Disease activity and fibrosis in patients with AIH

Monitoring disease activity and development of fibrosis is crucial in patients with autoimmune hepatitis (AIH) in order to adapt immunosuppressive treatment in case of insufficient response and thereby prevent disease progression. Hartl et al. recently published the results of a retrospective study which clearly demonstrates that complete biochemical remission – defined as the normalization of aminotransferases and IgG – is not only a reliable surrogate marker for low histological disease activity but also predicts fibrosis regression and a favorable course of disease (DOI:10.1016/j.jhep.2017.11.020). Further, the study established transient elastography as a non-invasive tool for monitoring liver stiffness which will have a great impact on future treatment monitoring and management of AIH patients.

In November 2017, the study “Usefulness of biochemical remission and transient elastography in monitoring disease course in autoimmune hepatitis” by Hartl et al. was published in the Journal of Hepatology (DOI:10.1016/j.jhep.2017.11.020). The authors investigated the role of complete biochemical remission as a surrogate of histological disease activity and fibrosis development, and further examined the value of repeated liver stiffness (LS) measurements by transient elastography (TE) for monitoring disease progression in patients with autoimmune hepatitis (AIH). The study was conducted retrospectively, all patients were recruited from a German tertiary care center. Complete biochemical remission was defined as normalization of aminotransferase and IgG levels according to current guidelines and correlated with histological staging and grading in follow-up liver biopsies (131 biopsies from 60 patients) as well as LS measurements (343 TE from 125 patients). All patients received immunosuppressive treatment at the time of the follow-up biopsy or TE, and the minimum time interval between consecutive liver biopsies and TE were 12 months.

Complete biochemical remission was correlated with histological disease activity in the follow-up biopsies and proved to be a surrogate for low disease activity. While only 18% of patients in complete biochemical remission showed persisting inflammatory activity on histological examination (modified hepatitis index > 3), 70% of patients who failed to achieve biochemical remission displayed residual inflammatory activity. In addition, biochemical remission was identified as a strong predictor of fibrosis regression (at least equally to histological remission) and a favorable long-term course of AIH. During a median follow-up period of six years none of the patients in complete biochemical remission presented fibrosis progression on histology, the majority even displayed fibrosis regression or stable absence of fibrosis. On the other hand it was observed that 43% of patients with elevated aminotransferase and/or IgG levels experienced progression of fibrosis. The course of LS over time was analyzed in the AIH cohort as well as in patients with autoimmune cholestatic liver diseases. In contrast to primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), a significant yearly decrease of LS was observed in AIH (-6.2%/year vs. +5%/year in PSC and -0.65% in PBC). Complete biochemical remission was linked to regression of LS as these patients showed a significant decrease of LS whereas patients who failed to achieve remission tended to show an increase (-7.5 %/year vs. +1.7 %/year). The strongest decrease of LS and histological fibrosis stage was detected in patients with complete remission who had severe fibrosis or cirrhosis at baseline, emphasizing the potential of fibrosis regression in adequately treated AIH.

In summary, the present study illustrates the prognostic relevance of complete biochemical remission, and confirms that both biochemical remission and TE are reliable non-invasive means for the monitoring of inflammation and fibrosis in AIH patients. In contrast to a liver biopsy, TE is a fast and safe procedure with great acceptance among patients. Inflammatory activity has previously been discussed as a potential confounder in TE measurements leading to false positive LS values. However, the study ”Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis” published by Hartl et al. in 2016 demonstrated that LS was only influenced by hepatic inflammation within the first months of immunosuppressive treatment (DOI:10.1016/j.jhep.2016.05.023). After at least six months of treatment TE had an excellent accuracy for the detection of severe fibrosis and cirrhosis, making it a valuable follow-up tool for treated patients not experiencing a severe flare. Although the results of the current study still need to be confirmed in a larger cohort of patients, they will have important consequences for the future risk stratification and management of AIH patients: While monitoring of aminotransferase and IgG levels along with yearly TE is sufficient in patients with stable biochemical remission, a liver biopsy should be performed early in those patients lacking biochemical remission despite adequate immunosuppressive treatment, and/or showing a significant increase of LS in order to assess disease activity and progression. Unfortunately, this study was not large enough to perform reliable subgroup analyses. The prognostic relevance of a partial biochemical remission (e.g. normalized aminotransferases but elevated IgG level) would be of particular interest for upcoming studies.

Lisa Schulz
I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Contact: l.schulz@uke.de