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. 2022 Oct 13;5(1):100605.
doi: 10.1016/j.jhepr.2022.100605. eCollection 2023 Jan.

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination

Greta Codoni  1 , Theresa Kirchner  2   3 , Bastian Engel  2   3 , Alejandra Maria Villamil  4 , Cumali Efe  5 , Albert Friedrich Stättermayer  6 , Jan Philipp Weltzsch  7   3 , Marcial Sebode  7   3 , Christine Bernsmeier  8 , Ana Lleo  9   10 , Tom Jg Gevers  3   11 , Limas Kupčinskas  3   12 , Agustin Castiella  13 , Jose Pinazo  14 , Eleonora De Martin  15 , Ingrid Bobis  16 , Thomas Damgaard Sandahl  17 , Federica Pedica  18 , Federica Invernizzi  18 , Paolo Del Poggio  19 , Tony Bruns  3   20 , Mirjam Kolev  21 , Nasser Semmo  21 , Fernando Bessone  22 , Baptiste Giguet  23 , Guido Poggi  24 , Masayuki Ueno  25   26 , Helena Jang  27 , Gülsüm Özlem Elpek  28 , Neşe Karadağ Soylu  29 , Andreas Cerny  30 , Heiner Wedemeyer  2   3 , Diego Vergani  31 , Giorgina Mieli-Vergani  31 , M Isabel Lucena  14   32 , Raul J Andrade  14   32 , Yoh Zen  31 , Richard Taubert  2   3 , Benedetta Terziroli Beretta-Piccoli  1   30   31
Affiliations

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination

Greta Codoni et al. JHEP Rep. .

Abstract

Background & aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features.

Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines.

Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed.

Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition.

Impact and implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

Keywords: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, anti-mitochondrial antibody; ANA, anti-nuclear antibody; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; DILI, drug-induced liver injury; IAIHG, International Autoimmune Hepatitis Group; IFT, indirect immunofluorescence; LKM, liver kidney microsomal; LT, liver transplantation; PCA, parietal cell antigen; SARS-CoV-2 vaccines; SARS-CoV-2, severe acute respiratory syndrome coronavirus type 2; SLA, soluble liver antigen; SMA, anti-smooth muscle antibody; ULN, upper limit of normal; acute liver injury; autoimmune liver serology; liver histology; pIgG, polyreactive IgG.

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Conflict of interest statement

The authors do not have any conflict of interest pertaining to this study. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Sequence of SARS-CoV-2 vaccinations and infections before the onset of liver injury. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory coronavirus 2.
Fig. 2
Fig. 2
Longitudinal development of biochemistry tests in liver injuries associated with SARS-CoV-2 vaccines. ALP, alkaline phosphatase; ALT, alanine aminotransferase; SARS-CoV-2, severe acute respiratory coronavirus 2; ULN, upper limit of normal.
Fig. 3
Fig. 3
Histology of liver injury associated with SARS-CoV-2. The histological injury pattern can be categorized into predominant lobular (upper column) as well as predominant portal (mid column) injury pattern, each with subclassifications, and a small group of different manifestations (lower column). SARS-CoV-2, severe acute respiratory coronavirus 2.
Fig. 4
Fig. 4
Representative histological pattern of liver injury associated with SARS-CoV-2. Outlined are representative examples for the histological types from Fig. 3: (A) Lobular hepatitis with confluent necrosis (100x); (B) Panlobular hepatitis (200x); (C) Isolated central perivenulitis; (D) Portal hepatitis with interface injury (100x); (E) Eosinophilic aggregates (400x); (F) Plasma cell aggregates (400x).
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