Howard J. Worman, M. D.

Associate Professor of Medicine and Anatomy and Cell Biology

College of Physicians and Surgeons

Columbia UniversityNew York, NY 10032URL: http://www.columbia.edu/~hjw14/

Question 43

In light of the recent info about Tylenol and its effects, is it still the best pain reliever for those of us with PBC and arthritis? Has the maximum dose changed in light of this info? It seems to me that our livers are already compromised and Tylenol, which is not recommended for alcoholics or those drinking alcohol, would affect us adversely.

Answer 43

Aceptaminophen (Tylenol) is a very safe analgesic when used as directed. It is safe for use by individuals with chronic liver disease when used as directed on the package label. Of course, anyone with a chronic illness should discuss the use of medications, even over-the-counter ones, with her/his doctor.

Question 44

Why is CellCept being used in non-transplant, non-renal patients? What are the Benefits? Side Effects? Do you know of studies done?

Answer 44

Mycophenolate mofetil (CellCept) is an immunosuppressive agents used to prevent allograft (transplanted organ) rejection. As PBC is likely an autoimmune disease, some investigators have hypothesized that mycophenolate mofetil may be useful as a treatment. Nobody knows yet if it will work in PBC. Mycophenolate mofetil is not approved for the treatment of PBC and a patient should not take this medication unless it is part of an IBR-approved clinical trial. I am aware of at least one trial of mycophenolate mofetil in patients with PBC.

Question 45

What causes the change to have a positive AMA at one point and then a negative AMA at another? Whould this happen more in PBC or Autoimmune Cholengitis?

Answer 45

Recent studies using the most sensitive tests have shown that essentially all patients with PBC (~99%) have a "positive AMA." The problem in the clinical laboratory is that these very sensitive tests are not used. The clinical laboratories use indirect immunofluorescence that is open to subjective interpretation. For this reason, some individuals with low titer AMA (a low concentration or weakly reactive antibodies) may have a "positive" test at one time and a "negative" test at another time. There may also be changes in the AMA titer over time in an individual patient for reasons that are not clear. "Autoimmune cholangitis" is not a well-defined disease entity and I cannot comment on it.

Question 46

What are the symptoms for PBC stage 1? With early diagnosis can the PBC disease be reversed?

Answer 46

"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.

Question 47

Have there been any studies done on post-TX medications like Prograf and Rapamune causing Joint and Muscle Pain? Or leading to osteoporosis?

Answer 47

I am not aware of any studies that have specifically looked at tacrolimus (Prograf) or sirolimus (Rapamune) causing joint and muscle pain. However, in clinical trials of these drugs, patients have reported these symptoms. Osteoporosis is known to occur at an increased frequency after organ transplantation and is probably aggravated by anti-rejection medications. A few studies in laboratory animals suggest that bone loss may be faster with cyclosporine A, somewhat less with tacrolimus and even less with sirolimus. I am not aware of similar studies in human subjects but it is possible that they have been done. If you are interested in published studies, you may want to know about the National Library of Medicine resource Pub Med. You can search the medical literature using Pub Med on the Internet. The URL is:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

Question 48

What progress has been made with the development of an extracorporeal liver aid device?Is such a device currently available and would it be of benefit to anyone who is not eligible for a liver transplant?

Answer 48

Extracorporeal liver assist devices are currently being studied in humans in clinical trials. They are being studied at several medical centers as a "bridge" to liver transplantation; that is, to support someone with liver failure in need of a transplant for a few days until a donor liver becomes available. A lot of work still needs to be done. There are no such devices yet for "long-term" use, such as for an individual with an end-stage chronic liver disease who needs a transplant but is not eligible.

Question 49

At what point in the progression of PBC is an individual usually referred for transplant evaluation (ie. blood levels....)?

Answer 49

Several mathematical models based on clinical, laboratory and histological criteria have been devised to attempt to predict the progression of PBC.

One of the better-known models is the "Mayo" model, which is an equation that takes these parameters into consideration.

Putting these mathematical models aside, the blood bilirubin concentrations is probably the best prognostic indicator of all laboratory values in PBC. A blood bilirubin concentration of 6 mg/dl is associated with a mean survival of about 2 years (this number is from before the days of ursodiol). Therefore, given organ availability in most parts of the United States, once the serum bilirubin concentration reaches 4 mg/dl a patient with PBC should be referred for transplantation evaluation.

Any patient with PBC who develops signs of liver dysfunction or portal hypertension (e.g. ascites, bleeding esophageal varices) should also be referred for transplant evaluation regardless of the blood bilirubin concentration.

Question 50

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 50

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.

Question 51

What could be the cause of Thrombocytopenia in the early stages of PBC?

Answer 51

There are many causes of thrombocytopenia not related to advanced liver disease. A person with PBC could also have any of them. As subjects with PBC are more predisposed to having another autoimmune disease than someone in the general populations, I would give a little more consideration to a possible autoimmune cause of thrombocytopena (e.g. ITP) in someone with PBC who does not have cirrhosis.

Question 52

What is the difference between fibrosis and cirrhosis?

I thought they were both the same if they're not, can a person have both?

Answer 52

Fibrosis is scar tissue. Cirrhosis is nodules of abnormally regenerating liver cells combined with fibrosis. So if you have cirrhosis, you have fibrosis. However, you can have fibrosis but not cirrhosis.

Question 53

Some of us have found research indicating that PBCers have a subnormal

level of glutathione. Since a normal level of glutathione in the body is so important do you think it makes sense for PBCers to take a glutathione precurser such as Immunocal (in PDR) or N-acetyl-L-cisteine?

Answer 53

There are no studies showing that glutathione or any "glutathione precursor" is beneficial for patients with PBC. As far as I know, there also no solid scientific studies showing "subnormal levels of glutathione" in subjects with PBC.

If there is any reason for doctors or scientists to suspect that glutathione or "glutathione precursors" would be beneficial for subjects with PBC, they should design a randomized, double blind, placebo controlled trial to test this hypothesis (this is what the FDA generally requires for approval of a drug). Subjects should not take substances to treat a disease if they have not been shown to be effective in such studies.

Question 54

When taking Vitamin A shots can there be side effects and if so what are they?

Answer 54

I have never heard of anyone receiving vitamin A injections. I do not know when and if they are prescribed. I do not believe that such a preparation is available outside of the hospital or home care setting, where patients who cannot eat may receive vitamin A as part of an intravenous combination of vitamins.

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