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Dr. Howard Worman Answers Our Questions
September l999
1. Those with PBC have positive or elevated AMA indicating the presence of antimitochondrial antibodies. Are these antibodies what causes the damage to our bile ducts and resulting cirrhosis. If not, do doctors know what actually causes the damage to the bile ducts.
Answer
Nobody knows what causes the bile duct damage in PBC. Some studies have suggested that a protein similar or identical to the one recognized by the antimitochondrial antibodies is present on the bile ducts of individuals with PBC. However, it is still not clear if this is the target responsible for bile duct damage. Furthermore, some individuals with PBC do not have detectable antimitochondrial antibodies. In summary, much more research is needed to determine what actually causes the damage to the bile ducts in PBC.
2. Actigall and URSO has lowered many of our LFTs, since I LFTs are lowered does it also lower our AMA titers? Could the AMA ever be reduced back to normal? Is they were reduced to normal, could this be considered remission or do the medications actually cause a false reading of the LFTs while the disease still progresses?
Answer
Blood test results (so-called "LFTs") such as alkaline phosphatase activities do not necessarily correlate with disease severity in PBC. AMA titers also do not correlate with disease severity. In fact, some individuals with PBC do not have detectable AMA titers. (The best blood test that correlates best with disease severity in PBC is bilirubin concentration.) I would not say that "medications cause a FALSE reading of the LFTs" but it is true that the disease may progress despite improvements in biochemical test results. In fact, this was shown to be the case in a recent study of methotrexate for PBC (Hendrickse et al. Gastroenterology. 1999;117:400-497).
3. a. Is amount of itching directly related to the amount of damage to the liver? b. All of us have been told to drink at least 64 ounces of water per day....instead of drinking all plain water, can our fluids also consist of decaff tea?
Answer
I referred this question to my colleague Dr. Nora V. Bergasa. Dr. Bergasa is one of the world's leading experts on prutitus (itching) of cholestasis. Dr. Bergasa replied: THERE ARE NO STUDIES THAT HAVE SPECIFICALLY COMPARED THE PERCEPTION OF ITCH WITH THE DEGREE OF LIVER INJURY, AS ASSESSED BY LIVER BIOPSY. THE ITCH OF LIVER DISEASE DOES NOT TEND TO CORRELATE WITH THE VALUES OF LIVER ENZYMES REPORTED IN LABORATORY RESULTS, AND IT DOES NOT CORRELATE WITH BILIRUBIN LEVELS. THERE IS NO APPARENT CONTRAINDICATION TO THE ADDITION OF DECAF TEA TO THE LIQUIDS INGESTED.
4. Since most in our group have been diagnosed with an overlap syndrome, what is your suggested treatment options and alternatives for patients with more than one liver disease. Some have been told to 'wait and see' which disease becomes more dominant prior to treatment. Wouldn't it be more effective to treat the disease which show causing the most damage or is that possible?
Answer
I find it remarkable that "most" in your group have been diagnosed with overlap syndrome. In my experience, most cases of PBC occur in individuals with only PBC and no other "overlapping" or concurrent liver diseases. If two diseases actually are present, specific recommendations for treatment would depend upon the particular case and the nature of the other condition. It would not be possible to provide specific recommendations without knowing the complete history.
5. Why is it so many of us get those horrid cramps { charley horses } in feet, legs, hands, neck, everywhere..and they are so very intense and do not go away for a while. We have discussed this in the digest numerous times and can't figure it out. What is the normal cause of the cramps to someone who does not have PBC?
Answer
I don't think that cramps in the feet, legs, hands, neck, everywhere are associated with PBC. Depending upon the study, between 4% and 50% of individuals with PBC may have arthritis. Rare patients with PBC will have bone tenderness. But muscle cramps just have not been reported to be associated with PBC. The "normal" cause of cramps in someone who does not have PBC is probably the same as in the members of your group. There are many different causes; in the vast majority of cases, they are not serious.
6. Are there different kinds of PBC? Some of us seem to deteriorate much faster than others in the group.
Answer
PBC is a diagnosis based on clinical, laboratory, immunological and histological (liver biopsy) criteria. (For more information on the diagnosis of PBC, you may want to see my recently published The Liver Disorders Sources, Lowell House, 1999; http://www.amazon.com/exec/obidos/ASIN/0737300906/diseaseofthelive). The cause(s) of PBC is not known. Most likely, the cause(s) is the same in the large majority of patients because most have the same histological (bile duct lesion) and immunological (antimitochondrial antibodies) abnormalities. Having said all this, it not clear why some individuals with PBC deteriorate faster than others. Differences in environmental factors may be one reason, for example, those who drink significant amounts of alcohol may have faster liver deterioration. Genetic factors are also likely to be important. The occurrence and course of many diseases are modified by various "suceptabiliy genes." Hypothetically, genes encoding proteins involved in the immune response may make a patient more susceptable to develop PBC or have a more rapidly progressive course. At the present time, none of these susceptability genes have been identified. In brief, much more research is needed to answer this question.
December 1999
7. What are your thoughts on the causes of PBC? Why such a small percentage of men diagnosed with PBC?
Answer
Neither I, nor anyone, knows what causes PBC. Genetic factors appear to be important in determining susceptibility to autoimmune diseases such as PBC. PBC is not inherited in a Mendelian fashion but it does tend to run in families. Studies of identical twins (who are gentically identical) show concordance rates (if one twin develops PBC so does the other) of less than 50%. Therefore, genetics clearly is not the whole story. Most likely, environmental factors act to trigger the disease in individuals who are already genetically susceptible. One common hypothesis is that an infectious agent or agents trigger autoimmune diseases in susceptible subjects.
Gender also plays a role in the development of PBC as the number of women with PBC far exceeds the number of men (about 10 to 1). One hypothesis is that this difference reflects the effects of sex hormones on the immune system. Another hypothesis that recurrent urinary tract infections, which are far more common in women then men, may trigger the disease. Neither of these hypotheses, nor any others, have been proven.
In short, there are many hypotheses on what causes PBC but few have been proven or refuted. Rigorous epidemiological and laboratory research is needed to study the disease. Most likely, genetic and environmental factors both play a role.
8. Eepatic encephalopathy....once this happens will we have to take the medicine everyday until we get the transplant? Information says the toxins damage the brain, when will the brain go back to normal or does it ever?
Answer
Hepatic encephalopathy occurs in individuals with failing livers. In individuals with PBC, it usually occurs once the patient has advanced cirrhosis. Once liver damage in cirrhosis is bad enough to cause hepatic encephalopathy, it is generally not reversible. For this reason, most patients will have to take medications to prevent encephalopathy until they receive a transplant. An exception may be those with reversible situations that exacerbate encephalopathy, such as gastrointestinal bleeding or infection.
9. Is it possible to be in stage 3 or 4 by the biospy 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 inviduals 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.
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 yet (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
11. Is there anything that a person with PBC can take that will help with the fatigue?
Answer
Some patients with liver disease suffer from fatigue, some don't.
The cause is not clear. There is no single activity that can relieve fatigue. Medications are 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, late afternoon) may also be beneficial. Finally, a regular exercise program may help one overcome fatigue. Before starting an exercise program, individuals with PBC should consult their doctors.
12. Sometimes my labs include GGT, and other times they don't. Is this a common lab for PBC? What does it mean for someone with PBC?
Answer
Testing for gamma-glutamyltranspeptidase (GGT) activity in blood is similar to testing for alkaline phosphatase. Alkaline phosphatase is present in other organs beside liver and bile ducts and may therefore be elevated in other conditions, such as bone disease. GGT is essentially only present in the bile ducts. Therefore, blood testing for both GGT and alkaline phosphatase adds specificity for bile duct diseases. If both alkaline phosphatase and GGT are elevated, it strongly suggest liver or bile duct disease
Elevations in GGT activities in blood suggest bile duct disease or abnormal bile flow. These can be diseases of either the large bile ducts outside the liver or of the tiny bile ducts within the liver. An example of the latter is PBC. GGT activity is an extremely sensitive and variable test and may be elevated to some degree in virtually any liver disease. It can also be elevated in some normal individuals and people with very subtle and clinically insignificant liver abnormalities. GGT is also induced by many drugs, including alcohol. Blood GGT activity may be elevated in heavy drinkers without structural liver disease.
As is the case with aminotransferase activities, elevations in the blood alkaline phosphatase or GGT activities do NOT tell anything about liver function. Patients with PBC should not focus too much on their blood GGT or alkaline phosphatase activities (see question 9 above).
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.
14. Ammonia smell in urine. Does the presence of ammonia indicate anything about liver condition? Is this a usual occurrance with PBC?
Answer
Individuals with advanced cirrhosis or acute liver failure may have elevated concentrations of ammonia in the blood. This is because ammonia, which is primarily generated in the gut by bacteria, bypasses the diseased liver and gets directly into the circulation. Such individuals may even smell like ammonia. This generally only occurs, however, in individuals with advanced liver disease.
The kidney also produces ammonia and ammonia is found in the urine, where it acts as a buffer (enables the kidney to excrete more acid). Urine can smell like ammonia in any normal individual and the intensity can vary depending upon different factors (e.g. urine concentration). There is no association between "ammonia smell in urine" and PBC, except perhaps in the setting of advanced liver disease.
15. What approaches, medications, techniques are being investigated for PBC? Recently,several articles have appeared in newspapers & on the PBC site on bone marrow treatment for lowering the immune system activity. Has this technique been explored in connection with PBC?
Answer
There are not that many different experimental treatments for PBC currently under investigation. Most of you are probably aware of trials of methotrexate. Some trials are being planned for cytokines, which are naturally occurring compounds in the body that modulate the immune system in various ways. Bone marrow ablation followed by transplantation is being examined in a few experimental trials of various autoimmune disorders. I am not aware of such trials for individuals with PBC. As such treatment is very intense and even life-threatening, it may not be suitable for PBC, a disease that is only slowly progressive and can be "cured" by livertransplantation if and when its necessary.
16. Why do PBC patients have high cholesterol values? Is this the case with most PBC patients or only some? Can this phenomenon be prevented or reduced with a diet? I have tried a low fat etc, diet, but it does not seem to help. I am not overweight at all.
Answer
Elevated serum cholesterol concentrations are associated with cholestasis (cholestasis roughly means "poor bile flow and back up into the liver" which is seen in PBC. As a result, many (not all) patients with PBC have elevated serum cholesterol. In cholestasis, the cholesterol circulates in the blood as part of an unusual lipid-protein complex known as "lipoprotein X." This is different from the "bad cholesterol" associated with coronary artery disease, which circulates as low density lipoprotein (LDL), or the "good cholesterol," which circulates as high density lipoprotein (HDL). As a result of production of lipoprotein X by the liver, serum cholesterol concentrations in PBC can become quite high. It is unclear if diet, or even drugs for that matter, can significantly reduce them. It is also not clear if this form of cholesterol increases the risk of coronary artery or other atherosclerotic diseases.
17. Doctors seem to disagree as to whether high cholesterol in PBCers is a cause for concern re heart disease. What do you think/know about it?
Answer
See my answer to question 16 immediately above.
18. Use of cortisone. I am participating a study in our university hospital where PBC patiens are given either Urso or Urso+cortisone (a new kind of product called budesonide, Entocort in Europe). What is your opinion on using cortisone in treating PBC?
Answer
The use of budesonide for PBC should only be examined in approved, controlled, clinical trials. Until such trials are completed and the results examined, nobody knows if budesonide treatment is helpful (or even harmful for that matter). Any individual considering taking budesonide for PBC should only do so in an approved, clinical trial. I will only be able to formulate an "opinion" on its use when I see the results of the studies.
April 2000
19. If immunosuppression can help prevent recurrence of PBC, isn't it plausible that immunosuppression could help deter the disease if it were provided in the early stage?
Answer
I'm not entirely sure of what you mean by "prevent the recurrence of PBC." I'll assume that you mean after liver transplantation. If so, this is not the same situation from an "immunological point of view" as the natural disease. Proteins on the cells of the transplanted liver that play important roles in recognition by the immune system are different. To put this another way, the new liver may not be susceptible to PBC. In addition, the cellular targets recognized by the immune system in transplant rejection are probably very different from whatever targets are recognized in PBC (nobody know what they are in PBC). Therefore, immunosuppression that keeps allograft rejection in check may not significantly deter the immune response against the liver in PBC.
Most trials of immunosuppressive agents to treat PBC have been disappointing. Corticosteroids, azathioprine, cyclosporin A, chlorambucil and methotrexate have all been tested and no trial has shown conclusive positive results. Trials of other immunosuppressive agents are currently in progress.
I should also comment the phrase "early stage" in reference to PBC. PBC is never really diagnosed until the person has some liver disease. Its really not possible at this time to know who might develop PBC before there is already liver involvement.
20. Do you know of any studies being done on benign tumors in the liver. Can these type of tumors become malignant? What effect, if any could these tumors have on a person with PBC or other autoimmune liver disease?
Answer
There are several different benign tumors of the liver. The most common is probably cavernous hemangioma. Others include ademonas and hamartomas. Benign tumors do not become malignant. The occurrence of a benign liver tumor in an individual with PBC or another autoimmune liver disease is probably coincidental. I am not aware of any studies showing that benign liver tumors are associated with PBC or other autoimmune liver diseases. I also do not know of any data showing that these tumors have any influence on disease progression or outcome in PBC.
21. What is the estimated life span of a Transjugular IntrahepaticPortosystemic Shunt (TIPS)? When an ultrasound is performed post-TIPS, there are several values listed. What are the most important ones to determine if TIPS is working properly?
Answer
Not being an interventional radiologist, I am not an expert of TIPS. I'll try my best to answer these questions as best I can. The initial success rate of TIPS is high and the shunt is successfully placed in about 90% of cases. Depending upon the published study, the rate of clogging of the shunt is between 33% and 71% at one year. I don't know of any studies that look beyond one year, but they may be out there.
I do not know exactly what "values" are measured when an ultrasound is performed to evaluate a TIPS. The most important parameter would be related to blood flow through the shunt. This could be obtained by a Doppler scan estimates the volume of blood flowing through the shunt in a given time period. You should direct this question to a radiologist if you want to know the precise values measured.
22. Is there evidence that Motrim used for joint pain & swelling is safe for those with PBC or other liver disease? Please give an update on other current treatments for joint pain/swelling in the states.
Answer
Depending upon the reported series, between 4% and 50% of people with PBC have arthropathies (joint problems). The causes are many and include rheumatoid arthritis, psoriatic arthritis, neuropathic joint pain, polymyalgia rheumatica, CREST syndrome and mixed connective tissue diseases. In short, many different conditions can cause the joint problems in people with PBC. The appropriate treatment could be different depending upon the cause of the joint pain and swelling. I can't begin to give an update on the current treatment for joint pain and swelling, as there are literally hundreds of different available drugs. A notable recent advance is the "COX-2" inhibitors that have fewer side effects than the older anti-inflammatory drugs.
Ibuprofen (Motrin) is safe for most people with liver disease as long as it is used as directed by an experienced physician. The major side effects associated with ibuprofen and this lass of drugs are on the stomach and kidneys. As with all other drugs, they should be used only as necessary and, if used for the long-term, only under the guidance of a doctor.
23. Could you explain the difference between osteoporosis, osteomalcoa, and osteopenia. Why are so many with PBC diagnosed with these bone diseases?
Answer
Osteopenia - metabolic bone disease characterized by reduced bone mass which can result from many causes.
Osteomalacia - defective bone mineralization characterized by softening of the bones; it usually results from deficiency of vitamin D and calcium.
Osteoporosis - reduction of bone mass per unit volume with no modification in the ratio between the mineral and organic phases of the bone.
In PBC, osteopenia (reduced bone mass) is mainly due to osteoporosis. This is the same condition that causes decreased bone mass in older women. Less commonly, osteomalacia can be the cause or a contributing factor to osteopenia in PBC. The loss of bone mass in PBC is about twice as high as age and sex matched controls. The exact reasons why patients with PBC develop osteopenia are still not known. Treatment with vitamin D and calcium may slow the rate of bone loss.
24. Is Actigall or Urso normally used in a blocked bile duct aftertransplant? 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.
