Histological activity despite normal ALT and IgG serum levels in patients with autoimmune hepatitis and cirrhosis

Abstract

Background & aims: In autoimmune hepatitis (AIH), normal levels of transaminases and IgG define biochemical remission and are considered the best surrogate markers for histological remission. This study assessed whether this also applies to patients with AIH cirrhosis.

Methods: In this European multicentric study, we included 125 biopsies from 113 patients with AIH and histologically proven cirrhosis; 105 biopsies from 104 patients with AIH without cirrhosis served as controls. Biochemical parameters were available within 4 weeks of biopsy. AIH activity was graded according to the modified Hepatitis Activity Index (mHAI), with mHAI ≥4/18 considered to indicate risk of disease progression.

Results: In total, 47 out of 125 liver biopsies were obtained from patients with AIH cirrhosis and normal ALT levels at time of biopsy. Only 26% (12/47) of those livers showed histological remission (mHAI <4/18), whereas 36% (17/47) showed moderate to high histological activity (mHAI ≥6/18). In patients with noncirrhotic AIH, 88% (46/52 biopsies) of cases with normal ALT levels had histological remission and only 4% (2/52) had an mHAI ≥6/18 (p <0.001). The addition of IgG to define complete biochemical remission only slightly improved the association with histological remission in the limited number of patients with AIH cirrhosis available for analysis [29% (5/17) of biopsies with mHAI <4/18]. ALT correlated closely with mHAI in AIH without cirrhosis but poorly in AIH with cirrhosis.

Conclusions: In contrast to patients with noncirrhotic AIH, in patients with AIH cirrhosis, who are at risk of disease progression, normal ALT levels and potentially also complete biochemical remission are poor surrogate markers of histological remission. Thus, new biomarkers are needed to monitor disease activity and progression in patients with AIH cirrhosis.

Lay summary: Autoimmune hepatitis (AIH) is an inflammatory disease of the liver that usually responds to immunosuppressive therapy. Serum transaminases and IgG levels within the normal ranges define complete biochemical remission and are considered as surrogate markers for histological disease activity. Here, we show that those biochemical markers are not sufficient to indicate low disease activity in patients with AIH and already established cirrhosis. Consequently, until better biomarkers for disease activity are found, only liver biopsy can reliably indicate disease activity in the presence of cirrhosis. Additional investigations, such as measurements of liver stiffness, should be undertaken to monitor non-invasively for disease progression in patients with AIH and established cirrhosis.

Keywords: AIH, autoimmune hepatitis; ALD, alcoholic liver disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Autoimmune hepatitis; Biochemical remission; Cirrhosis; EASL, European Association for the Study of the Liver; Histological activity; ICC, intraclass correlation coefficient; INR, international normalised ratio; LLN, lower limit of normal; Liver biopsy; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; TE, transient elastography; TIPS, transjugular intrahepatic portosystemic shunt; ULN, upper limit of normal; gamma-GT, gamma glutamyl transferase; mHAI; mHAI, modified Hepatitis Activity Index.

Graphical abstract

Fig. 1

Histological activity of patients in patients with AIH with and without cirrhosis depending on ALT levels. Histological activity scores subdivided into histological remission (mHAI <4), mild residual disease activity (mHAI 4–5), or moderate–high inflammatory activity (mHAI ≥6). Patients were subdivided into ALT levels within or above the normal ranges. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; mHAI, modified Hepatitis Activity Index.

Fig. 2

Examples of liver histologies of patients with AIH with and without cirrhosis with normal ALT serum levels. (A) Specimen of a patient with AIH without cirrhosis and normal ALT levels at time of biopsy; mHAI 1/18. (B) Specimen of a patient with AIH cirrhosis and normal ALT levels at time of biopsy; mHAI 8/18. Staining was performed with haematoxylin and eosin. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; mHAI, modified Hepatitis Activity Index.

Fig. 3

Histological activity of patients with AIH with and without cirrhosis depending on normal ALT and IgG levels. Histological activity scores subdivided into histological remission (mHAI <4), mild residual disease activity (mHAI 4–5), or moderate–high inflammatory activity (mHAI ≥6). AIH, autoimmune hepatitis; ALT, alanine aminotransferase; mHAI, modified Hepatitis Activity Index.

Fig. 4

Distribution of histological activity scores of patients with AIH with and without cirrhosis depending on normal ALT and IgG levels. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; mHAI, modified Hepatitis Activity Index.

Fig. 5

The mHAI activity in correlation of the transformed ALT and IgG data of patients with AIH with and without cirrhosis. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; mHAI, modified Hepatitis Activity Index.