Non‐invasive markers of inflammation in autoimmune hepatitis

The treatment of autoimmune hepatitis (AIH) aims to downregulate the inflammatory mechanisms responsible for the appearance of the disease and to achieve sustained disease remission. Remission is conventionally considered the resolution of the clinical symptoms, when present, the complete normalization of biochemical parameters (serum aminotransferases and c-globulins levels) and the complete resolution of hepatic inflammatory activity as the ideal treatment endpoint (1). A standardized, universally accepted, definition of remission in patients with AIH exists since 1999 (2). The concept of remission in the treatment of autoimmune hepatitis has changed over the years; in the past a reduction in aminotransferases levels below twice the upper limit of normal had been considered as a satisfactory remission (3). This definition of remission associated with persistent moderate ALT abnormalities derived from ancient clinical trials (4–6) for the treatment of AIH and remained unchanged for over 40 years. Randomized controlled trials (RCTs) in the 1970s that established the efficacy of corticosteroids in the treatment of AIH included severe cases of AIH with rapidly progressive disease. The goal of therapy was to reduce both mortality and inflammatory activity; authors were not concerned with the risk that residual inflammatory activity could be the cause of a slowly progressive disease. Patients with less severe disease probably were not included in those RCTs (7). Subsequently, several reports underlined that the persistence of mildly elevated transaminases and hypergammaglobulinaemia during treatment was associated with histological evidence of ongoing hepatic inflammatory activity, and this persistent inflammatory activity was a harbinger of disease progression and reactivation. These studies also told us that normal laboratory values during treatment do not guarantee the resolution of histological inflammatory activity. Thus, a diagnosis of resolution required the assessment of a liver biopsy (8–10). This formed the basis of the AASLD guidelines 2010 (1) that defined for the first time remission as a complete normalization of aminotransferases and immunoglobulin. In a retrospective analysis of disease progression in patients who achieved complete or incomplete normalization of laboratory parameters with immunosuppressive treatment, it was demonstrated that those patients who achieved complete and persistent normalization of transaminases and immunoglobulins had a significantly lower risk of histological progression when compared with patients who did not completely normalize liver tests (11). Recent progress has made the diagnosis of AIH possible in an earlier phase of its natural history. Thus, the aim of treatment is no longer solely focused on the reduction of medium term mortality but it has shifted to achieving persistent control of inflammatory activity. This in turn reduces or abolishes the risk of disease progression with the appearance of cirrhosis and its complications (i.e. decompensation, need of liver transplant and hepatocellular carcinoma). Balancing the control of liver inflammation through close monitoring of disease activity and steroid side effects is often a difficult task. Liver biopsy is the gold standard for the fibrosis and inflammation severity assessment. It is also an invasive procedure with a limited tangible morbidity, frequently not acceptable to patients, and not suitable to be frequently repeated (12). The accuracy of the liver biopsy in assessing fibrosis is hampered by intraand interobserver discrepancies and is poorly reproducible because of sampling error. Liver biopsy in fact is based on a sample that represents one fifty thousandth of the whole liver parenchyma and should be evaluated with caution and within the broader clinical context. Therefore, transaminases and immunoglobulin levels are commonly used in clinical practice to monitor disease activity, but data supporting the close relationship between these markers and histological activity are still an open question. L€ uth et al. have approached this problem by comparing the histological activity of liver biopsies with serum parameters. They demonstrated that normal ALT and IgG were in most cases (52%) indicative of a histological activity index (HAI) <6, but often associated with HAI scores of 4 or 5. None of the patients with a HAI score of 4 or 5 showed fibrosis progression during observation for 3 years (13). It must be said that a histological activity index of 4 or 5 cannot be considered histological remission. These patients have persistent albeit mild inflammatory activity and are at high risk of reactivation after drug withdrawal. A reliable assessment of the inflammatory activity is crucial in determining progression and may