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01-11-2022 | Magnetic Resonance Imaging | Abdominal Radiology

Quantitative T2* MRI for bone marrow iron overload: normal reference values and assessment in thalassemia major patients

Authors: Antonella Meloni, Laura Pistoia, Gennaro Restaino, Massimiliano Missere, Vincenzo Positano, Anna Spasiano, Tommaso Casini, Antonella Cossu, Liana Cuccia, Antonella Massa, Francesco Massei, Filippo Cademartiri

Published in: La radiologia medica | Issue 11/2022

Abstract

Purpose

We evaluated the feasibility and reproducibility of bone marrow T2* values and established the lower limit of normal in a cohort of healthy subjects. We investigated the clinical correlates of bone marrow T2* values in patients with thalassemia major (TM).

Material and Methods

Thirty healthy subjects and 274 consecutive TM patients (38.96 ± 8.49 years, 151 females) underwent MRI at 1.5T. An axial slice in the upper abdomen was acquired by a T2* gradient-echo multiecho sequence and the T2* value was calculated in a circular region of interest defined in the visible body of the first or second lumbar vertebra. In patients, also liver and heart T2* values were assessed.

Results

In healthy subjects bone marrow T2* values were independent of age and gender. The lower limit of normal for bone marrow T2* was 13 ms.

In both healthy subjects and 30 randomly selected patients, the coefficient of variation for inter-operator-reproducibility was < 10%. TM patients exhibited significantly lower bone marrow T2* values than healthy subjects (7.47 ± 5.18 ms vs. 17.08 ± 1.89 ms; p < 0.0001).

A pathological bone marrow T2* was detected in 82.8% of TM patients. In TM, the female sex was associated with reduced bone marrow T2* values. Bone marrow T2* values were inversely correlated with mean serum ferritin levels (R = -0.431; P < 0.0001) and hepatic iron load (R = − 0.215; P < 0.0001). A serum ferritin level > 536 ng/ml predicted the presence of a pathological bone marrow T2*. A positive correlation was found between bone marrow and heart T2* values (R = 0.143; P = 0.018). A normal bone marrow T2* showed a negative predictive value of 100% for cardiac iron.

Conclusion

Bone marrow T2* measurements can be easily obtained using the same sequences acquired for liver iron quantification and may bring new insights into the pathophysiology of iron deposition; hence, they should be incorporated into clinical practice.

Rund D, Rachmilewitz E (2005) Beta-thalassemia. N Engl J Med 353(11):1135–1146CrossRef

Weatherall DJ, Provan AB (2000) Red cells I: inherited anaemias. Lancet 355(9210):1169–1175. https://doi.org/10.1016/s0140-6736(00)02073-0CrossRefPubMed

Manglani MV, Kini PS (2017) Management of ß-thalassemia – consensus and controversies! Pediatric Hemato Oncol J 2(4):94–97. https://doi.org/10.1016/j.phoj.2017.10.003CrossRef

Cazzola M, Borgna-Pignatti C, de Stefano P, Bergamaschi G, Bongo IG, Dezza L, Avato F (1983) Internal distribution of excess iron and sources of serum ferritin in patients with thalassemia. Scand J Haematol 30(4):289–296. https://doi.org/10.1111/j.1600-0609.1983.tb01494.xCrossRefPubMed

Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, Wasi P, Ma L, Schrier SL (2000) A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood 96(7):2606–2612CrossRef

Galaris D, Barbouti A (1866) Pantopoulos K (2019) Iron homeostasis and oxidative stress: an intimate relationship. Biochim Biophys Acta Mol Cell Res 12:118535. https://doi.org/10.1016/j.bbamcr.2019.118535CrossRef

Chai X, Li D, Cao X, Zhang Y, Mu J, Lu W, Xiao X, Li C, Meng J, Chen J, Li Q, Wang J, Meng A, Zhao M (2015) ROS-mediated iron overload injures the hematopoiesis of bone marrow by damaging hematopoietic stem/progenitor cells in mice. Sci Rep 5:10181. https://doi.org/10.1038/srep10181CrossRefPubMedPubMedCentral

Okabe H, Suzuki T, Uehara E, Ueda M, Nagai T, Ozawa K (2014) The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice. Eur J Haematol 93(2):118–128. https://doi.org/10.1111/ejh.12309CrossRefPubMed

Lee SE, Yahng SA, Cho BS, Eom KS, Kim YJ, Lee S, Min CK, Kim HJ, Cho SG, Kim DW, Min WS, Park CW, Lee JW (2013) Improvement in hematopoiesis after iron chelation therapy with deferasirox in patients with aplastic anemia. Acta Haematol 129(2):72–77. https://doi.org/10.1159/000342772CrossRefPubMed

10.

Rossi F, Perrotta S, Bellini G, Luongo L, Tortora C, Siniscalco D, Francese M, Torella M, Nobili B, Di Marzo V, Maione S (2014) Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels. Haematologica 99(12):1876–1884. https://doi.org/10.3324/haematol.2014.104463CrossRefPubMedPubMedCentral

11.

Kontoyiannis DP, Chamilos G, Lewis RE, Giralt S, Cortes J, Raad II, Manning JT, Han X (2007) Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation. Cancer 110(6):1303–1306. https://doi.org/10.1002/cncr.22909CrossRefPubMed

12.

Santarone S, Pepe A, Meloni A, Natale A, Pistoia L, Olioso P, Papalinetti G, Cuccia L, Spasiano A, Lisi R, Di Ianni M, Bonfini T, Accorsi P, Salvadori S, Papola F, Angelini S, Di Bartolomeo P (2018) Secondary solid cancer following hematopoietic cell transplantation in patients with thalassemia major. Bone Marrow Transplant 53(1):39–43. https://doi.org/10.1038/bmt.2017.214CrossRefPubMed

13.

Werner S, Krauss B, Haberland U, Bongers M, Starke U, Bakchoul T, Enkel S, Nikolaou K, Horger M (2019) Dual-energy CT for liver iron quantification in patients with haematological disorders. Eur Radiol 29(6):2868–2877. https://doi.org/10.1007/s00330-018-5785-4CrossRefPubMed

14.

Ghugre NR, Coates TD, Nelson MD, Wood JC (2005) Mechanisms of tissue-iron relaxivity: nuclear magnetic resonance studies of human liver biopsy specimens. Magn Reson Med 54(5):1185–1193CrossRef

15.

Westwood MA, Firmin DN, Gildo M, Renzo G, Stathis G, Markissia K, Vasili B, Pennell DJ (2005) Intercentre reproducibility of magnetic resonance T2* measurements of myocardial iron in thalassaemia. Int J Cardiovasc Imaging 21(5):531–538CrossRef

16.

Pepe A, Lombardi M, Positano V, Cracolici E, Capra M, Malizia R, Prossomariti L, de Marchi D, Midiri M, Maggio A (2006) Evaluation of the efficacy of oral deferiprone in beta-thalassemia major by multislice multiecho T2*. Eur J Haematol 76(3):183–192CrossRef

17.

Ramazzotti A, Pepe A, Positano V, Rossi G, De Marchi D, Brizi MG, Luciani A, Midiri M, Sallustio G, Valeri G, Caruso V, Centra M, Cianciulli P, De Sanctis V, Maggio A, Lombardi M (2009) Multicenter validation of the magnetic resonance T2* technique for segmental and global quantification of myocardial iron. J Magn Reson Imaging 30(1):62–68CrossRef

18.

Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM, Pennell DJ (2001) Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 22(23):2171–2179CrossRef

19.

Noetzli LJ, Papudesi J, Coates TD, Wood JC (2009) Pancreatic iron loading predicts cardiac iron loading in thalassemia major. Blood 114(19):4021–4026CrossRef

20.

Brewer CJ, Coates TD, Wood JC (2009) Spleen R2 and R2* in iron-overloaded patients with sickle cell disease and thalassemia major. J Magn Reson Imaging 29(2):357–364CrossRef

21.

Meloni A, Positano V, Pepe A, Rossi G, Dell’Amico M, Salvatori C, Keilberg P, Filosa A, Sallustio G, Midiri M, D’Ascola D, Santarelli MF, Lombardi M (2010) Preferential patterns of myocardial iron overload by multislice multiecho T*2 CMR in thalassemia major patients. Magn Reson Med 64(1):211–219CrossRef

22.

Noetzli LJ, Carson SM, Nord AS, Coates TD, Wood JC (2008) Longitudinal analysis of heart and liver iron in thalassemia major. Blood 112(7):2973–2978CrossRef

23.

ElAlfy MS, Khalil Elsherif NH, Ebeid FSE, Ismail EAR, Ahmed KA, Darwish YW, Ibrahim AS, Elghamry IRF, Shokrey NA, Alajeil DN (2018) Renal iron deposition by magnetic resonance imaging in pediatric beta-thalassemia major patients: relation to renal biomarkers, total body iron and chelation therapy. Eur J Radiol 103:65–70. https://doi.org/10.1016/j.ejrad.2018.04.007CrossRefPubMed

24.

Pepe A, Pistoia L, Gamberini MR, Cuccia L, Peluso A, Messina G, Spasiano A, Allo M, Bisconte MG, Putti MC, Casini T, Dello Iacono N, Celli M, Vitucci A, Giuliano P, Peritore G, Renne S, Righi R, Positano V, De Sanctis V, Meloni A (2020) The close link of pancreatic iron with glucose metabolism and with cardiac complications in thalassemia major: a large. Multicenter Observ Study Diabetes Care 43(11):2830–2839CrossRef

25.

Manara R, Ponticorvo S, Tartaglione I, Femina G, Elefante A, Russo C, Carafa PA, Cirillo M, Casale M, Ciancio A, Di Concilio R, De Michele E, Weiskopf N, Di Salle F, Perrotta S, Esposito F (2019) Brain iron content in systemic iron overload: a beta-thalassemia quantitative MRI study. Neuroimage Clin 24:102058. https://doi.org/10.1016/j.nicl.2019.102058CrossRefPubMedPubMedCentral

26.

Meloni A, Ramazzotti A, Positano V, Salvatori C, Mangione M, Marcheschi P, Favilli B, De Marchi D, Prato S, Pepe A, Sallustio G, Centra M, Santarelli MF, Lombardi M, Landini L (2009) Evaluation of a web-based network for reproducible T2* MRI assessment of iron overload in thalassemia. Int J Med Inform 78(8):503–512CrossRef

27.

Meloni A, Luciani A, Positano V, De Marchi D, Valeri G, Restaino G, Cracolici E, Caruso V, Dell’amico MC, Favilli B, Lombardi M, Pepe A (2011) Single region of interest versus multislice T2* MRI approach for the quantification of hepatic iron overload. J Magn Reson Imaging 33(2):348–355CrossRef

28.

Positano V, Salani B, Pepe A, Santarelli MF, De Marchi D, Ramazzotti A, Favilli B, Cracolici E, Midiri M, Cianciulli P, Lombardi M, Landini L (2009) Improved T2* assessment in liver iron overload by magnetic resonance imaging. Magn Reson Imaging 27(2):188–197CrossRef

29.

Meloni A, Positano V, Ruffo GB, Spasiano A, D’Ascola DG, Peluso A, Keilberg P, Restaino G, Valeri G, Renne S, Midiri M, Pepe A (2015) Improvement of heart iron with preserved patterns of iron store by CMR-guided chelation therapy. Eur Heart J Cardiovasc Imaging 16(3):325–334CrossRef

30.

Positano V, Pepe A, Santarelli MF, Scattini B, De Marchi D, Ramazzotti A, Forni G, Borgna-Pignatti C, Lai ME, Midiri M, Maggio A, Lombardi M, Landini L (2007) Standardized T2* map of normal human heart in vivo to correct T2* segmental artefacts. NMR Biomed 20(6):578–590CrossRef

31.

Meloni A, Rienhoff HY Jr, Jones A, Pepe A, Lombardi M, Wood JC (2013) The use of appropriate calibration curves corrects for systematic differences in liver R2* values measured using different software packages. Br J Haematol 161(6):888–891CrossRef

32.

Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD, Coates TD (2005) MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 106(4):1460–1465CrossRef

33.

Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C, Galimberti M, Polchi P, Lucarelli G (2000) Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 343(5):327–331CrossRef

34.

Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS (2002) Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the cardiac imaging committee of the council on clinical cardiology of the American heart association. Circulation 105(4):539–542CrossRef

35.

Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, Hoffman TM, Kiernan MS, Lerakis S, Piga A, Porter JB, Walker JM, Wood J (2013) Cardiovascular function and treatment in beta-thalassemia major: a consensus statement from the American heart association. Circulation 128(3):281–308CrossRef

36.

Pepe A, Meloni A, Pistoia L, Cuccia L, Gamberini MR, Lisi R, D’Ascola DG, Rosso R, Allo M, Spasiano A, Restaino G, Righi R, Mangione M, Positano V, Ricchi P (2018) MRI multicentre prospective survey in thalassaemia major patients treated with deferasirox versus deferiprone and desferrioxamine. Br J Haematol 183(5):783–795CrossRef

37.

Levin TL, Sheth SS, Ruzal-Shapiro C, Abramson S, Piomelli S, Berdon WE (1995) MRI marrow observations in thalassemia: the effects of the primary disease, transfusional therapy, and chelation. Pediatr Radiol 25(8):607–613. https://doi.org/10.1007/BF02011827CrossRefPubMed

38.

Meloni A, De Marchi D, Positano V, Neri MG, Mangione M, Keilberg P, Lendini M, Cirotto C, Pepe A (2015) Accurate estimate of pancreatic T2* values: how to deal with fat infiltration. Abdom Imaging 40(8):3129–3136CrossRef

39.

Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT (1999) Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol 276(5 Pt 1):E977-989PubMed

40.

Schwenzer NF, Machann J, Haap MM, Martirosian P, Schraml C, Liebig G, Stefan N, Haring HU, Claussen CD, Fritsche A, Schick F (2008) T2* relaxometry in liver, pancreas, and spleen in a healthy cohort of one hundred twenty-nine subjects-correlation with age, gender, and serum ferritin. Invest Radiol 43(12):854–860CrossRef

41.

Restaino G, Meloni A, Positano V, Missere M, Rossi G, Calandriello L, Keilberg P, Mattioni O, Maggio A, Lombardi M, Sallustio G, Pepe A (2011) Regional and global pancreatic T*(2) MRI for iron overload assessment in a large cohort of healthy subjects: normal values and correlation with age and gender. Magn Reson Med 65(3):764–769CrossRef

42.

Grassedonio E, Meloni A, Positano V, De Marchi D, Toia P, Midiri M, Pepe A (2015) Quantitative T2* magnetic resonance imaging for renal iron overload assessment: normal values by age and sex. Abdom Imaging 40:1700–1704CrossRef

43.

Drakonaki EE, Maris TG, Papadakis A, Karantanas AH (2007) Bone marrow changes in beta-thalassemia major: quantitative MR imaging findings and correlation with iron stores. Eur Radiol 17(8):2079–2087. https://doi.org/10.1007/s00330-006-0504-yCrossRefPubMed

44.

Papakonstantinou O, Alexopoulou E, Economopoulos N, Benekos O, Kattamis A, Kostaridou S, Ladis V, Efstathopoulos E, Gouliamos A, Kelekis NL (2009) Assessment of iron distribution between liver, spleen, pancreas, bone marrow, and myocardium by means of R2 relaxometry with MRI in patients with beta-thalassemia major. J Magn Reson Imaging 29(4):853–859CrossRef

45.

Jensen CE, Tuck SM, Agnew JE, Koneru S, Morris RW, Yardumian A, Prescott E, Hoffbrand AV, Wonke B (1998) High prevalence of low bone mass in thalassaemia major. Br J Haematol 103(4):911–915. https://doi.org/10.1046/j.1365-2141.1998.01108.xCrossRefPubMed

46.

Majumdar S, Genant HK (1992) In vivo relationship between marrow T2* and trabecular bone density determined with a chemical shift—selective asymmetric spin-echo sequence. J Magn Reson Imaging 2(2):209–219. https://doi.org/10.1002/jmri.1880020215CrossRefPubMed

47.

Harju E, Pakarinen A, Larmi T (1984) A comparison between serum ferritin concentration and the amount of bone marrow stainable iron. Scand J Clin Lab Invest 44(6):555–556. https://doi.org/10.1080/00365518409083610CrossRefPubMed

48.

Krause JR, Stolc V (1980) Serum ferritin and bone marrow biopsy iron stores II Correlation with low serum iron and Fe/TIBC ratio less than 15%. Am J Clin Pathol 74 (4): 461–464.

49.

St Pierre TG, Clark PR, Chua-Anusorn W (2005) Measurement and mapping of liver iron concentrations using magnetic resonance imaging. Ann N Y Acad Sci 1054:379–385CrossRef

50.

Meloni A, Maggio A, Positano V, Leto F, Angelini A, Putti MC, Maresi E, Pucci A, Basso C, Perazzolo Marra M, Pistoia L, De Marchi D, Pepe A (2020) CMR for Myocardial iron overload quantification: calibration curve from the MIOT network. Eur Radiol 29(5):2246–2252CrossRef

Title: Quantitative T2* MRI for bone marrow iron overload: normal reference values and assessment in thalassemia major patients
Authors: Antonella Meloni
Laura Pistoia
Gennaro Restaino
Massimiliano Missere
Vincenzo Positano
Anna Spasiano
Tommaso Casini
Antonella Cossu
Liana Cuccia
Antonella Massa
Francesco Massei
Filippo Cademartiri
Publication date: 01-11-2022
Publisher: Springer Milan
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Thalassemia
Published in: La radiologia medica / Issue 11/2022
Print ISSN: 0033-8362
Electronic ISSN: 1826-6983
DOI: https://doi.org/10.1007/s11547-022-01554-w

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Springer Medicine

Quantitative T2* MRI for bone marrow iron overload: normal reference values and assessment in thalassemia major patients

Abstract

Purpose

Material and Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Material and Methods

Results

Conclusion

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