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  • Review Article
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Hepatic immune regulation and sex disparities

Nature Reviews Gastroenterology & Hepatology (2024)Cite this article

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Abstract

Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.

Key points

  • Increasing evidence indicates that biological sex modifies hepatic immune regulation, thereby contributing to hepatic immune outcomes in health and disease.

  • Changes in gut microbiota might substantially affect liver diseases in a sex-specific manner through the regulation of sex hormones, bile acid, lipid and hepatic xenobiotic metabolism.

  • Genetics have revealed few clues to sex disparities in liver disease, but dedicated studies are scarce; only for primary biliary cholangitis has a dedicated chromosome X-wide association study been performed.

  • Incidence, phenotype and disease progression in autoimmune liver diseases vary according to sex: men have an increased risk of disease progression, suboptimal treatment response and hepatobiliary malignancies.

  • Sex influences haemodynamics and portal hypertension in animal models; however, whether this translates into sex-specific responses to treatments lowering portal pressure in individuals with chronic liver disease is unclear.

  • Marked differences in body mass composition exist between sexes, both in health and chronic liver disease, potentially affecting the risk of hepatic decompensation and survival.

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Fig. 1: Main pathways involved in sexual dimorphism of liver immunity.
Fig. 2: Genome-wide landscape of liver disease associations utilizing data from the GWAS catalogue.
Fig. 3: Sex-effect on body composition abnormalities in end-stage liver disease.

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Data availability

The publicly available GWAS catalogue referred to in Fig. 2 can be accessed, and the summary statistics contained therein can be downloaded from https://www.ebi.ac.uk/gwas/. For generation of the panels contained in Fig. 2, two publicly available tools were used: PhenoGram (https://ritchielab.org/software/phenogram-downloads) and the resource at https://bioinformatics.psb.ugent.be/webtools/Venn/.

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Acknowledgements

The authors thank NIH center P30 DK120515 for support to B.S. and the German Research Foundation (DFG Ta434/8-1, SFB/TRR 296 and CRC1382, project ID 403224013) for support to F.T.

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Author notes

  1. These authors contributed equally: Patrizia Burra, Alberto Zanetto.

Authors and Affiliations

  1. Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy

    Patrizia Burra & Alberto Zanetto

  2. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Bernd Schnabl

  3. Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA

    Bernd Schnabl

  4. Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria

    Thomas Reiberger

  5. Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada

    Aldo J. Montano-Loza

  6. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Rosanna Asselta

  7. IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Rosanna Asselta

  8. Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway

    Tom Hemming Karlsen

  9. Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway

    Tom Hemming Karlsen

  10. Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany

    Frank Tacke

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  1. Patrizia Burra
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Patrizia Burra.

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Competing interests

P.B. has received lecture and consulting fees from Biotest, Chiesi Farmaceutici and Sandoz. B.S. has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen and Takeda. B.S. is founder of Nterica Bio. UC San Diego has filed several patents with B.S. as inventor related to this work. B.S.’s institution, UC San Diego, has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, Intercept Pharmaceuticals, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. T.R. received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore & Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche. T.H.K. received speaker fees from Gilead and did consulting for Falk Pharma, Albireo, MSD and Boeringer Ingelheim – consulting. F.T.’s laboratory has received research funding from Gilead, AstraZeneca, and MSD (funding to the institution). F.T. has received honoraria for consulting or lectures from AstraZeneca, Gilead, AbbVie, BMS, Boehringer, Madrigal, Intercept, Falk, Inventiva, MSD, GSK, Orphalan, Merz, Pfizer, Alnylam, CSL Behring, Novo Nordisk, Sanofi, and Novartis. A.Z., A.J.M.-L. and R.A. have nothing to disclose.

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Burra, P., Zanetto, A., Schnabl, B. et al. Hepatic immune regulation and sex disparities. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00974-5

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