Liver Iron Content in Individuals with β-Thalassemia Trait and Hyperferritinemia: Role of Metabolic Alterations, HFE Genotypes, and Cirrhosis. 

Giulia Risca1,2, Raffaella Mariani3,4, Mara Botti3,4, Sara Pelucchi2, Stefania Galimberti1,5 and Alberto Piperno4,6.


1 Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, University of Milano-Bicocca, Monza, Italy.
2 Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
3 Rare Disease Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
4 European Reference Network for Rare Hematological Diseases, EuroBloodNet.
5 Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy.
6 Centro Ricerca Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.







Correspondence to: Prof. Alberto Piperno. Centro Ricerca Tettamanti - Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. Tel: +39 339 633 2915. E-mail address: alberto.piperno@unimib.it 
 
Published: July 01, 2026
Received: March 02, 2026
Accepted: June 16, 2026
Mediterr J Hematol Infect Dis 2026, 18(1): e2026051 DOI 10.4084/MJHID.2026.051

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background. An increased serum ferritin is a frequent finding in adults with β-thalassemia trait (BTT). However, whether such an increase is associated with a proportional increase in iron stores is unclear.
Objectives. We aimed to evaluate liver iron stores in a consecutive cohort of BTT with hyperferritinemia who underwent magnetic resonance imaging (LICMRI) for clinical purposes.
Methods. Sixty-six BTT subjects with hyperferritinemia were studied. Clinical, biochemical, and genetic evaluations were done to assess the cause of hyperferritinemia. LICMRI was classified as: grade-1= <3 mg/g (normal/mild); grade-2= >3<7 mg/g (moderate); grade-3= >7 (severe).
Results. 80.3% showed normal/mild (n=29, 43.9%) or moderate LICMRI (n=24, 36.4%), while 19.7% (n=13) showed values >7 mg/g. The latter had lower haemoglobin concentration (p=0.004) and higher transferrin saturation and ferritin compared to subjects with lower LICMRI (p<0.001), while steatotic liver disease was more frequent in subjects with lower LICMRI grades (p=0.012). Liver cirrhosis was significantly more frequent in subjects with moderate/severe than in those with lower LICMRI grades (p=0.001 and p=0.025, respectively). We found a higher frequency of HFE and non-HFE iron-related genotypes (risk genotypes) in LICMRI grades 2-3 compared to none in LICMRI grade 1 (p=0.003 and p<0.0001, respectively). A regression analysis identified risk genotypes, liver cirrhosis, and BMI as significantly associated with LICMRI.
Conclusions. Hyperferritinemia is common in BTT subjects, but major iron overload is limited to a minority of cases. They present associated genetic and acquired causes of iron accumulation and increased risk of liver damage.

Introduction

About 1.5% of the world's population is a carrier of β-thalassemia (BTT). While the highest prevalence is in the traditional malaria-endemic regions, BTT is now encountered worldwide due to population migrations from high-prevalence areas.[1] Subjects with BTT show mild ineffective erythropoiesis, erythroid hyperplasia, and hepcidin suppression.[2-4] Some authors suggest that even slight hepcidin suppression may increase iron absorption, possibly leading to iron overload.[4-5] Indeed, serum ferritin levels were significantly higher in adults with BTT than in controls.[6-8] However, it is unclear whether this increase is proportional to liver iron stores, as none of these studies measured liver iron concentration (LIC). Recently, Busti et al.[9] studied 30 subjects with BTT and liver iron overload as assessed by MRI or liver biopsy. They found variable serum ferritin levels (from 441 to 3650 μg/L), transferrin saturation (TSAT) (from 28 to 100%), and amount of iron overload, from mild to severe. Other studies evaluated the role of HFE variants (p.C282Y and p.H63D) on serum ferritin levels in BTT, yielding conflicting results, mainly due to the small sample sizes and the lack of liver iron measurement.[10-14] By contrast, it was shown that the presence of BTT may contribute to the severity of iron overload in patients with HFE-hemochromatosis homozygous for the p.C282Y mutation[5] and the same was suggested for those carrying the p.H63D homozygous genotype.[10] However, although hyperferritinemia is quite common in BTT patients, there are still unclear questions: i. how many patients with BTT and hyperferritinemia have liver iron overload amounts at risk for liver damage ii. What role do concomitant factors (e.g., alcohol, metabolic alterations, HFE variants) play in favouring hyperferritinemia and/or iron overload in BTT. To achieve these objectives, we studied 66 consecutive subjects with BTT and hyperferritinemia who underwent liver iron quantification by magnetic resonance imaging (LICMRI) for clinical purposes.

Materials and Methods

From a large series of 684 subjects with hyperferritinemia (serum ferritin > 350 μg/L in men and > 200 μg/L in women) who underwent LICMRI quantification from January 2008 to October 2024,[15] we selected the 66 patients with BTT. All MRIs were performed at diagnosis, prior to iron depletion therapy, together with other investigations usually needed for the characterisation of hyperferritinemia.[16,17] Accurate clinical and biochemical evaluations were performed before the MRI. Age at time of MRI, sex, alcohol intake, body mass index (BMI), presence of arterial hypertension and diabetes, blood count, iron parameters (TSAT and ferritin), liver and metabolic indices (triglycerides, HDL cholesterol, glycemia) were collected. Subjects with a chronic history of alcohol consumption ≥30 g/day in men and ≥20 g/day in women were classified as alcohol drinkers. BMI cut-off points for overweight and obesity were >26 kg/m2 in men and >25 kg/m2 in women, and >30 kg/m2, respectively, and those for metabolic indices were as reported elsewhere.[18] The presence of liver steatosis was assessed by abdominal ultrasound by an expert internal medicine sonographer. Subjects were further classified according to the EASL-EASD-EASO guideline for Metabolically active steatotic liver disease (MASLD).[18] In subjects with steatotic liver disease (SLD), chronic hepatitis, high alcohol intake, and marked iron overload, the assessment of liver damage (e.g., severe fibrosis/cirrhosis) was done by liver function tests, blood-based score (FIB-4),[18] abdominal ultrasound, at diagnosis and during follow-up, and fibroelastography and liver biopsy when needed. LICMRI was assessed as previously reported[19] and was graded according to the severity of iron overload: <3 mg/g (grade 1), >3 <7 mg/g (grade 2), and >7 mg/g (grade 3). Grade 1 included patients with normal or slightly increased LIC not deserving therapeutic intervention, grade 2 those with mild-moderate iron overload in which tailored iron depletion therapy could be considered but is not mandatory, and grade 3 those with moderate-severe iron overload worthy of therapeutic intervention.[20,21] Genotyping of iron-related genes was performed according to the current hemochromatosis guidelines.[22] According to the recent hemochromatosis classification recommendation,[23] we considered p.Cys282Tyr homozygosity, compound heterozygosity for p.Cys282Tyr and another pathogenic HFE variant, and digenic genotypes as genotypes able to favour iron overload (henceforth defined as risk genotypes). In addition, we also included in the group of risk genotypes, the p.His63Asp homozygous and p.His63Asp/p.Cys282Tyr genotypes based on the evidence that they can lead to hepatic iron loading in the animal model,[24] and can act as modifiers of iron phenotype in humans when coexisting with other conditions favoring iron overload.[5,9-10,23] The manuscript is in accordance with ethical standards stated in the 1964 Declaration of Helsinki and its later amendments. Informed written consent for molecular testing and data recording in the local database was obtained from all participants, and the collection was conducted in accordance with Institutional rules.

Statistical methods. Due to the skewed nature of continuous variables, median and 1st-3rd quartiles (Q1-Q3) were calculated for descriptive purposes, while qualitative variables were reported as absolute and relative frequencies. The Kruskal-Wallis rank-sum test and the Fisher’s exact test were performed to compare LICMRI grades, as appropriate, and were adjusted for multiple comparisons using the Benjamini-Hochberg method. A linear regression model was performed to evaluate the relationship between LICMRI and risk genotypes, alcohol intake, BMI, SLD, and liver cirrhosis. The effect of each factor was first evaluated alone in univariate models and then combined in a multivariable model to consider their additive effect. All tests were two-sided with a significance level of 0.05. All analyses were performed using R (Version 4.4.3, www.r-project.org).

Results

Table 1 shows clinical and biochemical data for subjects according to LICMRI grade. The majority showed normal/mild (n=29, 43.9%) or moderate LICMRI (n=24, 36.4%), and 13 (19.7%) showed LICMRI above 7 mg/g. There was a marked prevalence of men in all the classes. There were two patients with HCV-related chronic hepatitis, one with associated metabolic syndrome, and MASLD showing mild iron accumulation (grade 1), and the second (grade 3) was a heavy alcohol drinker. They both had cirrhosis. A single patient had a history of about twenty transfusions during hospitalisation for multiple trauma. Subjects with higher LICMRI were slightly but not significantly older (p=0.373), had lower haemoglobin concentration (p=0.004), and higher TSAT and ferritin compared to subjects with lower LICMRI (p<0.001). Figure 1 shows the distribution of TSAT and serum ferritin according to LICMRI: 84.6% of BTT subjects with grade 3 LICMRI had TSAT >60%, compared to 25% and 6.9% of those with grade 2 and 1, respectively; 84.6% of patients with grade 3 LICMRI had ferritin >1000 μg/L compared to 45.8% and 31.0% in those with grade 2 and 1, respectively. BMI was significantly higher in subjects with lower LICMRI grades than in those with grade 3 (p=0.002). In detail, 20/29 (69.0%) subjects with LICMRI grade 1 were overweight (14/29, 48.3%) or obese (6/29, 20.7%) compared to 12/24 (50%) and 2/24 (8.3%) of those with grade 2, and 2/13 (15.4%) and 0/13 of those with LICMRI grade 3, respectively (p=0.005). Accordingly, SLD was more frequent in the lower LICMRI classes (p=0.012). Supplementary Table 1 reports the different categories of SLD according to LICMRI, showing a higher frequency of MASLD/MetALD in the lower LICMRI classes (p=0.019). By contrast, liver cirrhosis was significantly more frequent in subjects with grade 3 than in those with grade 1 and 2 (p=0.001 and p=0.025, respectively). Of the four patients with liver cirrhosis in the lower classes of LICMRI, three were heavy alcohol drinkers, one had HCV-chronic hepatitis, and all presented with more than two metabolic alterations.
Table 1 Table 1. Data of subjects with β-thalassemia trait according to LICMRI grades. 

Figure 1 Figure 1. Transferrin saturation and serum ferritin. Box and whiskers plot of a) transferrin saturation (%) and b) serum ferritin (μg/L) according to LICMRI grades (●=Females, ●=Males). The median is represented by a horizontal line and means are indicated by black triangles (▲). LICMRI: Magnetic Resonance Imaging for Liver Iron Concentration.
Results of genetic testing according to LICMRI grading are reported in Table 2, showing a higher frequency of genotypes at risk in LICMRI grade 2 and 3 compared to LICMRI grade 1 (p=0.003 and p<0.0001, respectively). Table 3 shows clinical and genetic details of the 13 subjects with major iron overload. A regression analysis identified risk genotypes, liver cirrhosis, and BMI as significantly associated with LICMRI. Table 4 reports the coefficients of the univariate and multivariable models. The presence of risk genotypes or liver cirrhosis was associated with an increase in LICMRI of 5.9 mg/g (p<0.001) and 5.3 mg/g (p=0.002), respectively. Conversely, for each additional kg/m² in BMI, LICMRI significantly decreased by 0.45 mg/g (p=0.021).
Table 2 Table 2. HFE and non-HFE in subjects with β-thalassemia trait according to LICMRI grades.

Table 3Table 3. Clinical and genetic details of the 13 subjects with β-thalassemia trait with LICMRI >7 mg/g.
Table 4 Table 4. Results of the univariate and multivariable linear regression models on LICMRI, respectively.


Discussion

In the present study, we showed that: i. most of the 66 subjects with BTT and hyperferritinemia were males (89.4%); ii. 44% of BTT with hyperferritinemia had normal or slightly increased LICMRI, another 36% had moderate liver iron overload, while only 20% had LIC above the threshold generally considered at risk for liver damage (7 mg/g); iii. The distribution of overweight/obesity, fatty liver, HFE, and non-HFE genotypes favouring iron overload (risk genotypes), and liver cirrhosis significantly differed among the three classes of LICMRI. The higher prevalence of males is consistent with epidemiological studies showing a high prevalence of hyperferritinemia in men.[25] However, determining the risk of iron-related complications in patients with hyperferritinemia based on serum ferritin levels alone is inadequate, as serum ferritin is an unreliable index of liver iron overload.[16,26,27] In fact, while serum ferritin threshold (> 1000 μg/L) has been established in HFE-hemochromatosis to define such risk,[28] this is a major challenge in other patients with hyperferritinemia, as serum ferritin often overestimates the true amount of LIC.[16,26,27] Accordingly, in this series, serum ferritin levels did not differ between LICMRI grades 1 and 2, and many patients had levels above 1000 μg/L, even in lower LICMRI grades (Figure 1). Indeed, only a minority of subjects showed LICMRI above 7 mg/g. This value can be considered a reasonable threshold to distinguish patients at risk of iron-related liver injury who merit iron removal from those who can be followed up to monitor biochemical and clinical trends.[20,21,29] Overweight or obesity and SLD were more frequent in the lower class of LICMRI. This finding confirms that hyperferritinemia associated with metabolic alterations often overestimates the true amount of liver iron stores, confirming that they both can lead to disproportionate serum ferritin levels. By contrast, liver cirrhosis and risk genotypes were more frequent in the most severe class of LICMRI. Other factors, such as chronic viral hepatitis, high alcohol intake, and a history of multiple transfusions, might have favoured the development of major iron overload and/or the progression to liver cirrhosis in individual patients. This highlights the need to carefully evaluate hyperferritinemic subjects at the clinical, biochemical, and instrumental levels to ensure adequate clinical monitoring and appropriate therapies.
The role of HFE variants in causing liver iron overload in BTT is controversial, with some suggesting an effect of even single variants in the heterozygous state.[10-14] We have shown that the frequency of heterozygous HFE variants did not differ from that expected in the general population.[30] By contrast, eight out of 13 subjects (61.5%) with severe LICMRI (Table 2 and 3) carried homozygous p.H63D or p.C282Y genotypes, and compound or digenic genotypes (risk genotypes). These results require some further consideration. While it was previously shown that coexistence of BTT can aggravate the iron overload phenotype in subjects homozygous for the p.C282Y mutation,[5] this remains debated for p.H63D homozygosity, which is generally considered a very poor penetrant genotype. However, our findings, together with previous reports,[9,10] support the hypothesis that BTT is an important modifier of p.H63D homozygous penetrance. In the remaining five subjects with high LICMRI, high alcohol intake, chronic hepatitis, multiple transfusions, and liver cirrhosis were variably present, suggesting they may contribute to the development of iron overload (Table 3).[31-35] Multivariable regression analysis showed that overweight, risk genotypes and cirrhosis variably influenced liver iron content as assessed by MRI (Table 4). While we can assume that HFE and non-HFE iron-related risk genotypes were causally involved in the development of iron overload, we cannot define the cause-and-effect relationship between iron overload and liver cirrhosis, as iron overload can favour liver fibrogenesis and liver cirrhosis can increase iron absorption.[29,34] Accordingly, Busti et al.[9] suggested that various cofactors, especially dysmetabolic features, alcohol consumption, and HFE genotypes, can favour the development of hyperferritinemia in BTT, sometimes leading to clinically relevant iron overload.


Conclusions

Our findings indicate that: i. even in patients with BTT, the presence of metabolic alterations and excessive alcohol intake should be evaluated before hyperferritinemia is considered a definitive index of major iron overload; these patients should be managed for lifestyle modification to avoid or limit the risk of alcohol- and metabolic-related complications at both hepatic and cardiovascular level and reevaluated at follow-up; ii. BTT can be considered a modifier of phenotype expression in individuals with HFE and non-HFE genotypes at risk for iron overload, but it is unlikely that BTT alone or in combination with heterozygous HFE variants can cause significant parenchymal iron overload in the liver unless other coexistent factors are present; iii. Quantification of liver iron by MRI is a useful tool for distinguishing BTT subjects with hyperferritinemia who can be followed up from those with major iron overload who deserve iron removal therapies. In clinical practice, accurate collection of patients’ medical history (previous transfusions, high alcohol intake, coexistent metabolic and hepatic diseases) and serum iron parameters can be useful to distinguish those who should first be managed with lifestyle changes and clinical-laboratory monitoring from those who should be started directly on MRI quantification of LIC.[16] Iron parameters would guide gene testing,[18] providing further information for the optimal diagnostic and therapeutic approach for patients. Accordingly, in a large cohort of subjects with hyperferritinemia, we recently showed that TSAT and serum ferritin can identify more than 95% of patients with severe LIC, reducing MRI requirements by more than 50%.[15]


Acknowledgements

The project is supported (not financially) by the European Reference Network on Rare Haematological Diseases (ERN-EuroBloodNet)—Project ID No. 10108571. ERN- EuroBloodNet is partly co-funded by the European Union within the framework of the Fourth EU Health Programme. We thank the "Associazione per lo Studio dell'Emocromatosi e delle Malattie da Sovraccarico di Ferro-ETS", Monza, Italy, for supporting the study.


Grant Support

G.R. was funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS project code PNRR-MAD-2022-12376033, title “Evidence-based models for high impact chronic disease prevention and risk of progression management in outpatient community services and community hospitals: towards eHealth integrating stratification on individual history with predictive models of disease progression, using machine learning and artificial intelligence on administrative and clinical databases”, PI Antonio Giampiero Russo. S.G. participated in the manuscript preparation during their personal involvement in the Italian Ministry of University MUR Dipartimenti di Eccellenza 2023-2027 (l. 232/2016, art. 1, commi 314–337). S.G. was partially supported by the grant PRIN 2022SYXEH.

References   

  1. Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing patterns in the epidemiology of β-thalassemia. Eur J Haematol. 2020;105(6):692-703. doi: 10.1111/ejh.13512. https://doi.org/10.1111/ejh.13512 PMid:32886826 PMCid:PMC7692954 
  2. Guimarães JS, Cominal JG, Silva-Pinto AC, Olbina G, Ginzburg YZ, Nandi V, Westerman M, Rivella S, de Souza AM. Altered erythropoiesis and iron metabolism in carriers of thalassemia. Eur J Haematol. 2015;94(6):511-8. doi: 10.1111/ejh.12464. https://doi.org/10.1111/ejh.12464 PMid:25307880 PMCid:PMC4393762 
  3. Pippard MJ, Wainscoat JS. Erythrokinetics and iron status in heterozygous beta thalassaemia, and the effect of interaction with alpha thalassaemia. Br J Haematol. 1987;66(1):123-7. https://doi.org/10.1111/j.1365-2141.1987.00115.x-i1 
  4. Jones E, Pasricha SR, Allen A, Evans P, Fisher CA, Wray K, Premawardhena A, Bandara D, Perera A, Webster C, Sturges P, Olivieri NF, St Pierre T, Armitage AE, Porter JB, Weatherall DJ, Drakesmith H. Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait. Blood. 2015;125(5):873-80. doi: 10.1182/blood-2014-10-606491. https://doi.org/10.1182/blood-2014-10-606491 PMid:25519750 PMCid:PMC4321326 
  5. Piperno A, Mariani R, Arosio C, Vergani A, Bosio S, Fargion S, Sampietro M, Girelli D, Fraquelli M, Conte D, Fiorelli G, Camaschella C. Haemochromatosis in patients with beta-thalassaemia trait. Br J Haematol. 2000;111(3):908-14. https://doi.org/10.1046/j.1365-2141.2000.02436 PMid:11122155 
  6. Mehta BC, Pandya BG. Iron status of beta thalassemia carriers. Am J Hematol. 1987;24(2):137-41. doi: 10.1002/ajh.2830240204. https://doi.org/10.1002/ajh.2830240204 PMid:3812467 
  7. Fargion S, Taddei MT, Cappellini MD, Piperno A, Fiorelli G. The iron status of Italian subjects with beta-thalassemia trait. Acta Haematol. 1982;68(2):109-14. doi: 10.1159/000206961. https://doi.org/10.1159/000206961 PMid:6812365 
  8. White JM, Richards R, Jelenski G, Byrne M, Ali M. Iron state in alpha and beta thalassaemia trait. J Clin Pathol. 1986;39(3):256-9. doi: 10.1136/jcp.39.3.256. https://doi.org/10.1136/jcp.39.3.256 PMid:3958216 PMCid:PMC499758 
  9. Busti F, Castagna A, Marchi G, Vianello A, Chesini F, Bozzini C, Lima CDS, Martinelli N, Nemeth E, Ganz T, Girelli D. A case series of patients with β-thalassemia trait and iron overload: from multifactorial hepcidin suppression to treatment with mini-phlebotomies. Haematologica. 2025;110(5):1226-1231. doi: 10.3324/haematol.2024.286413. https://doi.org/10.3324/haematol.2024.286413 
  10. Melis MA, Cau M, Deidda F, Barella S, Cao A, Galanello R. H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers. Haematologica. 2002;87(3):242-245. 
  11. Martins R, Picanço I, Fonseca A, Ferreira L, Rodrigues O, Coelho M, Seixas T, Miranda A, Nunes B, Costa L, Romão L, Faustino P. The role of HFE mutations on iron metabolism in beta-thalassemia carriers. J Hum Genet. 2004;49(12):651-655. doi: 10.1007/s10038-004-0202-z. https://doi.org/10.1007/s10038-004-0202-z PMid:15538648 
  12. Nadkarni AH, Singh AA, Colaco S, Hariharan P, Colah RB, Ghosh K. Effect of the Hemochromatosis Mutations on Iron Overload among the Indian β Thalassemia Carriers. J Clin Lab Anal. 2017;31(3):e22054. doi: 10.1002/jcla.22054. https://doi.org/10.1002/jcla.22054 PMid:27561698 PMCid:PMC6816897 
  13. Mónaco ME, Alvarez Asensio NS, Haro C, Terán MM, Ledesma Achem ME, Issé BA, Lazarte SS. Effect of HFE Gene Mutations on Iron Metabolism of Beta-Thalassemia Carriers. Thalass. Rep. 2023;13:113-121. doi: 10.3390/thalassrep13010010. https://doi.org/10.3390/thalassrep13010010 
  14. Estevão IF, Peitl Junior P, Bonini-Domingos CR. Serum ferritin and transferrin saturation levels in β0 and β(+) thalassemia patients. Genet Mol Res. 2011;10(2):632-9. doi: 10.4238/vol10-2gmr1016. https://doi.org/10.4238/vol10-2gmr1016 PMid:21491373 
  15. Risca G, Pelucchi S, Mariani R, Botti M, Capitoli G, Di Gennaro F, Galimberti S, Piperno A. Transferrin Saturation and Serum Ferritin Are Main Predictors of Liver Iron Content in Subjects With Hyperferritinemia. Clin Gastroenterol Hepatol. 2026;24(1):141-149.e6. doi: 10.1016/j.cgh.2025.02.033. https://doi.org/10.1016/j.cgh.2025.02.033 PMid:40398831 
  16. Piperno A, Pelucchi S, Mariani R. Hereditary Hyperferritinemia. Int J Mol Sci. 2023;24(3):2560. doi: 10.3390/ijms24032560. https://doi.org/10.3390/ijms24032560 PMid:36768886 PMCid:PMC9917042 
  17. Aguilar-Martinez P, Schved JF, Brissot P. The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. Am J Gastroenterol. 2005;100(5):1185-94. doi: 10.1111/j.1572-0241.2005.40998.x. https://doi.org/10.1111/j.1572-0241.2005.40998.x PMid:15842597 
  18. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542. doi: 10.1016/j.jhep.2024.04.031. https://doi.org/10.1016/j.jhep.2024.04.031 PMid:38851997 
  19. Galimberti S, Trombini P, Bernasconi DP, Redaelli I, Pelucchi S, Bovo G, Di Gennaro F, Zucchini N, Paruccini N, Piperno A. Simultaneous liver iron and fat measures by magnetic resonance imaging in patients with hyperferritinemia. Scand J Gastroenterol. 2015;50(4):429-38. doi: 10.3109/00365521.2014.940380. https://doi.org/10.3109/00365521.2014.940380 PMid:25633726 
  20. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997 Feb 1;89(3):739-61. Erratum in: Blood 1997;89(7):2621. https://doi.org/10.1182/blood.V89.3.739 PMid:9028304 PMCid:PMC11969382 
  21. Farmakis D, Porter J, Taher A, Domenica Cappellini M, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia. Hemasphere. 2022;6(8):e732. doi: 10.1097/HS9.0000000000000732. https://doi.org/10.1097/HS9.0000000000000732 PMid:35928543 PMCid:PMC9345633 
  22. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol. 2022;77(2):479-502. https://doi.org/10.1016/j.jhep.2022.03.033 PMid:35662478 
  23. Girelli D, Busti F, Brissot P, Cabantchik I, Muckenthaler MU, Porto G; on behalf of the Nomenclature Committee of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society), Hemochromatosis classification: update and recommendations by the BIOIRON Society. Blood 2022; 139 (20): 3018-3029. doi: 10.1182/blood.2021011338 https://doi.org/10.1182/blood.2021011338 PMid:34601591 PMCid:PMC11022970 
  24. Tomatsu S, Orii KO, Fleming RE, Holden CC, Waheed A, Britton RS, Gutierrez MA, Velez-Castrillon S, Bacon BR, Sly WS. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc Natl Acad Sci USA. 2003;100(26):15788-93. doi: 10.1073/pnas.2237037100. https://doi.org/10.1073/pnas.2237037100 PMid:14673107 PMCid:PMC307646 
  25. Sandnes M, Ulvik RJ, Vorland M, Reikvam H. Hyperferritinemia-A Clinical Overview. J Clin Med. 2021;10(9):2008. doi:10.3390/jcm10092008 https://doi.org/10.3390/jcm10092008 PMid:34067164 PMCid:PMC8125175 
  26. Olynyk JK, Gan E, Tan T. Predicting iron overload in hyperferritinemia. Clin Gastroenterol Hepatol. 2009;7(3):359-62. doi: 10.1016/j.cgh.2008.11.010. https://doi.org/10.1016/j.cgh.2008.11.010 PMid:19095082 
  27. Adams PC. The (Il)logic of iron reduction therapy for steatohepatitis. Hepatology. 2015;62(3):668-670. https://doi.org/10.1002/hep.27866 PMid:25914250
  28. Allen KJ, Bertalli NA, Osborne NJ, Constantine CC, Delatycki MB, Nisselle AE, Nicoll AJ, Gertig DM, McLaren CE, Giles GG, Hopper JL, Anderson GJ, Olynyk JK, Powell LW, Gurrin LC; Health-Iron Study Investigators. HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis. Hepatology. 2010;52(3):925-33. doi: 10.1002/hep.23786. https://doi.org/10.1002/hep.23786 PMid:20583211 PMCid:PMC2932765 
  29. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986;6(1):24-9. doi: 10.1002/hep.1840060106. https://doi.org/10.1002/hep.1840060106 PMid:3943787 PMCid:PMC11969382 
  30. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997;34(4):275-8. doi: 10.1136/jmg.34.4.275. https://doi.org/10.1136/jmg.34.4.275 PMid:9138148 PMCid:PMC1050911 
  31. Harrison-Findik DD. Role of alcohol in the regulation of iron metabolism. World J Gastroenterol. 2007;13(37):4925-30. doi: 10.3748/wjg.v13.i37.4925. https://doi.org/10.3748/wjg.v13.i37.4925 PMid:17854133 PMCid:PMC4434614 
  32. Trinder D, Ayonrinde OT, Olynyk JK. HCV, iron, and oxidative stress: the new choreography of hepcidin. Gastroenterology. 2008;134(1):348-51. doi: 10.1053/j.gastro.2007.11.048. https://doi.org/10.1053/j.gastro.2007.11.048 PMid:18166363 
  33. Shander A, Cappellini MD, Goodnough LT. Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sang. 2009;97(3):185-97. doi: 10.1111/j.1423-0410.2009.01207.x. https://doi.org/10.1111/j.1423-0410.2009.01207.x PMid:19663936 
  34. Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology. 1997;112(3):882-8. doi: 10.1053/gast.1997.v112.pm9041250. https://doi.org/10.1053/gast.1997.v112.pm9041250 PMid:9041250  
  35. Ioannou GN, Dominitz JA, Weiss NS, Heagerty PJ, Kowdley KV. The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia. Gastroenterology. 2004;126(5):1293-301. doi: 10.1053/j.gastro.2004.01.020. https://doi.org/10.1053/j.gastro.2004.01.020 PMid:151317904.01.020.

Supplementary Files
Suppl Table 1
Supplementary Table 1. Classes of steatotic liver disease (SLD) according to LICMRI grades.