The challenge of diagnosing autoimmune hepatitis: Less is more
Authors: Gina Choi, Marion G. Peters
Journal: Hepatology (2008)

The diagnosis of autoimmune hepatitis (AIH) continues to be a challenge for clinical hepatologists. Multiple descriptions for over 50 years have recognized the female preponderance; hypergammaglobulinemia; autoantibodies; elevated serum aminotransferases; characteristic liver biopsy (chronic active hepatitis with lymphoplasmocytic interface hepatitis); and response to corticosteroid therapy.1-3 However, not all patients fit these criteria and the diagnosis of AIH continues to be problematic, given its lack of specific clinical and biochemical findings.3 In 1992, the International Autoimmune Hepatitis Group (IAIHG) met in Brighton, UK to devise a diagnostic scoring system to objectively identify patients with either "definite" or "probable" AIH.4 The panel recognized that disease onset was varied and often ill-defined; signs and symptoms covered a wide spectrum between asymptomatic and acute fulminant presentations; serum aminotransferase levels varied widely; and autoantibodies were not consistently found. In their evaluation, up to 20% of patients did not have antinuclear antibody (ANA), smooth muscle antibody (SMA) or liver/kidney microsome type 1 (LKM-1) antibodies at presentation, a number considerably higher than prior studies.5 In addition, the diagnosis was often complicated by the presence of confounders such as alcohol, viruses, and drug use. After analysis of presentation in 145 patients with AIH and 250 patients with other liver disorders, the panel developed criteria to diagnose AIH. A positive weighting was given to female gender, hepatocellular rather than cholestatic damage; and the presence of autoantibodies. Because there was insufficient evidence that any of the autoantibodies were directly involved in the pathogenesis of the disease, the panel did not exclude a diagnosis of AIH in the absence of ANA, SMA or LKM-1 antibodies at presentation. The panel asserted that the diagnosis of definite AIH required a liver biopsy. Finally, IAIHG acknowledged in their report that these recommendations would require prospective validation. Three subsequent studies found that the scoring system had very high sensitivity, ranging from 97% to 100% for diagnosis of AIH in North America, Europe, and Japan.6-8 The overall diagnostic accuracy of the scoring system in multiple reports was calculated to be 89.8%.9 AIH, autoimmune hepatitis; IAIHG, International Autoimmune Hepatitis Group; PSC, primary sclerosing cholangitis; ALP, alkaline phosphatase; ANA, antinuclear antibody; SMA, smooth muscle antibody; LKM-1, liver/kidney microsome type 1; Ig, immunoglobulin; ULN, upper limits of normal. However, the scoring system was cumbersome, with over 18 variables needed to diagnose "definite" or "probable" AIH. The IAIHG met again in 1999 to make modifications and revisions to the original scoring system.9 The main deficiencies they recognized were its relative complexity and lack of specificity in distinguishing "probable" AIH from other liver disorders, particularly autoimmune biliary diseases, such as primary sclerosing cholangitis (PSC) with autoimmune features. They noted only moderate elevations in alkaline phosphatase (ALP) in some cases of PSC, with mild-to-moderate elevations of serum aminotransferase (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]). In such cases, the ALP:AST ratio fell below the cutoff that was set for negative weighting, thus contributing to a high proportion of patients with biliary diseases achieving a "probable" diagnosis of AIH. The scoring was thus adjusted to allocate no points for ALP:AST ratios between 1.5 and 3.0 but deducted 2 points for ratios over 3.0. This adjustment did not affect scores for the large majority of AIH patients. To increase the weighting against biliary diseases, the negative score for AMA seropositivity was raised from −2 to −4 and the negative scoring for histological evidence of bile duct damage was increased from −1 to −3. Using these modifications, reanalysis of autoimmune features in a group of 114 PSC patients10 increased the specificity for exclusion of AIH from 64.9% to 89.5%. The negative score for recent or current hepatotoxic drug use was increased from −2 to −4, providing additional weight against drug-induced syndromes similar to AIH. Biopsy was again central, with 5 points deducted for absence of characteristic histological evidence of AIH. Finally, since some patients with AIH may not respond to immunosuppressive therapy, it was considered inappropriate to deduct points for nonresponse. While the revised scoring system augmented the diagnostic accuracy of AIH and improved the ability to exclude other forms of autoimmune liver diseases, it remained cumbersome and difficult to apply in clinical practice. In this issue of HEPATOLOGY, Hennes and his collaborators11 introduce a new scoring system for the diagnosis of AIH. Their goal was to design a simplified scoring system geared for routine clinical practice, as opposed to the original criteria designed with research purposes in mind. This goal has been achieved. The study established two cohorts of patients: a "training set" and a "validation set." The training set consisted of 250 patients who had "definite" AIH responsive to prednisone therapy and 193 controls with other well-defined liver diseases from 11 international centers. After analysis of the training set, patients recruited for the validation set consisted of an additional 109 patients with AIH and 284 controls. The training set included 10 overlap AIH patients (8 with primary biliary cirrhosis and 2 with PSC), while the validation set had no such patients. The authors included patients with overlap syndromes in the AIH patient group because they stated it was essential to diagnose the AIH component of overlap cases. They further stated that moving these patients to the control group did not change their results. However, overlap patients may have significantly different pathobiology and outcome, as seen in children who may initially present with AIH features responsive to corticosteroid therapy, but then transition to PSC.12 Univariate analysis showed that immunoglobulin G (IgG), gamma globulin levels, SMA and liver histology were good discriminators of AIH; immunoglobulin M (IgM), AMA and ANA titers and gender were less useful. Stepwise logistic regression identified the best predictors for AIH to be ANA and SMA titers, IgG levels, and liver histology (see Appendix in Hennes et al.11). Together, they reached an area under receiver operating characteristic (AUC) under the receiver operating characteristic (ROC) curve of 0.99. The proposed new scoring system is outlined in Table 1: one point for an ANA or SMA titer ≥1:40 and IgG levels greater than upper limits of normal (ULN) and 2 points for ANA or SMA titer ≥1:80, LKM titer greater than or equal to 1:40, positive SLA or an IgG greater than 1.1×ULN. The maximum number of points for all autoantibodies is 2 and total is 8. The new system condenses the liver histology criteria into three categories: typical, compatible, and atypical. "Typical" includes interface hepatitis, lymphocytic/lymphoplasmocytic infiltrates in portal tracts extending into the lobule, emperipolesis and liver-cell rosette formation, which merit 2 points. Unfortunately, emperipolesis,13 active penetration by one cell into and through a larger cell, is not commonly used. Thus the value of this particular histological finding is questionable. "Compatible" describes chronic hepatitis with lymphocytic infiltration without all the features considered typical (1 point) and "atypical" includes evidence of another diagnosis (0 point). The prior system deducted points for histological features consistent with other diseases, including steatosis, iron overload, or biliary changes. In the proposed system, no finding deducts points from the total score and each finding has a maximal contribution of 2 points. Finally, the absence of viral hepatitis garners 2 points, emphasizing the importance of excluding viral hepatitis. The authors state that a "probable" diagnosis of AIH has a cutoff of ≥6 points and "definite" AIH of ≥7 points. However it is not clear what cutoff distinguishes "probable" from "definite". The optimal combination of variables (IgG levels, ANA/SMA titers, and liver histology) predicted 99% of AIH in the training set. The efficacy of the scoring system was then tested on the validation set. Unfortunately, the authors did not compare the new scoring system to the existing scoring system, which would have added information about the diagnostic accuracy. The authors acknowledged autoantibody testing as a limitation of their study. Since autoantibody and immunoglobulin testing are not standardized throughout centers, they suggested halving the autoantibody score if HEp-2 cells are used instead of tissue sections. But there were no recommendations about scoring if ELISA tests are used. SLA/LP antibodies are not universally available but have high specificity with limited sensitivity. For this reason they were included in the score. But neither SLA/LP nor LKM antibodies were identified as predictors by logistic regression analysis. Three additional points require consideration. First, the validation and training groups were not comparable in terms of geography and etiology of non-AIH patients: distribution of North American and Japanese patients was unequal in the two sets; and there were no overlap patients in the validation set. Therefore, the validity of the new scoring system was tested on a potentially different cohort of patients. Second, the new proposed system does not tackle the original diagnostic conundrum outlined in 1992: how to differentiate AIH from other autoimmune liver diseases. The distinction between primary biliary cirrhosis and AIH, PSC and AIH, in addition to autoimmune cholangiopathy and overlap syndromes is not achievable with this or any current scoring system, underscoring the complexities of various autoimmune liver diseases with similar overlapping common manifestations and unclear etiologies. Finally, response to immunosuppressive therapy was not applied, although it is a characteristic of AIH commonly used in practice.3, 14 The new criteria are simpler and thus more likely to be utilized in clinical practice. However, whether they are equal or superior to prior systems has not been demonstrated by this report since the authors did not compare the new diagnostic criteria with former algorithms. Future studies will be required to validate these new, simpler and more user-friendly diagnostic criteria for AIH.