Autoimmune hepatitis: clinical challenges.

Waldenström first described the disease entity now termed autoimmune hepatitis (AIH) in 1950, when he observed a chronic form of hepatitis in young women.1 This hepatitis led to cirrhosis and was associated with jaundice, elevated gamma globulins, and amenorrhea.2 The disease was found to be associated with other autoimmune syndromes3 and was later termed “lupoid hepatitis” because of the presence of antinuclear antibodies (ANA); however, the term “lupoid” hepatitis has been abandoned because AIH is not part of the organ manifestations of systemic lupus erythematosus. The identification and characterization of serum autoantibodies have been a driving force in the systematic evaluation, classification, and diagnosis of AIH.4 Beginning in the 1970s, the detection of autoantibodies against proteins of the endoplasmic reticulum (microsomes) expressed in liver and kidney (liver-kidney microsomal antibodies, LKM)5–9 led to the identification of a second form of AIH not characterized by ANA.8 Molecular analysis soon identified cytochrome P450 (CYP) monoxygenases as hepatocellular target antigens of LKM-1 autoantibodies found in this second form of AIH (AIH type 2).7,10,11 Finally, a third serologically defined group of AIH was categorized after the detection by radioimmunoassay of antibodies to a soluble liver antigen (SLA) identified in the 100,000 g supernatant of liver homogenates.12 It is evident from the chronology of events that AIH does not represent a homogeneous entity and that seroimmunologic and genetic markers discriminate among its subgroups.13,14 AIH is a chronic, mainly periportal hepatitis associated with hypergammaglobulinemia and circulating autoantibodies, which, in most cases, responds to immunosuppressive treatment. There is a striking prevalence among females,15 an immunogenetic association with the HLA A1-B8-DR3 or DR4 haplotype,16 and the presence of extrahepatic syndromes.17 This complex definition indicates that a single cause or a single test for the accurate diagnosis of AIH has not been found. In contrast, the diagnosis is established by a number of diagnostic criteria, as recently defined by the International Autoimmune Hepatitis Group (IAHG), and the exclusion of other causes of chronic hepatitis18,19 (Tables 1 and 2). However, AIH frequently overlaps with other autoimmune liver diseases that affect the biliary tract: primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).20,21 The combination of seroimmunologic and molecular biologic tests4 with a recently revised diagnostic scoring system permits a precise discrimination between AIH and other causes of chronic hepatitis. The exclusion of replicating hepatitis virus infection together with female sex, hypergammaglobulinemia, and response to immunosuppressive treatment are the hallmarks of an accurate diagnosis.18,19