Primary Biliary Cirrhosis (cont.)
John M. Vierling, MD, FACP
John M. Vierling M.D. is Professor of Medicine and Surgery at the Baylor College of Medicine in Houston, Texas, where he also serves as Director of Baylor Liver Health and Chief of Hepatology. In addition, he is the Director of Advanced Liver Therapies, a center devoted to clinical research in hepatobiliary diseases at St. Luke's Episcopal Hospital. Dr. Vierling is board certified in internal medicine and gastroenterology and a Fellow of the American College of Physicians.
Leslie J. Schoenfield, MD, PhD
Dr. Schoenfield served as associate professor of medicine and consultant in gastroenterology on the faculty of the Mayo Clinic for seven years. He became a professor of medicine in residence at UCLA from 1972 to 1999 (now emeritus). He was the director of gastroenterology at Cedars-Sinai Medical Center in Los Angeles for 25 years, where he received the chief resident's teaching award, the president's award, and the pioneer of medicine award.
In this Article
- What is PBC?
- What is the scope of the problem?
- What is the cause of PBC?
- What are the symptoms and physical findings in PBC?
- What manifestations are specifically due to PBC itself?
- What are the manifestations of the complications of cirrhosis in PBC?
- What are the manifestations of diseases associated with PBC?
- What are risk factors for PBC?
- How is PBC diagnosed?
- What is the role of blood tests?
- What is the role of testing for antimitochondrial antibodies?
- What is the role of imaging tests?
- What is the role of liver biopsy?
- What are the criteria for a definitive diagnosis of PBC
- What is the course of natural progression in PBC?
- What are the sequential clinical phases of PBC?
- What is the role of mathematical models in predicting the outcome (prognosis) in PBC?
- What about pregnancy in PBC?
- Find a local Gastroenterologist in your town
What is the cause of PBC?
The cause of PBC remains unclear. Current information suggests the cause may involve autoimmunity, infection, or genetic (hereditary) predisposition, acting either alone or in some combination. A complete understanding of the cause of PBC will require two types of information. One, referred to as the etiology, is identification of the initiating (triggering) events. The other, referred to as the pathogenesis, is a discovery of the ways (mechanisms) by which the triggering events lead to the inflammatory destruction of bile ducts and hepatocytes. Unfortunately, neither the etiology nor the pathogenesis of PBC has yet been defined.The following topics relate to the cause of PBC:
- What is the role of autoimmunity?
- What are antimitochondrial antibodies (AMA)?
- Do the AMA react with the bile ducts?
- What causes destruction of the bile ducts in PBC?
- What is the role of infection?
- What is the role of genetics?
What is the role of autoimmunity?
PBC is presumed by most experts to be an autoimmune disease, which is an illness that occurs when the body's tissues are attacked by its own immune (defense) system. (Auto means self.) Childhood diabetes is one example of an autoimmune disease in which some type of transient infection (one that later goes away) triggers an immune reaction in a susceptible (genetically predisposed) person. This particular immune reaction in diabetes selectively destroys the cells in the pancreas that produce insulin.
Despite strong evidence to support the concept that PBC likewise is an
autoimmune disease, some features of PBC are uncharacteristic of autoimmunity. For example, all other autoimmune diseases occur in both children and
adults, while, as already mentioned, PBC has never been diagnosed in childhood.
PBC and other autoimmune diseases, however, are associated with antibodies
(small proteins found in the blood and bodily secretions) that react with the
body's own proteins, which are referred to as autoantigens.
Table 1 shows a comparison between primary biliary cirrhosis and classic autoimmune diseases.
|Feature||Primary Biliary Cirrhosis||Classic Autoimmunity|
|Age at diagnosis||Adults only||Children and adults|
|Antigens recognized by autoantibodies||Restricted (few)||Diverse (many)|
|HLA (Human Lymphocyte Antigen) associations||Weak||Strong|
|Association with other autoimmune diseases||Yes||Yes|
|Response to drugs that suppress the immune system||Poor||Good|
Specific types of white blood cells called B-lymphocytes make antibodies. Antibodies recognize specific protein targets called antigens (substances that are capable of causing the production of antibodies.) To facilitate our discussion of autoimmunity, let us first look at what happens in the more common type of immunity. It takes new or foreign antigens to produce this usual type of immunity. Vaccines, infectious organisms (like viruses or bacteria), or surgically transplanted tissues contain such foreign antigens. So, for instance, when a person is first vaccinated to prevent tetanus, that person is newly exposed to tetanus proteins, which are foreign antigens. What happens then?
First, specialized cells within tissues of the body take up and digest the tetanus proteins. Then the protein fragments are attached to special molecules called HLA molecules that are produced by the HLA complex. (HLA is an abbreviation for Human Leukocyte Antigen). The HLA complex is a group of inherited genes located on chromosome 6. The HLA molecules control a person's immune response. Next, the protein (antigen) fragments bound to the HLA molecules set into action (activate or stimulate) specialized white blood cells called T-lymphocytes. The T-lymphocytes then begin to multiply (reproduce) and secrete chemical signals into their environment.
Another type of white blood cell, called B-lymphocytes, also enters the picture. B-lymphocytes have molecules on their surface, called immunoglobulins (Ig) that can bind directly to undigested tetanus antigens. An essential part of the body's immune system, immunoglobulins are antibodies that attach to foreign substances, such as bacteria, and assist in destroying them. This binding activates the B-lymphocytes, that is, gets them ready for action. Meanwhile, the above-mentioned secreted chemicals of the activated T-lymphocytes provide a helper signal for the B-lymphocytes. This signal tells the B-lymphocytes to begin secreting the immunoglobulins (specific antibodies) that precisely recognize the stimulating tetanus antigen.
The bottom line here is that antibodies that specifically bind and inactivate tetanus proteins prevent an immunized person from developing tetanus. What is more, both the T- and B-lymphocytes reside in the body as memory cells. This means that they can remember to generate increased amounts of antibodies against tetanus antigens whenever a person has a booster shot of the vaccine. So, that's what happens in the common type of immunity.
By contrast, in autoimmunity, autoantibodies, produced by B-lymphocytes react against self or auto antigens rather than against foreign antigens. In this reaction, the activated B-lymphocytes still require help from chemicals secreted by activated T-lymphocytes. Although the human immune system is capable of recognizing a nearly infinite number of antigens, normally it does not recognize or respond to autoantigens. The expected absence of immune responses against self is called tolerance.
Thus, in all autoimmune diseases, including PBC, tolerance (absence of an immune response) becomes defective (is lost) for autoantigens recognized by both T- and B-lymphocytes. In other words, an immune response to autoantigens does occur. What's more, in autoimmune diseases, B-lymphocytes initially produce autoantibodies that recognize a single autoantigen. With time, however, B-lymphocytes produce new autoantibodies that recognize additional autoantigens that are distinct from the initial autoantigen. PBC, however, is the only allegedly autoimmune disease in which this sequence does not occur. In other words, in PBC, the autoantibodies recognize only the initial autoantigen.
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