PBC disease
stages
Alfred
L. Baker, M.D.
Division
of Gastroenterology & Hepatology
Northwestern Memorial Hospital
Chicago,
IL
8/20/2002
Question 20
a. Is it common to have different results from liver biopsies two years apart?
One a regular biopsy (four nodes) showing stage 3, the other a wedge taken
during surgery for an unrelated problem showing stage 1.
b. Could the liver disease have improved or can different parts of the liver
be in different stages?
Answer 20
Most liver diseases do not involve all parts of liver equally. Thus, it possible
that a biopsy from one area may yield different results than a biopsy from
another. In addition to the somewhat irregular distribution of liver
injury, the biopsy samples may not be entirely representative. Comparisons
between two biopsies are more likely to differ if the samples are small.
Physicians should try to obtain a biopsy sample that is at least 1" in length.
A needle biopsy that samples liver tissue more deeply is often more
representative than a surgically preformed wedge biopsy.
Thomas
Shaw-Stiffel, MD,
Medical
Director,
Living
Donor Liver Transplantation
Univ.
of Pittsburgh Medical Center - Presbyterian Hospital Center for Liver
Diseases
March
2003
Question 3
At
what stage of PBC does ammonia level normally become high. Can ammonia levels
be high before the liver becomes cirrhosis?
Answer 3
Serum
ammonia levels are notoriously inaccurate when drawn routinely (venous samples)
and arterial ones are best, though impractical unless the patient is in an
Intensive Care Unit. Cirrhosis is the primary cause for elevated ammonia
levels but certain defects in urea metabolism in the level, or medications
(valproate) can do this by affecting ammonia breakdown. Symptoms and clinical
findings (liver flap) are best to assess for this problem rather than blood
levels alone (can be high in advanced cirrhosis and vice
versa).
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
18.)
What would be the most important advice you would give a person newly diagnosed
with stage 3 PBC?
Answer
The
most important advice I would give this person is not to panic. My next
recommendation would be to find the doctor in your area with the most experience
in PBC and seek his/her opinion of your case. Although PBC is not uncommon,
most practitioners have not had a lot of experience caring for this disease.
Once you find the right caregiver for you, you can address the disease in
a calm fashion. Once this person is found, I recommend that you learn as
much as possible about the disease and ask questions of your physician. Finally,
I feel that support groups made up of peers are extremely helpful in the
overall care of a PBCer.
Dr. Young-Mee Lee & Dr. Daniel Pratt
New
England Medical Center
Boston,
Ma 02111
2001
2.)
Would you encourage or discourage a patient of yours with stage 3 PBC from
taking Milk Thistle. Please explain your answer.
Answer
There
are no data of which I am aware about milk thistle in PBC. Hence I would
not encourage anyone with PBC, no matter what stage, to take it. I am not
aware of any side effects. Many patients take it on their own because it
is sold over the counter. I would rather not have patients take milk thistle
but do not feel strongly because it is seems to be safe in the doses taken.
David
Bernstein, M.D.
Chief,
Division of Gastroenterology
North
Shore University Hospital
Manhasset,
NY
July
2000
Question 19:
Can
you describe the manner in which a person finally dies from cirrhosis? If
a person chooses, can he/she be sedated deeply and allowed to die without
enduring days or weeks of encephalopathy and delusion?
Answer 19
People
with advanced liver disease usually die from a complication of cirrhosis
but not the cirrhosis itself. The most common cause of death is infection.
The infection may be as common as the flu, pneumonia or a urinary tract
infection. People with decompensated liver disease are unable to fight off
infection as well as those without liver disease, despite the use of antibiotics.
Another common cause of death is massive bleeding from esophageal or gastric
varices. Primary liver cancer, which is a result of cirrhosis, can also lead
to death but the cause of death is usually infection or bleeding.
Luckily,
people with advanced liver disease usually reach the fourth stage of
encephalopathy or coma prior to death. People in a coma do not feel discomfort.
Careful planning is required prior to ever reaching such a point so that
family members can follow a patients wishes and advanced directives. Euthanasia
is not permitted in the United States.
Dr. Nathan Bass
Professor
of Medicine, Medical Director, Liver
Transplantation
Program,
University
of California
San
Francisco
2000-2001
8.)
Can you describe "all" the symptoms of end stage PBC?
Answer
End-stage
(implying very advanced) PBC is attended by many symptoms of PBC including
itching, and fatigue, which may be present in the early stages as well. True
end-stage symptoms result from serious complications of the disease and include
leg edema, abdominal bloating from fluid, altered mental functioning, including
poor concentration, forgetfulness, or confusion from encephalopathy, and
internal (intestinal tract, variceal) bleeding. The latter may manifest as
vomiting blood or passage of blackish stool. Easy bruising and nose bleeds
may signal the deficiency of blood clotting factors that occurs in end-stage
liver disease. Patients with end-stage PBC are usually markedly jaundiced
as well, and the depth of jaundice will often worsen progressively. Severe
bone disease and fractures of vertebrae or other bones may occur before really
advanced liver failure, but is also considered a serious complication, usually
occurring in patients with longstanding disease. Rarely, patients may develop
a form of nerve damage from cholesterol deposits called xanthomatous neuropathy.
There are many other symptoms that can occur in PBC, but these do not signify
end-stage disease: These include CREST, and sicca symptoms
The Mount Sinai Medical Center
New
York, New York 10029
February
2000
22.)
Question
I
know that PBC varies from individual to individual, but if a patient is diagnosed
in Stage 1 and progresses to stage 4 in 6 years using medication what is
the "typical" range of life expectancy before transplant or death? Do younger
patients have any preferential treatment on listing?
Answer
I
am assuming that the staging the question refers to is based on liver biopsy.
With that assumption, the question is whether progressing from the earliest
lesion of PBC to cirrhosis in 6 years is a negative finding. Liver biopsy
findings can be misleading when it comes to PBC. The staging can vary from
place to place in the liver. As a result, liver biopsies are subject to sampling
errors, and studies have not found any correlation between the histologic
stage of the disease (findings found on liver biopsy) and clinical findings
(how well the patients does). That said, studies suggest that the prognosis
is not quite as good for those that develop cirrhosis compared with those
that don't. Nonetheless, many patients with liver biopsy findings indicative
of cirrhosis live normal asymptomatic lives for prolonged periods of time.
Younger
patients do not get preferential treatment on listing. For one thing, what
one person considers a "younger patient" might not meet another person's
definition.
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
6 Could you explain how one determines what stage of PBC they are in?
Answer
6 Based on the liver biopsy, the pathologist assesses the degree of liver
scarring and inflammation to determine the stage. However, this is often
out of sink with how the patient feels or their labs, so not the ideal test
to begin with.
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.
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
13
a.
Some hepatologists do not do or order biopsies now and say that the biopsy
is no longer the "gold standard" for PBC since blood tests, especially showing
elevated AMA's and certain relationships of LFT's, are an equally good indication
for diagnosis. What are your opinions?
Answer
a.
Biopsies can be done for 2 reasons. They help to make the diagnosis and also
help to stage the disease. As nearly all our PBC patients are in clinical
trials, we usually perform biopsies to help assess response to treatment
Howard J. Worman, M. D.
Associate Professor of Medicine and Anatomy and Cell Biology
College of Physicians and Surgeons
Columbia University
New York, NY
9-29-03
Question 2
Why is it that some patients are negative to Antinuclear Antibodies(ANA), Antismooth Muscle Ab, and Antimitochondrial Aba (AMA) but have PBC as diagnosed through Liver Biopsy?
Answer 2
The diagnosis of PBC is based on clinical (e.g. patients i a woman), laboratory (e.g. elevated serum alkaline phosphatase), immunological (e.g. positive AMA) and histological (consistent biopsy) criteria. All of these must be considered in diagnosis.
About 90% of subjects with PBC are women. Most are middle aged when first diagnosed. Therefore, being a woman is more consistent with PBC than being a
man.
Blood testing for alkaline phosphatase activity is of critical importance for the diagnosis of PBC. It is elevated in virtually every patient with the disease (assuming they are not yet taking ursodiol). If the blood alkaline phosphatase activity if not elevated, the diagnosis of PBC must be suspect.
If tests for AMA are done using the most sensitive methods available in research laboratories, virtually all patients with PBC have positive tests. However, since the assays used in routine clinical laboratories are less sensitive and less specific, only about 90% to 95% of subjects with PBC will have
positive AMA.
About 50% of subjects with PBC will have ANA, which are found in many different conditions and are not specific for the diagnosis of PBC. Tests available only in research laboratories can sometimes determine if the ANA is a type specific for PBC. Antismooth muscle antibodies are a very non-specific test of limited utility in the diagnosis of PBC. About 90% to 95% of subjects with PBC will have an elevated blood immunoglobulin M (IgM) concentration.
In PBC, the biopsy findings are usually "consistent with PBC" but not "diagnostic." The diagnosis usually can only be made when consistent biopsy results are obtained in the presence of other compatible diagnostic criteria (AMA, elevated serum IgM, disease in a middle aged woman, etc). In rare instances, the liver biopsy may be diagnostic (stage I "florid bile duct lesion").
So an experienced doctor make the diagnosis of PBC based on several criteria. In the 5% to 10% of cases in which the AMA is negative in the routine clinical laboratory, many of the other criteria must be met and a biopsy must certainly at least be consistent.
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
7
What
is the correlation of labs, biopsy and symptoms? Isn't it true a person can
have normal labs and the disease still progress?
Answer
The
correlation of labs, biopsy and clinical symptoms is not absolute. The liver
function tests and clinical symptoms can vary with episodes of deterioration
as well as improvement. Even though the stage of the biopsy progresses from
1 through 4, the level of inflammation can also vary with progression of
the disease.
For
all patients we use a combination of liver function tests, liver biopsy and
clinical symptoms to get a general idea of how severe the liver disease is.
Unfortunately you are correct in thinking that a patient can have cirrhosis
when the liver function tests appear to be relatively benign. However, it
is also true to say that the bilirubin becomes raised with progressive liver
disease when patients develop cirrhosis.
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.
Nathan Bass
Professor
of Medicine, Medical Director, Liver
Transplantation
Program,
University
of California
San
Francisco
January
2002
18.)
Question
Drinking
at least 8 ounces of water per day is recommended for those with liver disease.
Must it be water or can it be other fluids such as juice and herbal tea?
Do you recommend a special diet for PBC?
Answer
Usually
it will not matter in which reasonable form one take in fluid. Fruit juices
contain more calories and potassium. Overweight or diabetic patients or patients
taking potassium-sparing diuretics (e.g., spironolactone) may need to be
cautious with these. Herbal teas are usually fine, especially the common
commercially available types. Specialized herbal teas obtained from herbal
medicine practitioners or web sites should be checked with your physician,
as there are some herbal products that may actually cause liver disease.
Diet in PBC depends on stage of disease. There is no medically recognized
"special" or healing diet for PBC per se, but there are certainly important
dietary aspects to the management of patients with this disease. Patients
at all stages of disease may benefit from a multivitamin and trace mineral
supplement. Calcium supplements are also recommended to prevent and treat
bone thinning. Patients with very early disease can eat almost anything that
agrees with them, but it is wise to adhere to a generally balanced, healthy
cardiovascular diet. Patients with more advanced disease, especially with
evidence of fluid retention should limit their salt intake to 2 grams or
less per day. Limiting protein intake is very rarely indicated and may be
harmful. Only patients with very advanced disease who have severe hepatic
encephalopathy which is difficult to control with medication are candidates
for carefully controlled protein restriction under medical supervision. Some
patients with PBC are intolerant of fatty foods as these may cause diarrhea.
In these cases, patients should reduce their intake of fat but consume more
in the way of carbohydrate calories to meet their daily requirement. Patients
with established cirrhosis may want to avoid raw shellfish. This is general
advice for patients with all types of cirrhosis who are particularly susceptible
to a rare but extremely serious type of food poisoning that can result from
eating raw shellfish.
Dr.
Ira M. Jacobson
Weill
Medical College of Cornell University
Chief,
Division of Gastroenterology & Hepatology
New York Presbyterian Hospital-Cornell Campus
Director,
Gastrointestional & Liver Service
New
York, NY
April
2001
1.
Do you believe liver biopsies give a correct assessment as to the stage of
the disease?
Answer
I
believe liver biopsies are quite reliable, though with any liver disease
there is a possibility of "sampling error."
It
remains the "gold standard".
Dr.
Melissa Palmer Answers Our Questions
Specialty:
Gastroenterology and Hepatology
Medical
advisory board of the ALF New York Chapter
ALF
National Chapter Nutrition Education Subcommittee
November
1999
2.)
How often should liver biopsies be done on a patient already diagnosed with
PBC?
Answer
There
is no agreed upon, standardized "correct" time for patients with PBC to undergo
repeat liver biopsies, (if ever). Patients on a study protocol often are
required to have a biopsy performed at the beginning and at the end of the
study. However, patients not on a study, need never have a biopsy repeated
( so long as at least one biopsy was done in order to correctly diagnose
and stage the disease).
Dr.
Nathan Bass
Professor
of Medicine, Medical Director, Liver
Transplantation
Program,
University
of California
San
Francisco
January
2002
15.)
Question
I
am stage 3 PBC, and sometimes have pain in the liver area, but this is my
only symptom. When should a person in stage 3 be evaluated for the transplant
list? What is the criteria?
Answer
Stage
3 disease is a histological definition, i.e., this is purely the appearance
of the liver on a liver biopsy. If occasional liver pain is your only symptom,
it may still be early for you to undergo a transplant evaluation. Liver pain
is a well-recognized symptom in PBC. The cause is not clear, but it may include
stress on the thin capsule that covers the liver which we know is rich in
nerve fibers and very sensitive to stretching. However, many patients may
have varying amounts of liver pain or discomfort without evidence of advanced
liver disease. The usual indications for a liver transplant evaluation include
abnormal levels of serum bilirubin, serum albumin or prothrombin time. also,
any symptoms of edema, ascites (fluid in the abdomen) or altered nervous
system function known as hepatic encephalopathy. Patients with severe symptoms
of disease including itching, pain or fatigue may also qualify for an evaluation,
even though they still have early disease by the other usual criteria.
The Mount Sinai
Medical Center
New
York, New York 10029
October
1999
4.)
Is there a direct impact on one's fatigue level if the thyroid as well as
LFT's are in the high ranges? Does any one blood test indicate fatigue? Do
symptoms of fatigue and general malaise correlate with stages of the disease?
Answer
Thyroid
disease, independent of liver disease, may cause fatigue, and thyroid disease
is more common in PBC than the general population. So, the answer to the
first part of the question is a definite yes.
However,
no blood test can predict fatigue in patients with liver disease. In fact,
the level of elevation of the liver blood tests has no bearing on fatigue.
As
well, fatigue can occur during any stage of the disease.
Fatigue
is reported in 60 to 90 percent of patients with PBC and the cause is unknown.
The fatigue may be intermittent, or it may occur for prolonged periods of
time.
The
subjective nature of the complaint has made it difficult to scientifically
study this symptom.
Melissa Palmer, M.D.
Specialty: Gastroenterology and Hepatology
Private Practice Long Island, NY
01/25/04
QUESTION
I would like to know what you measure and what the measurements are to identify that you have reached stage 4 of PBC.
How it is possible for a person to have Stage 3-4 via biopsy and yet have normal labs and no symptoms. Why is a biopsy "not the ideal test to begin with"? I know there are at least a few of us with this situation. I wonder if those of us in this situation are on the edge of a cliff and one morning we'll wake up itching, depressed and in the beginning stages of liver failure.
ANSWER
PBC may be diagnosed by a combination of the symptoms that a person is experiencing, the physical findings detected on an exam, the results of blood work, the findings of a liver biopsy, and the results from imaging studies.
As opposed to other liver disorders, PBC has been neatly classified into four distinct stages that can only be determined by a liver biopsy.
Stage 1 is characterized by the finding of damaged bile ducts. Granulomas-nodules filled with a variety of inflammatory cells-are often detected in this stage.
Stage 2 is characterized by the finding of a proliferation of small bile ducts known as bile ductules.
Stage 3 is characterized by fibrosis, and stage 4 is characterized by cirrhosis.
Occasionally, a single specimen from a liver biopsy may show evidence of more than one stage of the disease. In such cases, the most advanced stage present should be considered the correct stage. People may progress through the different stages at varied, and largely unpredictable, rates. For example, a person may stay in stage 1 for many years, and then rapidly progress from stage 2 to stage 3. Or a person may rapidly progress through stage 1 and then stay in stage 2 for many years.
There is a wide spectrum of symptoms associated with PBC. At one end of the spectrum, a person with PBC can be asymptomatic (have no symptoms). These people are typically found to have PBC during evaluation of elevated AP and GGTP levels found on blood tests. However, some asymptomatic people with PBC have normal levels of AP and GGTP. In these instances, a positive antimitochondrial antibody (AMA) is the sole indication that the disease is present. Up to 60 percent of people discovered to have PBC have no symptoms. Diagnosis in such people has become more common due to routine blood tests which are performed during the course of a regular check-up. Note, however, that most people who are initially asymptomatic eventually do develop symptoms. This occurs in about three to four years from the time of initial diagnosis. However, symptoms can take as long as ten years to manifest. Interestingly, even in advanced stages of PBC, some people will still have no symptoms.
End....