Autoantibodies and Autoantigens in Autoimmune Hepatitis

Christian P. Strassburg, MD, Michael P. Manns, MD


Semin Liver Dis. 2002;22(4) 

In This Article

Abstract and Introduction


The diagnosis of autoimmune hepatitis (AIH) relies on the exclusion of viral, metabolic, genetic, and toxic etiologies of chronic hepatitis or hepatic injury. There are few parameters that positively predict the presence of AIH. Autoantibodies have been intensively evaluated in this respect and have led to the classification of AIH into three serological subgroups: antinuclear and smooth muscle antibody-positive (ANA/SMA, type 1), liver-kidney microsomal antibody-positive (LKM-1, type 2), and soluble liver antigen/liver-pancreas antigen antibody-positive (SLA/LP, type 3) AIH. Although there are few clinical implications resulting from this classification, autoantibody profiles indicate that AIH is a heterogenous group of entities. The molecular characterization of B cell autoimmunity has led to the identification of major phase I and phase II metabolic enzymes as well as structural and functional components of the cell nucleus as immunologic targets. Autoantibodies and their corresponding autoantigens are intensively studied to provide clues to the understanding of disease initiation, tissue specificity, and propagation of hepatic autoimmune diseases.


Ever since the first description of AIH in 1950 by Waldenström,[1] serological findings have attracted considerable attention not only for the diagnosis of this chronic liver disease but also as a means to study and eventually to understand its pathophysiology.[2,3,4] Waldenström described a disease affecting predominantly women and characterized by amenorrhea, jaundice, and elevated gamma globulins leading to cirrhosis of the liver. It was recognized that patients with AIH displayed antinuclear antibodies (ANA), which leads to the designation "lupoid" hepatitis.[5,6] However, the term lupoid hepatitis has been abandoned because AIH is not a part of the syndrome of systemic lupus erythematosus (SLE).

Autoantibodies have been the driving force of research aimed at elucidating the underlying mechanisms of AIH. They also serve as a means of serological subclassification of AIH.[7,8] Although this classification remains controversial, three subtypes can be distinguished based on the presence of serum autoantibodies. The classic form of AIH, AIH type 1, displays ANA. Research in the 1970s and 1980s led to the realization that autoantibodies in some patients are directed against antigens expressed in the endoplasmic reticulum (ER).[9,10,11,12,13] These antimicrosomal autoantibodies were later identified as possessing specificity against cytochrome P450 (CYP) monooxygenases expressed in the ER, which were identifiable in the microsomal fraction of cells. Antimicrosomal antibodies directed against CYP 2D6 expressed not only in the liver but also in the kidney (LKM) characterized a second form of AIH (LKM-1).[13] Finally, the analysis of serum from a patient with AIH by radioimmunoassay identified an antibody directed against a protein present in the 100,000 g supernatant of liver homogenate that was termed anti-SLA/LP.[14,15,16] These autoantibodies have recently been identified as being directed against a UGA repressor tRNA-associated protein.[17,18,19,20] The third serological group of AIH (AIH type 3) is clinically similar to AIH type 1, and therefore some researchers believe it does not represent a distinct subentity of its own.[21] The serological diversity of autoantibodies found in AIH supports the aforementioned subclassification and provides a framework for the scientific analysis of this heterogeneous disease group.[22] It also demonstrates that AIH is not a single disease with a single underlying mechanism but is most likely a group of diseases with a similar clinical presentation. This is further substantiated by the finding of AIH in 10% of patients with autoimmune polyglandular syndrome type 1 (APS-1, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]).[23,24,25] This disease syndrome combines hypoparathyroidism, mucocutaneous fungal infections, adrenal insufficiency, and a number of other immune-mediated syndromes, such as nail dystrophy, vitiligo, and alopecia. In patients with APS-1 who suffer from AIH autoantibodies against CYP 1A2 and CYP 2A6 have been identified.[26] APS-1 is associated with the presence of mutations within a single gene, the autoimmune regulator gene (AIRE), and represents the only known autoimmune disease with a monogenetic association to date.[27,28] However, patients with AIH in the absence of APS-1 do not display mutations of the AIRE gene and are therefore genetically distinct from this form of AIH.[29] Based on these considerations, AIH cannot be considered to represent a homogeneous disease manifestation in man.

Interestingly, none of the major autoantigens detected by common autoantibodies in AIH is liver specific, and only very few are disease specific. The diagnosis of AIH therefore cannot employ autoantibodies as a single marker to prove the presence of this disease. It is rather a diagnosis reached by the exclusion of other factors leading to chronic hepatitis that include viral, toxic, genetic, and metabolic etiologies. The diagnosis of AIH is a probability best reflected in the AIH diagnostic score published in 1993 and revised in 1999 by the International Autoimmune Hepatitis Group (IAHG).[30,31] This diagnostic score demonstrates that the presence of defined autoantibodies is an integral part of the diagnosis of AIH but not its single diagnostic phenomenon.

In recent years, much progress has been made in the characterization of hepatic autoantigens. This has led to the realization that some of the major autoantigen targets in AIH are active enzymes of human hepatic and extrahepatic microsomal xenobiotic metabolism.[4] They serve as a means to investigate this still-enigmatic liver disease. This article will focus on the data that have evolved in the course of the characterization of autoantibodies in AIH.


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