Autoimmune Hepatitis

This issue of Seminars in Liver Disease is dedicated to Karl-Hermann Meyer zum Büschenfelde, a pioneer in autoimmune hepatitis research and the mentor of the guest editor. He was also the guest editor of the previous issue on autoimmune hepatitis in Seminars in Liver Disease more than a decade ago.

Autoimmunity and autoimmune diseases are one of the major miracles in medicine, with numerous unsolved questions. Autoimmune hepatitis is just one of many examples of an autoimmune disease in which a loss of tolerance is regarded as the major pathogenetic mechanism.

In 1994, the International Association for the Study of the Liver (IASL) published a new definition of chronic hepatitis. This definition is based on the etiology of liver disease, followed by activity (grading) and fibrogenesis (staging). This new classification became necessary because several distinct etiologies of chronic hepatitis had been identified over the last several decades. Each of these distinct etiologies requires a specific therapeutic approach. Autoimmune hepatitis accounts for 10 to 20% of chronic hepatitis cases around the world. However, the disease has been studied mainly in Europe, North America, and Australia. Recently, data have become available from Japan and South America that show some peculiarities compared with the earlier reports.

Autoimmune hepatitis was first described by Waldenström in 1951. Later it became the first liver disease in which medical treatment was shown to prolong survival. Presumably, autoimmune hepatitis is heterogeneous in itself. Therefore, several efforts have been made to further subclassify autoimmune hepatitis into distinct subgroups based on either serological or genetic markers. Specific diagnostic criteria for autoimmune hepatitis are crucial because immunosuppressive treatment prolongs survival in this setting, while the same treatment may be harmful in viral hepatitis. In individual cases however, the differential diagnosis may sometimes be difficult. The diagnosis of autoimmune hepatitis is based on a scoring system summarizing several clinical and laboratory parameters. Among these diagnositic criteria are the presence of autoantibodies, which are very heterogenous. They are used as diagnostic markers and tools to study etiology, pathogenesis, and the molecular nature of the target autoantigens. The application of molecular biology to the field of autoimmunity led to the construction of recombinant antigens, some of which are now being used in diagnostic tests.

As in most autoimmune disorders, the genetic background of autoimmune hepatitis has been studied intensively. HLA antigens DR 3 or DR 4 characterize different rates of progression rather than being markers of different etiologies. The puzzle of genetic markers has become very complex, and every year several new genetic markers are added to the literature. The spectrum of polymorphic genes associated with autoimmune hepatitis includes cytokines-such as tumor necrosis factor-and adhesion molecules-such as CTLA 4. However, the elucidation of the genetic background of autoimmune hepatitis is like searching for a needle in a haystack. Certainly many more needles will be discovered. Still, very little is known about the precise pathogenetic mechanisms, the triggering events and, in particular, the role of T-cell immunology. Therefore, several animal models have been established using knock out and transgenic animal technology that allow us to ask specific questions and give us some clues to certain aspects of human autoimmune diseases, including autoimmune hepatitis. The use of genetically engineered animals may be, at present, the most fertile area for autoimmune hepatitis research. Although an animal model of autoimmune hepatitis that fully resembles the human disease has not yet been established, those available already answer some specific questions related to the complex mosaic of the pathogenesis of autoimmune hepatitis. Of particular relevance seems to be the use of animals expressing antigens of infectious agents such as viruses. In some of these animals, loss of tolerance and development of immune mediated disease is possible, but relies not only on the induction of a loss of immunological self tolerance but also on an inflammatory environment as an essential bystander effect.

As discussed earlier, autoimmune hepatitis was the first liver disease in which medical treatment was shown to prolong survival. Prednisolone alone or in combination with azathioprine has been the standard treatment for several decades. All the newer immunosuppressive drugs that have been developed for organ transplantation may only be used in patients who do not respond to standard treatment. In the majority of patients, liver transplantation does not become necessary or at least is significantly postponed due to the beneficial effects of standard immunosuppression. However, in the end stages of autoimmune liver disease, liver transplantation is a hope and not a threat to these patients.

Despite the fact that autoimmune hepatitis may recur in the transplanted liver, long-term survival is excellent, and is in fact better than for most other indications for liver transplantation. In the future, disease specific posttransplant management and immunosuppression will become available that are based on the etiology of the liver disease that led to the liver transplant. In the future, immunosuppression free of corticosteroids should become realistic for transplants for viral hepatitis; however, effective immunosuppression with the use of steroids will remain necessary to prevent severe recurrence of autoimmune liver disease. Apart from being a successful therapeutic approach, liver transplantation for autoimmune hepatitis is also a very attractive field of research. The interaction of the donor organ with the host's immune system, as well as his bone marrow, leads to a very intensive chimerism. Over the years the ``nonself'' donor liver becomes ``self''. A significant number of hepatocytes in the donor liver are replaced by liver cells derived from the host, most probably from the host's bone marrow stem cells. The microenvironment within the liver after transplantation must have a significant influence on recurrent disease as well as tolerance towards the transplanted organ. In this context the observation of de-novo autoimmune hepatitis in the donor liver is an important one. The study of this syndrome may give additional clues to the understanding of the still incompletely understood events leading from loss of tolerance towards a self-perpetuating autoimmune disease.

This issue of Seminars in Liver Disease provides an update on autoimmune hepatitis, summarizing the latest knowledge on disease definition and classification, on autoantibody and autoantigen identification and characterization, the haystack of immunogenetics and the latest developments in animal models for autoimmune hepatitis. Finally, autoimmune hepatitis is a treatable disease in which more specific immunosuppressive drugs or alternative treatments are needed despite the good results achieved with the standard immunosuppression used for several decades. Hopefully, with improved medical therapy, liver transplantation for autoimmune hepatitis will become a very rare event in the future, or may even become unnecessary.