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.
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.
Between 95 and 98% of patients with primary biliary cirrhosis (PBC) have autoantibodies (antibodies to self) in their blood that react with the inner lining of mitochondria. These autoantibodies are called antimitochondrial antibodies (AMA). Mitochondria are the energy factories present inside all of our cells, not just the cells of the liver or bile ducts. (The mitochondria use the oxygen carried in the blood from the lungs as a fuel to generate energy.) AMA actually bind to protein antigens that are contained in multienzyme complexes (packages of enzymes) within the inner lining of the mitochondria. These multienzyme complexes produce key chemical reactions necessary for life. The complexes are referred to as multienzyme because they are made up of multiple enzyme units.
AMA specifically react against a component of this multienzyme complex called E2. In PBC, AMA preferentially react with the E2 component of one of the multienzymes that is called the pyruvate dehydrogenase complex (PDC). Accordingly, the antigen is designated as PDC-E2. The practical importance of all of this is that the PDC-E2 antigen is now used, as discussed below, in a diagnostic test for PBC. The PDC-E2 antigen is also referred to as M2, a term introduced to designate it as the second mitochondrial antigen discovered by researchers interested in PBC.
Do AMA cause the destruction of the bile ducts in PBC?
In as much as the bile ducts are the main targets of destruction in PBC, the question was asked whether the AMA reacts with the epithelial cells that line the bile ducts. So, investigators prepared antibodies to PDC-E2. As expected, they found that these antibodies bound to the mitochondria within the cells. But, sure enough, recent information suggests that these AMA autoantibodies also bind to PDC-E2 that lies outside the mitochondria, yet within the epithelial cells lining the bile ducts.
This accumulation of PDC-E2 within the biliary epithelial cells is observed exclusively in the livers of patients with PBC, and not in normal livers or in livers from patients with any other types of liver disease. Interestingly, it was also observed in the livers of those two to five percent of PBC patients who do not have AMA in their blood (AMA-negative PBC). Furthermore, intense binding of these antibodies to biliary epithelial cells was also found to be the earliest indication of recurrence of PBC in a transplanted liver. (PBC is sometimes treated by liver transplantation.)
Nevertheless, no evidence exists that the AMA itself causes the destruction of the biliary epithelial cells lining the small bile ducts. Neither the presence nor the amount (titer) of AMA in the blood appears to be related to the inflammatory destruction of the bile ducts. Indeed, immunization of animals with PDC-E2 antigen results in production of AMA without any liver or bile duct damage (pathology).