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Cirrhosis-associated immune dysfunction

Nature Reviews Gastroenterology & Hepatology volume 19, pages 112–134 (2022)Cite this article

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Abstract

The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.

Key points

  • Systemic inflammation and immune deficiency are the key components of cirrhosis-associated immune dysfunction (CAID) and their intensity varies according to the stage of cirrhosis and the presence of incidental events.

  • The low-grade systemic inflammatory phenotype is present in patients with cirrhosis with no organ failure. It contributes to worsening systemic circulatory dysfunction, precipitating complications and acute decompensation.

  • The high-grade systemic inflammatory phenotype is the pathogenic driver of organ failure in acute-on-chronic liver failure.

  • A crucial component of the high-grade systemic inflammatory phenotype is an intense functional paralysis of immune system cells that critically increases the risk of infections.

  • An abnormal gut–liver axis, causing intestinal dysbiosis, a disrupted intestinal barrier and increased bacterial translocation, has a leading pathogenic role in systemic inflammation.

  • Treatment of CAID should involve strategies to modulate, rather than inhibit, the immune response as the abrogation or stimulation of the inflammatory response could respectively increase the infection risk or worsen immunopathology.

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Fig. 1: Immune cells in the liver.
Fig. 2: Low-grade systemic inflammation in cirrhosis.
Fig. 3: Pathogenesis and consequences of low-grade systemic inflammation in cirrhosis.
Fig. 4: Pathogenic contribution of low-grade and high-grade systemic inflammation to hepatorenal syndrome.
Fig. 5: Cirrhosis-associated immune dysfunction in ACLF.
Fig. 6: Dynamics of cirrhosis-associated immune dysfunction.
Fig. 7: Disruption of the gut–liver axis in cirrhosis: contribution to cirrhosis-associated immune dysfunction.

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Acknowledgements

The authors are supported by grants from the Spanish Ministry of Science and Innovation (SAF 2017-86343-R and Instituto de Salud Carlos III PI20/01302). CIBEREHD is funded by the Instituto de Salud Carlos III with grants co-financed by the European Development Regional Fund “A way to achieve Europe” (EDRF).

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

    Agustín Albillos & Rosa Martin-Mateos

  2. Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    Agustín Albillos, Rosa Martin-Mateos & Melchor Álvarez-Mon

  3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain

    Agustín Albillos, Rosa Martin-Mateos & Melchor Álvarez-Mon

  4. Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium

    Schalk Van der Merwe

  5. Department of Gastroenterology and Hepatology, University Hospital Gasthuisberg, Leuven, Belgium

    Schalk Van der Merwe

  6. Department of Visceral Surgery and Medicine, University Inselspital, Bern, Switzerland

    Reiner Wiest

  7. Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK

    Rajiv Jalan

  8. European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain

    Rajiv Jalan

  9. Department of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain

    Melchor Álvarez-Mon

Authors
  1. Agustín Albillos
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  2. Rosa Martin-Mateos
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  3. Schalk Van der Merwe
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  4. Reiner Wiest
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  5. Rajiv Jalan
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Contributions

A.A. researched data for the article, made a substantial contribution to the discussion of content, wrote the article, and reviewed/edited the manuscript before submission. R.M.-M. made a substantial contribution to the discussion of content, wrote the article, and reviewed/edited the manuscript before submission. S.V.d.M., R.W. and R.J. researched data for the article, made a substantial contributions to the discussion of content, and wrote the article. M.Á.-M. researched data for the article and made a substantial contribution to the discussion of content.

Corresponding author

Correspondence to Agustín Albillos.

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Competing interests

R.J. has research collaborations with Yaqrit and Takeda. R.J. is the inventor of L-ornithine phenylacetate, which has been patented by University College London and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Ltd, a spin out company from University College London, Cyberliver Ltd. and Hepyx Ltd. The other authors declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Jasmohan Bajaj, Tony Bruns and Frank Tacke for their contribution to the peer review of this work.

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Glossary

Cirrhosis-associated immune dysfunction

(CAID). Dysfunctional immune response associated with cirrhosis and characterized by systemic inflammation and immune paralysis.

Systemic inflammation

Increased expression of surface activation antigens in circulating immune cells and production of pro-inflammatory cytokines.

Acute-on-chronic liver failure

(ACLF). Acute decompensation of cirrhosis associated with organ failure and high short-term mortality.

Low-grade systemic inflammatory phenotype

Increased immune activation and mild to moderate compromise of the immune effector response in patients with compensated cirrhosis or acute decompensation with no organ failure.

High-grade systemic inflammatory phenotype

Extreme activation with a massive release of cytokines along with functional impairment of circulating immune system cells in patients with acute-on-chronic liver failure.

Gut–liver axis

Bidirectional functional connection between the liver and the intestine, particularly its microbiota and immune system.

Pathogen-associated molecular patterns

(PAMPs). Sets of microbial molecular patterns that can be recognized by specific receptors of immune system cells.

Damage-associated molecular patterns

(DAMPs). Intracellular molecules released by injured or dying cells that can be recognized by specific receptors of immune system cells.

Gut-associated lymphoid tissue

(GALT). Lymphoid tissue lining the intestine and composed of Peyer’s patches, intestinal lymphoid follicles, intraepithelial lymphocytes and mesenteric lymph nodes.

Immunopathology

Immune-mediated tissue damage due to excessive immune activation.

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Albillos, A., Martin-Mateos, R., Van der Merwe, S. et al. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 19, 112–134 (2022). https://doi.org/10.1038/s41575-021-00520-7

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