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  • Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease

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Hepatology
Original research
Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease
  1. Angelo Armandi1,2,
  2. Tiziana Sanavia3,
  3. Ramy Younes4,
  4. Gian Paolo Caviglia1,
  5. Chiara Rosso1,
  6. Olivier Govaere5,
  7. Antonio Liguori6,7,8,
  8. Paolo Francione9,
  9. Rocìo Gallego-Duràn10,
  10. Javier Ampuero10,
  11. Grazia Pennisi11,
  12. Rocio Aller12,
  13. Dina Tiniakos5,13,
  14. Alastair Burt5,
  15. Ezio David14,
  16. Fabio Vecchio15,
  17. Marco Maggioni16,
  18. Daniela Cabibi17,
  19. Duncan McLeod18,
  20. Maria Jesus Pareja19,
  21. Marco Y W Zaki5,20,21,
  22. Antonio Grieco22,
  23. Per Stål23,24,
  24. Stergios Kechagias25,
  25. Anna Ludovica Fracanzani9,26,
  26. Luca Valenti26,27,
  27. Luca Miele6,7,8,
  28. Piero Fariselli3,
  29. Mohammed Eslam28,
  30. Salvatore Petta11,
  31. Hannes Hagström23,24,
  32. Jacob George28,
  33. Jörn M Schattenberg2,29,
  34. Manuel Romero-Gómez10,
  35. Quentin Mark Anstee5,30,
  36. Elisabetta Bugianesi1
  1. 1Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy
  2. 2Metabolic Liver Disease Research Program, I. Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
  3. 3Computational Biomedicine Unit, Department of Medical Sciences, University of Turin, Turin, Italy
  4. 4Boehringer Ingelheim International GmbH, Ingelheim, Germany
  5. 5Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  6. 6Internal Medicine and Liver Transplant Unit, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
  7. 7CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
  8. 8Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
  9. 9Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
  10. 10UCM Digestive Diseases and SeLiver Group, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Seville, Spain
  11. 11Sezione di Gastroenterologia, PROMISE, Università di Palermo, Palermo, Italy
  12. 12Hospital Clínico de Valladolid, Valladolid, Spain
  13. 13Department of Pathology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  14. 14Department of Pathology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy
  15. 15Dipartimento Universitario Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Area Anatomia Patologica. Fondazione Policlinico Gemelli IRCCS, Rome, Italy
  16. 16Department of Pathology, Ca' Granda IRCCS Foundation, Milan, Italy
  17. 17Pathology Institute, PROMISE, University of Palermo, Palermo, Italy
  18. 18Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, New South Wales, Australia
  19. 19Pathology Unit, Hospital Universitario de Valme, Seville, Spain
  20. 20Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
  21. 21Centre for Research and Sustainability, Deraya University, New Minia, Minia, Egypt
  22. 22Dipartimento Universitario Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
  23. 23Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
  24. 24Department of Medicine, Huddinge Karolinska Institutet, Stockholm, Sweden
  25. 25Department of Health, Medicine and Caring Sciences, Linköping University, Linkoping, Sweden
  26. 26Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
  27. 27Biological Resource Center Unit and Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
  28. 28Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia
  29. 29Department of Medicine II, Saarland University Medical Center, Homburg, Germany
  30. 30Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  1. Correspondence to Dr Angelo Armandi, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy; angelo.armandi{at}unito.it

Abstract

Objective Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death.

Design We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell’s C-index and its improvement by including ferritin as a covariate.

Results Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65).

Conclusions This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

  • NONALCOHOLIC STEATOHEPATITIS
  • FIBROSIS

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

https://doi.org/10.1136/gutjnl-2023-330815

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Footnotes

    • AA and TS are joint first authors.

    • X @AngeloArmandi, @Dina Tiniakos, @lucavalenti75, @lmiele74, @hanneshagstrom, @mromerogomez

    • AA and TS contributed equally.

    • Correction notice This article has been corrected since it published Online First. An affiliation has been added for author Marco Zaki.

    • Contributors Manuscript concept and design: AA and EB. Writing: AA and TS. Data collection: RY, GPC, CR, OG, AL, PFrancione, RG-D, JA, GP, RA, DT, AB, ED, FV, MM, DC, DM, MJP, MYWZ, AG, PS, SK, ALF, LV, LM, ME, SP, HH, JG, JMS, MR-G and QMA. Statistical analysis: TS and PFariselli. Revision and editing: EB, QMA, MR-G, JMS, JG, HH, SP, LM, LV, ALF, SK, PS and PFariselli. Acceptance of the final version: all authors. EB is responsible for the overall content as guarantor.

    • Funding EB is supported by the Italian Ministry for Education, University and Research (MIUR) under the programme 'Dipartimenti di Eccellenza 2018-2022' Project code D15D18000410001. SP has received funding under PNRR M4C2I1.3 Heal Italia project PE00000019 CUP B73C22001250006, Italian PNRR-MAD-2022-12375656 project, Italian RF-2021-12372399 project and Italian PRIN-2022 2022L273C9 project. ALF is supported by: Ministry of Health grant Ricerca Finalizzata RF-2021-12374481 'Identification of lipid biomarkers to dissect hepatic and cardiovascular complication in NAFLD adult and children patients through a lipidomic approach'. JG is supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206), Project, Ideas and Investigator grants (APP2001692, APP1107178, APP1108422, APP1196492) and a Cancer Institute, NSW grant (2021/ATRG2028).

    • Competing interests LM is supported by Investigator Driven Grants: Gilead, Intercept, Siemens Healthineers. Advisor/Consultancy: Alfa-Sigma, Boehringer-Ingelheim, BMS, Echosens, Galmed, Gilead Sciences, IBSA, Intercept, MEDA, MyGenomics, Merck Sharp & Dohme, Novartis, Pfizer, ProLon, Promethera, Resalis, Rottapharm-Madaus, Siemens Healthineers, Synageva. HH’s institutions have received research funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. He has served as consultant or on advisory boards for Astra Zeneca, Bristol Myers-Squibb, MSD and Novo Nordisk and has been part of hepatic events adjudication committees for Boehringer Ingelheim, KOWA and GW Pharma.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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