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

Alena Laschtowitz; Kalliopi Zachou; Vasiliki Lygoura; Simon Pape; Finn Derben; Elmar Jaeckel; Sergio Oller-Moreno; Sören Weidemann; Till Krech; Felix Piecha; Gerhard Schön; Anna-Maria Liebhoff; Munira Al Tarrah; Michael Heneghan; Joost P H Drenth; George Dalekos; Richard Taubert; Ansgar Wilhelm Lohse; Christoph Schramm

doi:10.1016/j.jhepr.2021.100321

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

JHEP Rep. 2021 Jun 12;3(4):100321. doi: 10.1016/j.jhepr.2021.100321. eCollection 2021 Aug.

Authors

Alena Laschtowitz^{1

2}, Kalliopi Zachou³, Vasiliki Lygoura³, Simon Pape^{2

4}, Finn Derben^{2

5}, Elmar Jaeckel^{2

5}, Sergio Oller-Moreno⁶, Sören Weidemann^{2

7}, Till Krech⁷, Felix Piecha^{1

8}, Gerhard Schön⁹, Anna-Maria Liebhoff⁶, Munira Al Tarrah¹⁰, Michael Heneghan¹⁰, Joost P H Drenth^{2

4}, George Dalekos³, Richard Taubert^{2

5}, Ansgar Wilhelm Lohse^{1

2

8

11}, Christoph Schramm^{1

2

11

12}

Affiliations

¹ Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
² European Reference Network for Hepatological Diseases (ERN-RARE LIVER).
³ Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Centre of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece.
⁴ Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁵ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
⁶ Institute of Medical Systems Biology, Centre for Molecular Neurobiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
⁷ Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
⁸ German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
⁹ Institute of Medical Biometry and Epidemiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Institute of Liver Studies and Transplantation, King´s College Hospital, London, UK.
¹¹ Hamburg Centre for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
¹² Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

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.