.) I have always been told that
PBC will not actually improve, but the progress can only be slowed by
Actigall or URSO. Besides medications, can anything
else slow the progress of PBC? Have you observed improvement in the liver
condition in subsequent biopsies that would indicate a turnaround rather
than simply a lack of progress?
Answer
The goal of treatment with URSO or
Actigall is to suppress or reverse the underlying
process. URSO has been shown in studies to improve the inflammation seen
on liver biopsy but it does not seem to have an effect in reversing fibrosis.
It has, however, been shown to slow the progression of disease and delay
the need for liver transplantation. I personally have not observed significant
improvements on serial liver biopsies in many patients but I have noted the
lack of progression on therapy.
Unfortunately, no other medications,
including health food store and natural herbal products, have been shown
to slow the progression of disease.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
April 2000
24. Is
Actigall or Urso normally
used in a blocked bile duct after transplant? How successful are stints?
At this time are there any other treatments available?
Answer
Biliary obstruction ("blocked bile duct") occurs in about 15% to 25%
of patients after liver transplantation.
Endoscopically placed
stents are sometimes successful in relieving the
blockage. I cannot give a precise answer as to "how successful"
stents are. Balloon dilation of the obstruction
is another treatment that sometimes works. Surgical reconstruction is very
often the treatment of choice for bile duct obstruction after liver
transplantation. Ursodiol
(Actigall or Urso) is
probably of little or no benefit in large bile duct obstruction that occurs
after liver transplantation.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
April 2000
Question
42
Other than URSO what is the treatment
to lower indirect bilirubin in a post transplant
PBC person?
Answer
There are many causes of elevated
bilirubin concentrations. Elevated
bilirubin in the blood per se is NOT something
that is treated, except in infants in whom very high concentrations of
bilirubin can cause problems with the undeveloped
nervous system.
If a patient has an elevated serum
bilirubin in blood post-transplant or otherwise,
a diagnostic work-up must be performed to determine the causes. The underlying
cause is treated. URSO (ursodiol) is NOT indicated
to "lower the bilirubin" in any condition. It is
used in PBC because in several studies it has been shown to slow the progression
of the disease, not because it lowers the blood
bilirubin concentration.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
Question
27
Does
Methetrexate, Urso or
chocline (sp) cause weight gain? Why? Any methods
to control it?
Answer
I am not aware of
methotrexate, ursodiol
or cholchicine causing significant weight
gain.
Thomas
Shaw-Stiffel, MD,
MMM Medical Director,
Living Donor Liver Transplantation
Univ of Pittsburgh Medical Center Presbyterian Hospital
Center for Liver Diseases
Pittsburgh, PA
9/22/03
Question 2 I know this disease varies
from individual to individual, but from Stage 4 PBC, what is the "typical"
range of life expectancy before transplant? Do younger patients get any
preferential treatment on listing?
Answer 2 This also varies considerably.
With ursodiol, the progression can be slowed and
liver transplant even prevented according to the trials published in 1998.
So without specific lab values to assess severity of disease, having stage
4 is less helpful in and of itself. NO, younger patients do not get preferential
treatment.
David Bernstein,
M.D.
Chief, Division of
Gastroenterology
North Shore University
Hospital
Manhasset, NY
July 2000
Question 21:
What, if any, are the differences
between URSO and Actigall? Once a
PBCer has started taking URSO or
Actigall, will we need to take it for the rest
of our livers or will it depend on the LFT's?
Answer 21
URSO and
Actigall are both compounds comprised of the bile
acid, ursodeoxycholic acid. For most purposes,
these two medications are basically the same. Although both are usually tolerated
without difficulty, each individual medication may have certain side effects
in any given patient. Therefore, the only reason that I use to change from
URSO to Actigall is when people complain of side
effects such as nausea, diarrhea or headache. It is important to remember
that URSO is the only one of the two medications currently approved by the
FDA for use in PBC. Once people are started on either URSO or
Actigall, they should expect to be on these compounds
for life, regardless of the liver enzymes. It is important to remember that
having normal liver tests on these compounds does not guarantee that they
are working. Therefore, repeat liver biopsies are periodically recommended
if the initial biopsy did not show cirrhosis. This may change as new medications
are developed in the future.
David Bernstein,
M.D.
Chief, Division of
Gastroenterology
North Shore University
Hospital
Manhasset, NY
July 2000
Question 23:
Recently I heard that the recommended
dosages for URSO have increased significantly. Is this true or is the dosage
still based on the person's weight? When itching increases, would it help
to increase the URSO dosage by one tablet?
Answer 23
Initial URSO dosing is still recommended
to be 13-15 mg per kilogram of body weight. If the liver enzymes do not
normalize, the dose can be increased to 20 or even 30 mg per kilogram. When
itching occurs, one of the treatment options is to increase the URSO.
Paradoxically, it is possible that increasing the URSO may also worsen the
itching. The mainstay of therapy for itching remains the bile resin binders
such as cholestyramine. It is important, however,
to remember that these bile resin binders can be taken at the same time as
the URSO or Actigall as they will lead to decreased
absorption of these compounds.
Kris V.
Kowdley, MD
Associate Professor of Medicine
University of Washington School of
Medicine
Division
of Gastroenterology/Hepatology
Seattle WA
2001
Question
1
Some claim
Actigall reduces the lab numbers in those with
PBC, but there are no long term studies as to the effect of talking this
drug long term. Even if the numbers go down, is the disease still progressing?
What does Acitgall do exactly? What are the long
term effects of taking this drug?
Answer
There are early concerns that
ursodiol may "whitewash" the lab tests in PBC without
change in outcome. We no know that ursodiol therapy
improves survival in PBC (especially those with moderately advanced disease),
delays progression of liver damage on liver biopsy and may reduce the development
of varices. We don't know exactly how
ursodil works in PBC, but we think that it replaces
the toxic bile acids which can worsen liver injury. There are no known long
term complications associated with taking this medication although a few
patients complain of loose stool.
Kris V.
Kowdley, MD
Associate Professor of Medicine
University of Washington School of
Medicine
Division
of Gastroenterology/Hepatology
Seattle WA
2001
Question
4
If one's weight is such that the
Actigall or URSO dosage formula doesn't hit exactly,
should the dosage be rounded up or down? And--with the recommended dose at
13-15mg. per kilo of weight should it be 13, 14, or 15 mgs?
Answer
I favor a dose of 15 mg/kg and would
adjust up not down unless there were side effects (diarrhea).
Kris V.
Kowdley, MD
Associate Professor of Medicine
University of Washington School of
Medicine
Division
of Gastroenterology/Hepatology
Seattle WA
2001
Question
5
How would a person know if
Actigall or URSO are working for them? Would their
labs go to normal or would the symptoms improve?
Answer
If you have a response to
urso it is usually seen by a reduction of liver
tests of >50% or normalization.
Dr.
Young-Mee Lee & Dr. Daniel Pratt
New England Medical Center
Boston, Ma 02111
2001
1.) The recommendation is to take
Ursodiol with food. Why? Does food increase
effectiveness or minimize side effects? If taking with food isn't possible
is it OK to take urso with water for one or two
doses? What is the difference between Actigall
and Ursodial aside from milligrams per tab? Is
major depression (which is out of character for the patient) be a side effect
of Actigall?
Answer
I don't think that it makes very much
difference whether or not you take ursodiol with
food. The active ingredient is the same in both drugs. They may be packaged
differently. Major depression is not usually a side effect of
Actigall.
Dr. Andrew
Mason
Medical Director of Liver Transplantation
Ochsner Clinic
Assistant Professor of Medicine, Tulane
University Medical Center
Assistant Professor of Microbiology,
Immunology, and Parasitology, Louisiana State
University Medical Center
New Orleans,
La
May 2000
3.) Can you recommend or suggest other
treatments for PBC besides Actigall &
Urso medications?
Answer
This is the only recommended treatment
for PBC at present but several groups are trying alternative immune based
and other therapies. We have conducted a pilot study using anti-viral treatment
for PBC patients and found that the treatment was well tolerated. Although
no one had a complete biochemical response, several patients with early disease
had marked improvements in their liver biopsies after a year’s treatment.
We will soon be commencing a second pilot study to assess efficacy and safety
of a more potent anti-viral regimen for PBC patients.
Dr. Andrew
Mason
Medical Director of Liver Transplantation
Ochsner Clinic
Assistant Professor of Medicine, Tulane
University Medical Center
Assistant Professor of Microbiology,
Immunology, and Parasitology, Louisiana State
University Medical Center
New Orleans,
La
August 2000
Question
9
Is it "normal" for
Actigall/URSO to reduce the anti-mitochondrial
antibodies?
Answer
We still do not know the precise role
of anti-mitochondrial antibodies in PBC. At this time, they are considered
a specific marker for PBC but there is no evidence to suggest that the titers
vary with disease stage. In fact, AMA positive and negative patients with
PBC have a similar disease process. Also, AMA are found in the serum of 70%
of patients with PBC following liver transplantation, but only a proportion
of these patients develop recurrent PBC in the new liver.
With regard to treatment, AMA levels
may fall with global improvement in the disease process but it is not known
why. So, patients taking Actigall/URSO can have
decreased AMA but this is not necessarily a universal finding.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
April 2000
Question 35
I am confused about the benefits/purpose of taking
Actigal/Urso - some doctors say it doesn't do anything
- others that it slows down the progression of PBC - others that it "improves
the numbers" but that doesn't really mean anything. What are your comments
on taking Actigall/Urso? If it slows down progression
of PBC-by how much? Do you have an idea of percentage of people it slows
progression? If your numbers (ALT-AST) improve -- what does that mean?
Answer
I can't answer this question briefly. Doctors and experts on PBC will debate
these issues for days. In short, several studies do show that
ursodiol (the active ingredient in
Urso and Actigall) slows
the progression to cirrhosis and decreases the number of patients who undergo
liver transplantation during several years of follow-up. So yes, there are
some data showing that ursodiol may "slow down
the progression of PBC." It is unclear "by how much" or "in what percentage
of people" as the studies no studies have been designed to answer these
questions. It is not clear what it means if "your numbers improve." There
are no data available to answer this question. My personal feeling is that
the numbers you are referring to (ALT, AST, alkaline
phosphatase) do not mean anything in the long term
outcome.
Dr. Hugo E. Vargas
Medical Director,
Transplantation
University of
Pittsburgh Medical Center
Pittsburgh,
PA
June 2000
18.) How important are elevated
Alk Phosphate levels in predicting the progression
of PBC? Can the disease still be
progressing even if
LFT's are back down to normal ranges? If taking
Actigall or Urso could
the labs drop down to
normal range, yet the disease still progress and
symotoms increase?
Answer
Alkaline phosphatase
is almost always elevated in PBC (it is related to the bile ducts, which
are the injured part of
the liver in PBC)
Ursodeoxycholic acid prolongs survival without
transplant but does not arrest progression.
Unfortunately, the hallmark of the disease is
a period of time with relatively normal numbers (this varies) followed by
relatively rapid decline in liver function, so no, normal numbers do not
guarantee a good long term outcome.
Dr. Hugo E. Vargas
Medical Director,
Transplantation
University of
Pittsburgh Medical Center
Pittsburgh,
PA
November 1999
xxx
1.) What is your opinion on the view that
urso causes weight gain in patients who take it.
Also is a fat stomach
related to fluid retention, or bad eating and
little activity. I find it strange that most of us with PBC report that they
have large stomachs.
Answer
I have not seen much weight gain in patients with
PBC, although a cirrhosis becomes more significant the
weight
gain may have to do with water retention and
ascites.
Dr. Hugo E. Vargas
Medical Director,
Transplantation
University of
Pittsburgh Medical Center
Pittsburgh,
PA
June 2000
13.) What is the criteria for determining
the dosage of Actigall? Is the dosage based on
the person's weight? Does the dosage increase as the disease progresses?
Is Actigall or Urso
recommended for those in the final disease stage, or is it stopped after
a certain stage of the disease?
Answer
Dose levels are usually 12-15 mg/kg,
adjusted to make the dosage easy and to toleration of the drug. Obviously,
the earlier the treatment starts the better. I generally do not start
ursodeoxycholic acid treatment at the end-stage.
I know that some investigators are looking at higher doses and at combinations
with methotrexate.
Dr. Nathan
Bass
Professor of Medicine, Medical Director,
Liver
Transplantation
Program,
University of
California
San Francisco
14.) Question
I am in a study at Einstein Medical
Center in Philadelphia, PA. It is a blind study, which includes taking
Actigal every night and taking
Methotrexate once a week, (5 tiny pills). Have
there been any new discoveries made lately, on how
Methotrexate helps put the disease of PBC into
remission. Do you have any facts or statistics?
Answer
Methotrexate has been used in a number of diseases for its anti-inflammatory
and immune modulating effects. These include psoriasis (a skin disease) and
rheumatoid arthritis. Some earlier observations made by experienced physicians
in patients with PBC who were treated with
methotrexate for other disease suggested that
methotrexate could improve blood tests and liver
biopsy findings. In order to determine whether this is a real or significant
effect, with a benefit in terms of quality of life as well as life expectancy,
a large, randomized study is currently underway. You are probably participating
in this study which is a national, multicenter
study currently being conducted at a number of medical centers. Some small
studies have reported that with short periods of treatment, a clear benefit
of methotrexate is not evident. However, the current
large multicenter study will have the advantage
of including a large number of patients followed for up to 10 years. When
the results of this study are published, I believe we will know whether there
is any real benefit or not from methotrexate in
PBC patients.
Dr. Nathan
Bass
Professor of Medicine, Medical Director,
Liver
Transplantation
Program,
University of
California
San Francisco
17.) Question
We have been told that taking
Actigall or Urso can
lower our lab results but the PBC still progress. If this is true, how would
we know our PBC is progressing? Can PBC progress without other symptoms
appearing?
Answer
This is an important question that
has been discussed and debated extensively. I think most experts now believe
that Ursodiol (aka
Urso, Actigall) significantly
slows but does not stop the progression of PBC. Available studies support
the view that improvement in laboratory tests is indeed associated with an
improvement in life expectancy, but the process of PBC still continues. Disease
progression occurs first at the level of liver cell and tissue structure
and function and more often than not, is asymptomatic or not perceived through
a change in symptoms until these changes are quite advanced. Liver biopsy
is not a completely reliable (or necessary) way to monitor disease progression.
Early warnings of disease progression are usually provided by laboratory
tests of liver function such as serum bilirubin
and albumin levels.
The Mount Sinai
Medical Center
New York, New York 10029
February 2000
11.) The insert for
Actigall says that if there is coughing you should
notify your doctor immediately. Is coughing a side effect of
Actigall or an association with PBC? If so for
either, why?
Answer
In rare cases, patients with PBC may
develop a lung problem that can cause coughing and shortness of breath. I
know of nothing to suggest that actigall causes
or is associated with the development of a cough.
The Mount Sinai
Medical Center
New York, New York 10029
February 2000
14) Actigall
does help my itching; does it do a better job of this if my pills are spaced
throughout the day instead of taking them all at once or just twice a day?
Answer
Most recommend dividing the dose of
Actigall (ursodeoxycholic
acid) based on the dosing schedules that were used in the large studies proving
benefit from the drug. In the only study I know that specifically looked
at dosing schedules, it appeared that taking the drug once daily was as effective
as dividing the drug up (of course assuming the total daily dosage was the
same). The benefit of once a day dosing is perhaps increasing compliance
with the medical regime.
Alfred L. Baker, M.D.
Division
of Gastroenterology & Hepatology
Northwestern
Memorial Hospital
Chicago, IL
2000-2001
4.) In reading many of the digest
notes from other PBCers, I see that often their
LFTs go down into the normal range after starting
Actigal or Urso. My
LFTs, after 10 1/2 years of
Actigal have never been in the normal range although
my bilirubin continues to be in the normal range
and my only symptoms are Sjorgen's and mild itching
and arthritis. Is this what is considered normal for those with PBC?
Answer
Ursodeoxycholic acid has been shown to delay the need for transplantation and
perhaps to improve survival in several controlled trials. The beneficial
effect is probably the greatest in individuals whose liver chemistry tests
show the most improvement. However, several studies suggest that a patient
with a normal serum bilirubin has a rather good
prognosis, although perhaps not so good as an individual whose liver chemistry
tests are entirely normal after treatment. For patients who do not have an
optimal response to ursodeoxycholic acid, additional
treatments may be available, particularly by way of ongoing clinical trials.
Patients who have continuing symptoms and abnormal liver chemistry tests
related to PBC should consult their physician about the need for additional
evaluation and the possibility of further treatment.
Alfred L. Baker, M.D.
Division of Gastroenterology & Hepatology
Northwestern Memorial Hospital
Chicago, IL
8/8/2003
Question 1
Does PBC liver disease (damage) continue to progress while taking the regimen
of Ursodiol. There have been testimonials asserting
that enzyme levels can return to normal after taking the medication. Does
liver damage and progression stop while taking the
Ursodiol?
Answer 1
A number of studies have shown that ursodioxicolic
acid improves liver chemistry tests in patients with PBC. Other trials
demonstrate that this drug can slow the progression of PBC, delaying the
time until transplantation or death. Thus, the drug is widely prescribed
for PBC, but the effect is to slow disease progression rather than to stop
it.
David Bernstein, M.D.
Chief, Division of Gastroenterology
North Shore University Hospital
Manhasset, NY
7/14/2002
QUESTION 29
Is nausea a symptom associated with PBC? If so, why?
ANSWER
Nausea is not a usual complaint associated with PBC. Nausea can occur as
a result of an associated condition such as
scleroderma and resultant
gastroesophageal reflux disease. Nausea can also
occur as a side effect of Actigall or URSO.
David Bernstein, M.D.
Chief, Division of Gastroenterology
North Shore University Hospital
Manhasset, NY
7/14/2002
QUESTION 30
Is it possible for PBC to go into remission with or without medications?
If the symptoms decrease after taking
actigall/urso, could this be due to the slowing
of disease progression?
ANSWER
PBC is a progressive disease in almost all patients. However, PBC can progress
at different rates in different people. Therefore, it is possible that the
rate of progression may be extremely slow in some people who may be unaffected
by the disease in the long term. Others may rapidly progress in a period
of 3-5 years to advanced disease.
We do not fully understand the rate of progression. It appears reasonable
that the disease may progress at some points and remain quite at other times.
Unfortunately, no spontaneous remissions have been reported.
Certainly, therapy with ursodeoxycholic acid has
been associated with slowing the progression of the disease in some people.
These medications have been shown to lengthen the time until liver
transplantation and to slow the development of fibrosis.
Specialty: Gastroenterology and Hepatology
Private Practice Long Island, NY
QUESTION
Does Ursodiol treatments help those diagnosed with PBC at early stage? Can it actually slow the disease progress? How is ursodiol treatments prescribed, according to weight or manufactures instructions?
ANSWER
Ursodeoxycholic acid (also known as UDCA or ursodiol) is the drug most commonly used to treat PBC. In fact, it is the only drug that is FDA approved for the treatment of PBC. Ursodeoxycholic acid was initially found to be beneficial for people with PBC in the early 1980s and became FDA approved in 1998. It is manufactured by Axcan Pharma (Mont Saint Hillaine, Quebec, Canada) under the brand name URSO 250. URSO 250 is taken with food in oral pill form at a dosage of 12 to 15 milligrams per kilograms of body weight each day administered in four divided doses. Each pill is 250 milligrams. Actigall is another brand name for ursodeoxycholic acid. Actigall is marketed by Watson (previously Novartis) in tablets of 300mg. This drug is not FDA approved for the treatment of PBC, therefore its use is considered "off label". Generic ursodeoxycholic acid is also available and known as ursodiol. Since ursodiol costs about 10 percent less than the brand name products (URSO 250 and Actigall), many insurance companies prefer its use for the treatment of PBC.
The exact mechanism by which ursodeoxycholic acid works in people with PBC is not known. However, it has been established that increasing the amount of UDCA in the body will generally decrease the amount of liver-toxic bile acids in the body. This, in turn, should diminish or prevent destruction of bile duct cells. In fact, in some studies, people treated with ursodeoxycholic acid have been shown to have decreased bile duct destruction. However, other studies have shown that UDCA does not prevent bile duct destruction. Instead, UDCA appears only to protect against the consequences of bile duct destruction. This finding explains that while UDCA can delay, it does not prevent, the progression of disease to cirrhosis in people with PBC.
UDCA provides significant benefits to people with PBC. Levels of liver function tests, IgM, AMA, and cholesterol typically show notable improvement. People find that UDCA, on occasion, relieves some of the symptoms associated with PBC, such as fatigue and itching. Most importantly, ursodeoxycholic acid has been found to slow the progression of PBC, and to delay the occurrence of cirrhosis. Thus, people with PBC who are treated with UDCA have been found to live longer, have less liver-related complications, and need liver transplants less often when compared with those who are not treated with UDCA. UDCA may also have the additional benefit of decreasing the recurrence of colon polyps, however, this finding needs to be confirmed by further studies. The beneficial effects of ursodeoxycholic acid are experienced by approximately 80 percent of people with PBC who use this medication. These effects are most likely to occur the sooner a person is treated-for example, when the person is treated during the first or second stage of the disease.