One characteristic biochemical abnormality of AIH is hypergammaglobulinemia in the absence of cirrhosis with selective elevation of serum IgG. Typically, IgA and IgM remain normal. The elevation of IgG is not only important for diagnosing AIH but also a reliable marker of disease activity. Elevation of liver enzymes shows a hepatitic pattern in most cases. However, aminotransferase activity (ALT , AST) and bilirubinemia may range from just above the upper limit of normal (ULN) to 50-fold ULN, but this level does not correlate to histological inflammatory activity [11]. AP and γ-glutamyl transferase (γGT) usually are only moderately elevated or normal. In patients with liver cirrhosis, thrombopenia, hypalbuminemia, and elevated INR levels may be present.

The serological assessment of the diagnosis includes testing ANA, SMA, anti-LKM-1, and anti-liver cytosol type 1-antibodies (anti-LC1) . The majority of adult patients show significant titers (>1:40) of ANA, SMA, or both, 3–4 % are positive for anti-LKM1 and up to 20 % present with no antibodies. None of these antibodies is specific for AIH and their presence is not sufficient for affirming the diagnosis nor does their absence preclude AIH. The expression of antibodies can vary during the course of disease, but in contrast to children, the titer level does not correlate to disease activity in adults. In case of seronegativity for ANA, SMA, and anti-LKM-1, testing for atypical perinuclear staining antineutrophil cytoplasmatic antibodies (pANCA) and antibodies to soluble liver antigen (SLA/LP) should be performed. Atypical pANCA were originally considered to be specific for IBD and PSC [12, 13] but are also found in AIH, sometimes as the only positive antibody. Anti-SLA have a limited sensitivity but a high specificity for AIH. Moreover, the presence of anti-SLA is associated with a more severe course of disease and a worse outcome [14, 15]. Serological evaluation should include AMA to preclude PBC. For further investigation of seronegative patients, LKM-2 and -3 antibodies, and LM antibodies (Table 51.3) may be of interest. For a valid diagnosis, the exclusion of other liver diseases is essential. In particular, hereditary disorders as Wilson disease and alpha 1 antitrypsin deficiency, viral hepatitis, steatohepatitis, and drug induced hepatitis should be ruled out. The differentiation between AIH and the autoimmune cholestatic liver diseases PBC or PSC may be difficult, but the effort should be undertaken given the implications for treatment regimen and prognosis.

A liver biopsy is recommended for establishing the diagnosis and for evaluation of the response to treatment. In patients with coexisting IBD, it is also useful to rule out small duct PSC. Although the histological appearance of AIH is characteristic, there are no pathognomonic features. Typical findings are mononuclear cell infiltrates with infiltration of the limiting plate, also called piece meal necrosis or interface hepatitis, which can progress to lobular hepatitis or central–portal bridging necrosis. Plasma cell infiltrates are regularly seen. Biliary lesions as ductopenia or destructive cholangitis or granulomas are indicative for a different diagnosis. Fibrosis is seen in all but the mildest forms and the degree ranges from mild fibrosis to bridging fibrosis or cirrhosis (Fig.51.1).

Diagnosing AIH is especially delicate in autoantibody-negative patients. If AIH is suspected in an autoantibody-negative patient , a liver biopsy may become of immense importance. Otherwise, the patients are diagnosed and treated late.

Also the setting of autoantibodies or other results matching to more than one autoimmune liver disease may cause confusion. Overlapping features of AIH and PSC or AIH and PBC are not uncommon. Practically, that means for example that a patient with AIH can be AMA-positive, what is highly specific for PBC. Or a patient with AIH presents with an abnormal cholangiography, being indicative for PSC. Some authors also count AMA-negative patients with otherwise typical PBC to AIH-PBC overlap or “autoimmune cholangitis.” The overlapping diseases can appear simultaneously or sequentially in one individual patient. However, criteria for diagnosing an overlap are lacking and there are ongoing discussions about the terminology and diagnostic criteria [16]. This is why the estimated prevalence of AIH-PSC overlap ranges from 7.6 % to 53.8 % in different studies [17]. Overlaps of AIH and PBC can be found in 5–10 % of the patients with AIH. In patients with IBD and AIH, an overlap with PSC should always be considered. Particularly children present overlapping signs of AIH and PSC very often (30–50 %) [18]. The AIH-PSC overlap in children is also called “autoimmune sclerosing cholangitis.” In clinical practice, patients often require therapy both with anti-inflammatory agents and ursodeoxycholic acid. The prognosis of the AIH-PSC overlap is worse than of AIH alone, mainly because of the risk of developing a malignancy, which is highly elevated in PSC [19]. The outcome of the AIH-PBC overlap is better than in AIH alone [20].

Similar to AIH patients, sera of HCV-infected patients are frequently positive for ANA, SMA, and LKM. LKM-1 antibodies are found in 5–10 % of patients with chronic HCV infection. The clinical relevance of these autoantibodies for HCV patients remains elusive. LKM are regarded as autoimmune phenomena associated with HCV infection, only high titer antibodies are considered to be a sign for a relevant autoimmune reaction. In individual patients, hepatitic flares can occur under interferon based treatment for HCV.