Diagnosing autoimmune hepatitis in paediatric patients – we still haven’t found what we are looking for

Field: Medicine (Health Sciences)

In this issue of Acta Paediatrica, Niță and Păcurar 3 draw our attention to the important topic of autoimmune liver disease diagnostics by presenting a retrospective comparison of these two scorings systems 1, 2. In their study, 28 paediatric patients previously diagnosed with autoimmune hepatitis and 28 patients with hepatitis B were classified as having definite, probable or nondiagnostic autoimmune hepatitis according to these scoring systems. Their main finding was the marked discrepancy between the systems, as 85.7% of the cases were classified as autoimmune hepatitis according to the 1999 score 1 and 57% were classified according to the simplified score 2. This was markedly lower than the findings of Mileti et al., who found that the sensitivity of the simplified score was 87% 4, but in line with two other studies that reported that the sensitivity of the simplified score was 55% and 72%, respectively 5, 6. Differences in the composition of the control groups, namely the nonautoimmune hepatitis cases, can affect the positive and predictive value of the scoring systems. Thus, the predictive value of the scoring systems may differ in population with different rates of other nonautoimmune hepatitis diseases, such as viral hepatitis. Such studies face a common challenge when it comes to a definite diagnosis of autoimmune hepatitis. Some studies have used the 1999 score as the gold standard and compared the simplified score to this. In the Niță and Păcurar 3 study, the final diagnosis of autoimmune hepatitis was related to scoring systems, treatment responses and clinical judgement. Both approaches remind us that we still need a gold standard for diagnosing autoimmune hepatitis. The most important factor that explained the discrepancy between the scoring systems was whether a liver biopsy had been performed or not. A liver biopsy is usually performed to establish a diagnosis, but it may sometimes be contraindicated because of risk factors like coagulopathy, thrombocytopenia, ascites or fulminant liver failure. In the study by Niță and Păcurar, histology was only available for a minority of the patients and this had a significant impact on scores. This highlights the importance of liver biopsies in the diagnostics of autoimmune hepatitis. Risk factors for bleeding in liver biopsies have been thoroughly investigated, and thrombocytopenia and coagulopathy may be corrected to modify the risk of bleeding related to the procedure 7, 8. The 2018 recommendations from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) state that percutaneous liver biopsy is the most important investigation and should be performed unless contraindicated 9. One factor that contributed to the differences between the scoring systems was the presence or absence of other associated autoimmune disorders. Many of the patients scored as nondiagnostic for autoimmune hepatitis in the simplified system had an associated autoimmune disorder, such as cholangitis, ulcerative colitis, autoimmune thyroiditis, pancreatitis, autoimmune haemolytic anaemia or coeliac disease. Diagnostics of autoimmune hepatitis should include evaluating other associated autoimmune disorders, both to treat these disorders and as valuable information on the child's susceptibility to autoimmunity. ESPGHAN recommends that a positive family history for autoimmune conditions should be considered in the diagnosis of autoimmune liver disease and that faecal calprotectin should be used as a screening test for inflammatory bowel disease 9. In children and adolescents, the overlap syndrome between autoimmune hepatitis and sclerosing cholangitis is often termed autoimmune sclerosing cholangitis. Many of these patients are positive for autoantibodies like antinuclear antibodies and smooth muscle antibodies and have increased serum levels of immunoglobulin G. The scoring systems are not constructed to differentiate between autoimmune hepatitis, autoimmune sclerosing cholangitis, overlap syndrome or sclerosing cholangitis. This has been demonstrated in several of the studies. Hiejima et al. found that all five children with primary sclerosing cholangitis were classified as having probable or definite autoimmune hepatitis in both scoring systems 5. Mileti et al. found that three out of eight children with primary sclerosing cholangitis were classified as probable autoimmune hepatitis 4. Two children with autoimmune sclerosing cholangitis or overlap were graded as nondiagnostic in the 1999 system presented in the study by Niță and Păcurar 3. Furthermore, several of the studies shared the limitation that examinations with cholangiograms were lacking in many patients, and thus, the real specificity of the diagnostics was not assessed. The inadequacy of the scoring systems to differentiate between autoimmune hepatitis, overlap syndrome or autoimmune cholangitis is especially visible in children as overlapping forms are more frequent than in adults. ESPGHAN now recommends that a cholangiogram is obtained at diagnosis 9. If this is implemented, future studies will benefit from more precise data. Scoring systems may be useful, both as a research tool to ensure comparability between studies and as a clinical diagnostic tool in order to pick the right patients for treatment. Another interesting aspect is whether scoring systems could predict treatment responses. Although most children with autoimmune hepatitis respond well to standard treatment, a substantial number experience incomplete remission and need alternative treatment. If a clinician could predict that a child was unlikely to respond to standard treatment, alternative treatment could be considered at an early stage. Diestelhorst et al. evaluated whether autoimmune hepatitis score and interleukin 2 measured at baseline could predict responses to standard therapy 10. This approach is interesting, and further investigations should be encouraged. The simplified score 2 has been associated with low sensitivity in some paediatric studies. Although these studies had limitations, they indicated that the simplified tool may risk false-negative diagnoses. Both the 1999 score and the simplified score were mainly developed for adult patients and both used the adult cut-off for smooth muscle antibodies (1:40) rather than the paediatric cut-off (1:20), although the explanatory notes of 1999 mention that lower titres in children should be given a score 1. The weight put on adult patients is also reflected in alcohol intake as one of the parameters in the 1999 score. European Society for Paediatric Gastroenterology, Hepatology and Nutrition suggests validating a new scoring system to reliably diagnose autoimmune hepatitis and autoimmune sclerosing cholangitis in children and adolescents 9. Whether this approach will reduce false-negative diagnoses of autoimmune hepatitis, and improve the differentiation between autoimmune hepatitis and autoimmune sclerosing cholangitis, needs to be evaluated. As illustrated above, the predictive value of the scoring systems may differ in population with different rates of other nonautoimmune hepatitis diseases, and thus, assessment of scoring systems in single centres has limitations. Diagnostics and management of autoimmune hepatitis in children and adolescents suffer from few high-quality international cooperations and studies and new multicentre studies should be encouraged. We still haven’t found what we are looking for. The author has no conflicts of interests to declare. None.