Iranian Journal of Pathology

Association between Serum Ferritin level and Liver Fibrosis Severity in Non-Alcoholic Fatty Liver Disease Patients

Articles in Press

Document Type : Original Research

Authors

Bahram Memar 1
Alireza Khodadadi 2
Pegah Bahrami 3
Ali Beheshti Namdar 2
Hassan Mehrad-Majd 4
Mitra Ahadi 2

1 Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

4 Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

https://doi.org/10.30699/ijp.2025.2065639.3487
Abstract
Background & Objective: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by hepatic fat accumulation, which can progress to fibrosis and cirrhosis. Serum ferritin has been proposed as a biomarker for liver disease, but its relationship with fibrosis severity in NAFLD remains unclear. This study explored the relationship between serum ferritin levels and liver fibrosis severity in NAFLD patients.
Methods: In this cross-sectional study, 204 NAFLD patients were enrolled, including 139 with mild fibrosis and 65 with severe fibrosis. Baseline and demographic characteristics were compared between groups. Serum ferritin and other biochemical parameters were measured. Logistic regression analyses assessed the predictive value of serum ferritin levels for liver fibrosis severity, and a receiver operating characteristic (ROC) curve determined the optimal ferritin cutoff for identifying sever fibrosis.
Results: Patients with severe fibrosis had significantly higher serum ferritin levels than those with mild fibrosis (197.70 ± 79.40 vs 95.70 ± 73.20, P<0.001). Logistic regression analysis confirmed a significant association between ferritin levels and fibrosis severity (OR = 1.015, 95% CI = 1.009–1.02, P<0.001). ROC analysis showed that ferritin distinguished severe from mild fibrosis with 80% sensitivity and 80% specificity at a cutoff of 129 ng/ml (AUC = 0.86).
Conclusion: Elevated serum ferritin levels are associated with more severe liver fibrosis in NAFLD patients, supporting ferritin’s potential as a non-invasive biomarker for fibrosis severity. Further studies are needed to validate these findings and explore ferritin’s diagnostic and prognostic utility in diverse populations.

Keywords

NAFLD
liver fibrosis
Serum Ferritin
Fibroscan
non-invasive diagnostic biomarkers

Subjects

1.      Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology. 2018;155(2):443-57 e17.      [DOI:10.1053/j.gastro.2018.04.034] [PMID]
2.      Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-57.           [DOI:10.1002/hep.29367] [PMID]
3.      Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int. 2020;14(6):889-919. [DOI:10.1007/s12072-020-10094-2] [PMID]
4.      Stefanska A, Bergmann K, Suwala S, Mankowska-Cyl A, Kozinski M, Junik R, et al. Performance Evaluation of a Novel Non-Invasive Test for the Detection of Advanced Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Metabolites. 2024;14(1):52. [DOI:10.3390/metabo14010052] [PMID] [PMCID]
5.      Robinson KE, Shah VH. Pathogenesis and pathways: nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol. 2020;5:49. [DOI:10.21037/tgh.2019.12.05] [PMID] [PMCID]
6.      Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology,
7.      clinical management and effects of weight loss. BMC Endocr Disord. 2022;22(1):63. [DOI:10.1186/s12902-022-00980-1] [PMID] [PMCID]
8.      Valenti L, Dongiovanni P, Fracanzani AL, Santorelli G, Fatta E, Bertelli C, et al. Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis. Dig Liver Dis. 2003;35(3):172-8. [DOI:10.1016/S1590-8658(03)00025-2] [PMID]
9.      Barros RK, Cotrim HP, Daltro CH, Oliveira YA. Hyperferritinemia in patients with nonalcoholic fatty liver disease. Rev Assoc Med Bras (1992). 2017;63(3):284-9. [DOI:10.1590/1806-9282.63.03.284] [PMID]
10.    Mannisto VT, Hakkarainen K, Jula A, Lundqvist A, Vihervaara T, Erlund I, et al. Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population. Scand J Gastroenterol. 2024;59(5):592-9. [DOI:10.1080/00365521.2024.2314707] [PMID]
11.    Yang N, Lu Y, Cao L, Lu M. The association between non-alcoholic fatty liver disease and serum ferritin levels in American adults. J Clin Lab Anal. 2022;36(2):e24225. [DOI:10.1002/jcla.24225] [PMID] [PMCID]
12.    Du SX, Lu LL, Geng N, Victor DW, Chen LZ, Wang C, et al. Association of serum ferritin with non-alcoholic fatty liver disease: a meta-analysis. Lipids Health Dis. 2017;16(1):228. [DOI:10.1186/s12944-017-0613-4] [PMID] [PMCID]
13.    Suresh D, Li A, Miller MJ, Wijarnpreecha K, Chen VL. Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease. Liver Int. 2024;44(2):389-98. [DOI:10.1111/liv.15787] [PMID] [PMCID]
14.    Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(1):77-85. [DOI:10.1002/hep.24706] [PMID] [PMCID]
15.    Singh SK, Singh TG, Reema N, Ajaykumar R, Kriibve SL, Laishram S. TO STUDY IRON PROFILE IN CHRONIC LIVER DISEASE IN A TERTIARY CARE HOSPITAL IN MANIPUR. Journal of Population Therapeutics and Clinical Pharmacology. 2023;30(19): 111-20.
16.    Armandi A, Sanavia T, Younes R, Caviglia GP, Rosso C, Govaere O, et al. Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease. Gut. 2024;73(5):825-34. [DOI:10.1136/gutjnl-2023-330815] [PMID]
17.    Manousou P, Kalambokis G, Grillo F, Watkins J, Xirouchakis E, Pleguezuelo M, et al. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int. 2011;31(5):730-9.          [DOI:10.1111/j.1478-3231.2011.02488.x] [PMID]
18.    Buzzetti E, Petta S, Manuguerra R, Luong TV, Cabibi D, Corradini E, et al. Evaluating the association of serum ferritin and hepatic iron with disease severity in non-alcoholic fatty liver disease. Liver Int. 2019;39(7):1325-34. [DOI:10.1111/liv.14096] [PMID]
19.    Yoneda M, Thomas E, Sumida Y, Imajo K, Eguchi Y, Hyogo H, et al. Clinical usage of serum ferritin to assess liver fibrosis in patients with non-alcoholic fatty liver disease: Proceed with caution. Hepatol Res. 2014;44(14):E499-502. [DOI:10.1111/hepr.12327]
20.    Ando Y, Jou JH. Nonalcoholic Fatty Liver Disease and Recent Guideline Updates. Clin Liver Dis (Hoboken). 2021;17(1):23-8. [DOI:10.1002/cld.1045] [PMID] [PMCID]
21.    Wong VW, Chan WK, Chitturi S, Chawla Y, Dan YY, Duseja A, et al. Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 1: Definition, risk factors and assessment. J Gastroenterol Hepatol. 2018;33(1):70-85. [DOI:10.1111/jgh.13857] [PMID]
22.    Seyedian SS, Hajiani E, Hashemi SJ, Masjedizadeh A, Shayesteh AA, Alavinejad P, et al. Relationship between serum ferritin level and transient elastography findings among patients with nonalcoholic fatty liver disease. J Family Med Prim Care. 2017;6(4):750-4. [DOI:10.4103/jfmpc.jfmpc_158_17] [PMID] [PMCID]
23.    Valenti L, Corradini E, Adams LA, Aigner E, Alqahtani S, Arrese M, et al. Consensus Statement on the definition and classification of metabolic hyperferritinaemia. Nat Rev Endocrinol. 2023;19(5): 299-310. [DOI:10.1038/s41574-023-00807-6] [PMID] [PMCID]
24.    Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol. 2019;25(5):521-38. [DOI:10.3748/wjg.v25.i5.521] [PMID] [PMCID]
25.    Liang S, Kisseleva T, Brenner DA. The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol. 2016;7:17. [DOI:10.3389/fphys.2016.00017] [PMID] [PMCID]
26.    Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells. 2019;8(11):1419. [DOI:10.3390/cells8111419] [PMID] [PMCID]
27.    Orino K, Lehman L, Tsuji Y, Ayaki H, Torti SV, Torti FM. Ferritin and the response to oxidative stress. Biochem J. 2001;357(Pt 1):241-7.      [DOI:10.1042/bj3570241] [PMID] [PMCID]
28.    Jia F, Hu X, Kimura T, Tanaka N. Impact of Dietary Fat on the Progression of Liver Fibrosis: Lessons from Animal and Cell Studies. Int J Mol Sci. 2021;22(19). [DOI:10.3390/ijms221910303] [PMID] [PMCID]
29.    Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants [Internet]. 2023; 12(9). [DOI:10.3390/antiox12091653] [PMID] [PMCID]
30.    Angulo P, George J, Day CP, Vanni E, Russell L, De la Cruz AC, et al. Serum ferritin levels lack diagnostic accuracy for liver fibrosis in patients with nonalcoholic fatty liver disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014; 12(7):1163-9 e1.      [DOI:10.1016/j.cgh.2013.11.035] [PMID] [PMCID]
31.    Jaruvongvanich V, Wijarnpreecha K, Ungprasert P. The utility of NAFLD fibrosis score for prediction of mortality among patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of cohort study. Clin Res Hepatol Gastroenterol. 2017; 41(6):629-34. [DOI:10.1016/j.clinre.2017.03.010] [PMID]
32.    Ishiba H, Sumida Y, Tanaka S, Yoneda M, Hyogo H, Ono M, et al. The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study. J Gastroenterol. 2018; 53(11):1216-24. [DOI:10.1007/s00535-018-1474-y] [PMID]
33.    Vali Y, Lee J, Boursier J, Spijker R, Loffler J, Verheij J, et al. Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis. J Hepatol. 2020;73(2):252-62. [DOI:10.1016/j.jhep.2020.03.036] [PMID]
Iranian Journal of Pathology

Articles in Press, Accepted Manuscript
Available Online from 26 December 2025

  • Receive Date 12 July 2025
  • Revise Date 18 November 2025
  • Accept Date 11 October 2025

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