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Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure

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A Correction to this article was published on 12 June 2023

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Abstract

Aim

Heavy alcohol consumption is the most common etiology of acute-on-chronic liver failure (ACLF) in Japan. In some patients, ACLF is associated with a fatal outcome in less than 6 months. We evaluated the prognosis of patients with alcohol-related ACLF in our cohort and explored the prognostic factors.

Methods

Forty-six patients with alcoholic liver cirrhosis who fulfilled the Japanese diagnostic criteria for ACLF, including those classified as extended and/or probable, were enrolled in this study. Serum concentrations of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were measured. We assessed prognosis and identified factors associated with survival.

Results

During the median 33-day observation period, 19 patients died, and 3 patients underwent living donor liver transplantation. Cumulative survival rates of patients treated without liver transplantation were 69, 48, 41, and 36% at 1, 3, 6, and 12 months, respectively. Eighteen of the 19 deceased patients died within 6 months after ACLF diagnosis. Serum concentrations of inflammatory cytokines were significantly elevated, and patients who underwent liver transplantation or who died within 6 months after admission had significantly higher serum IL-6 levels than the survival group. Multivariate analysis identified IL-6 > 23.3 pg/mL at admission and model for end-stage liver disease (MELD) score ≥ 25 on day 4 of admission as significant independent factors for mortality within 6 months.

Conclusion

Serum IL-6 level and Day-4 MELD were prognostic factors for alcohol-related ACLF. Early liver transplantation is a potential treatment option for patients whose prognosis is expected to be poor.

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Data availability

Supporting data for this study are available from the corresponding authors and the first authors upon reasonable request.

Change history

Abbreviations

ACLF:

Acute-on-chronic liver failure

DIC:

Disseminated intravascular coagulation

IL:

Interleukin

LC:

Liver cirrhosis

MELD:

Model for end-stage liver disease

PT-INR:

Prothrombin-INR

ROC:

Receiver operating characteristic

References

  1. Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Ginès P, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014;61:1038–1047

    Article  PubMed  Google Scholar 

  2. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144(7):1426–1437

    Article  PubMed  Google Scholar 

  3. Sarin SK, Kedarisetty CK, Abbas Z, Amarapurkar D, Bihari C, Chan AC, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL) 2014. Hepatol Int 2014;8:453–71

    Article  PubMed  Google Scholar 

  4. Hernaez R, Solà E, Moreau R, Ginès P. Acute-on-chronic liver failure: an update. Gut BMJ 2017;66:541–553

    Article  CAS  Google Scholar 

  5. Zhang Q, Li Y, Han T, Nie CY, Cai JJ, Liu H, et al. Comparison of current diagnostic criteria for acute-on-chronic liver failure. PLoS One 2015;10(3):e0122158

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nakayama N, Uemura H, Uchida Y, Tomiya T, Ido A, Inoue K, et al. A multicenter pilot survey to clarify the clinical features of patients with acute-on-chronic liver failure in Japan. Hepatol Res 2018;48:303–312

    Article  PubMed  Google Scholar 

  7. Khanam A, Kottilil S. Acute-on-chronic liver failure: pathophysiological mechanisms and management. Front Med (Lausanne) 2021;8:752875

    Article  PubMed  Google Scholar 

  8. Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, et al. Early liver transplantation for severe alcoholic hepatitis. New England J Med 2011;365:1790–1800. https://doi.org/10.1056/NEJMoa1105703

    Article  CAS  Google Scholar 

  9. Marroni CA, de Fleck Medeiros A, Fernandes SA, Galant LH, Mucenic M, de Mattos Meine MH, et al. Liver transplantation and alcoholic liver disease: history, controversies, and considerations. World J Gastroenterol 2018;24:2785–2805

    Article  PubMed  PubMed Central  Google Scholar 

  10. Im GY, Cameron AM, Lucey MR. Liver transplantation for alcoholic hepatitis. J Hepatol 2019;70:328–334

    Article  PubMed  Google Scholar 

  11. Mochida S, Nakayama N, Ido A, Inoue K, Genda T, Takikawa Y, et al. Proposed diagnostic criteria for acute-on-chronic liver failure in Japan. Hepatol Res 2018;48:219–224

    Article  CAS  PubMed  Google Scholar 

  12. Mochida S, Nakayama N, Terai S, Yoshiji H, Shimizu M, Ido A, et al. Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan. Hepatol Res 2022;52:417–421

    Article  CAS  PubMed  Google Scholar 

  13. Cl J, Stauber RE, Coenraad MJ, Moreau R, Jalan R, Pavesi M, et al. Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure. Hepatology 2016;64(4):1249–1264

    Article  Google Scholar 

  14. Zhou C, Zhang N, He TT, Wang Y, Wang LF, Sun YQ, et al. High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure. World J Gastroenterol 2020;26:4479–4488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Padia G, Mahajan B, Kumar A, Sonika U, Dahale AS, Sachdeva S, et al. Cystatin C and interleukin-6 for prognosticating patients with acute decompensation of cirrhosis. JGH Open 2021;5:459–464

    Article  PubMed  PubMed Central  Google Scholar 

  16. Agbim U, Sharma A, Maliakkal B, Karri S, Yazawa M, Goldkamp W, et al. Outcomes of liver transplant recipients with acute-on-chronic liver failure based on EASL-CLIF consortium definition: a single-center study. Transplant Direct 2020;6(4):e544

    Article  PubMed  PubMed Central  Google Scholar 

  17. Marot A, Dubois M, Trépo E, Moreno C, Deltenre P. Liver transplantation for alcoholic hepatitis: a systematic review with meta-analysis. PLoS One 2018;13(1):e0190823

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360:2758–2769

    Article  CAS  PubMed  Google Scholar 

  19. Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011;365:1790–1800

    Article  CAS  PubMed  Google Scholar 

  20. Cai YJ, Dong JJ, Dong JZ, Chen Y, Lin Z, Song M, et al. A nomogram for predicting prognostic value of inflammatory response biomarkers in decompensated cirrhotic patients without acute-on-chronic liver failure. Aliment Pharmacol Ther 2017;45:1413–1426

    Article  PubMed  Google Scholar 

  21. Wu W, Yan H, Zhao H, Sun W, Yang Q, Sheng J, et al. Characteristics of systemic inflammation in hepatitis B-precipitated ACLF: differentiate it from No-ACLF. Liver Int 2018;38:248–257

    Article  CAS  PubMed  Google Scholar 

  22. Jalan R, Stadlbauer V, Sen S, Cheshire L, Chang YM, Mookerjee RP. Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study. Crit Care 2012;16:R227

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C, et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015;62:243–252

    Article  PubMed  Google Scholar 

  24. Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015;63:1272–1284

    Article  CAS  PubMed  Google Scholar 

  25. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–454

    Article  CAS  PubMed  Google Scholar 

  26. Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol 2016;64:1403–1415

    Article  CAS  PubMed  Google Scholar 

  27. Xiang X, Feng D, Hwang S, Ren T, Wang X, Trojnar E, et al. Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice. J Hepatol 2020;72:736–745

    Article  CAS  PubMed  Google Scholar 

  28. Mayr U, Lukas M, Elnegouly M, Vogt C, Bauer U, Ulrich J, et al. Ascitic interleukin 6 is associated with poor outcome and spontaneous bacterial peritonitis: a validation in critically ill patients with decompensated cirrhosis. J Clin Med 2020;9:1–15

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Emi Nishio for clerical assistance and Yoko Hayashi for her expert technical help. Part of this work was carried out at the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University. No external funding was received for this study.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan

    Serami Murakami, Michio Imamura, Takuro Uchida, Yosuke Suehiro, Maiko Namba, Yasutoshi Fujii, Shinsuke Uchikawa, Yuji Teraoka, Hatsue Fujino, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Wataru Okamoto, Masami Yamauchi, Tomokazu Kawaoka, Daiki Miki, Nelson C. Hayes, Masataka Tsuge, Hiroshi Aikata & Shiro Oka

  2. Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan

    Wataru Okamoto

  3. Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan

    Masataka Tsuge

  4. Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Masahiro Ohira & Hideki Ohdan

  5. Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan

    Masahiro Ohira

Authors
  1. Serami Murakami
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  2. Michio Imamura
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Contributions

Concept and design: MI. Data acquisition and analysis: SM, TU and YS. Project administration: MN, YF, YU, YT, HF, TN, AO, EM, WO, MY, TK, DM, MT, HA and SO. Writing and revision of manuscript: SM, TU, CNH and MI. Supervision: TU, MI, MO, HO, and SO.

Corresponding author

Correspondence to Michio Imamura.

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Conflict of interest

Michio Imamura has received research funding from AbbVie. Hiroshi Aikata has received honoraria from Eisai Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Serami Murakami, Takuro Uchida, Yosuke Suehiro, Maiko Namba, Yasutoshi Fujii, Shinsuke Uchikawa, Yuji Teraoka, Hatsue Fujino, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Wataru Okamoto, Masami Yamauchi, Tomokazu Kawaoka, Daiki Miki, Nelson C. Hayes, Masataka Tsuge, Masahiro Ohira, Hideki Ohdan and Shiro Oka declares that have no conflict of interest.

Informed consent in studies with human subjects

Informed consent was obtained from all patients for being included in the study. The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution (Committee of Hiroshima University Hospital, Approval No. E-2405) and conforms to the provisions of the Declaration of Helsinki.

Animal studies

This article does not contain any studies with human or animal subjects.

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Murakami, S., Imamura, M., Uchida, T. et al. Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure. Hepatol Int 17, 1225–1232 (2023). https://doi.org/10.1007/s12072-023-10532-x

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