Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions

British Journal of Haematology

Volumn 176, Issue 2, 2017, Pages 288-299

  Porter, John B ^a   Cappellini, Maria Domenica ^b   Kattamis, Antonis ^c   Viprakasit, Vip ^d   Musallam, Khaled M ^e   Zhu, Zewen ^e   Taher, Ali T ^f  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF MILAN   (Italy)

^c UNIVERSITY OF ATHENS   (Greece)

^d MAHIDOL UNIVERSITY   (Thailand)

^e NOVARTIS PHARMA AG   (Switzerland)

^f AMERICAN UNIVERSITY OF BEIRUT   (Lebanon)

Author keywords

anaemia; ineffective erythropoiesis; iron overload; non transfusion dependent thalassaemia

Indexed keywords

DEFERIPRONE; DEFEROXAMINE; ERYTHROPOIETIN; FERRITIN; GROWTH DIFFERENTIATION FACTOR 15; HEMOGLOBIN E; HEMOGLOBIN H; HEPCIDIN; IRON; NON TRANSFERRIN BOUND IRON; TRANSFERRIN; TRANSFERRIN RECEPTOR; UNCLASSIFIED DRUG; BIOLOGICAL MARKER; GDF15 PROTEIN, HUMAN;

ADOLESCENT; ADULT; AGED; ANEMIA; ARTICLE; BETA THALASSEMIA; BLOOD TRANSFUSION; CELL NUCLEUS; CHILD; CONTROLLED STUDY; DIAGNOSTIC TEST; DISEASE MARKER; ERYTHROCYTE; ERYTHROPOIESIS; FEMALE; FERRITIN BLOOD LEVEL; HEMOGLOBIN H SYNDROME; HEPCIDIN BLOOD LEVEL; HORMONE BLOOD LEVEL; HUMAN; HUMAN CELL; IRON BLOOD LEVEL; IRON METABOLISM; IRON OVERLOAD; LIVER HEMOSIDEROSIS; LIVER LEVEL; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NON TRANSFUSION DEPENDENT THALASSAEMIA; NUCLEATED RED BLOOD CELL; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL; REFERENCE VALUE; RISK ASSESSMENT; SCHOOL CHILD; SPLENECTOMY; SYNDROME; THALASSEMIA; THALASSEMIA INTERMEDIA; BLOOD; CLINICAL TRIAL; COMPLICATION; DOUBLE BLIND PROCEDURE; ERYTHROBLAST; LIVER; METABOLISM; MIDDLE AGED; PATHOLOGY; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; BIOMARKERS; BLOOD TRANSFUSION; CHILD; DOUBLE-BLIND METHOD; ERYTHROBLASTS; ERYTHROPOIESIS; FEMALE; FERRITINS; GROWTH DIFFERENTIATION FACTOR 15; HEPCIDINS; HUMANS; IRON; IRON OVERLOAD; LIVER; MALE; MIDDLE AGED; RECEPTORS, TRANSFERRIN; SPLENECTOMY; THALASSEMIA; TRANSFERRIN; YOUNG ADULT;

EID: 85006414874     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.14373     Document Type: Article

References (43)

1. Bansal, S.S., Halket, J.M., Fusova, J., Bomford, A., Simpson, R.J., Vasavda, N., Thein, S.L. & Hider, R.C. (2009) Quantification of hepcidin using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Communications in Mass Spectrometry, 23, 1531–1542.
2. Brissot, P., Wright, T.L., Ma, W.L. & Weisiger, R.A. (1985) Efficient clearance of non-transferrin-bound iron by rat liver. Implications for hepatic iron loading in iron overload states. The Journal of Clinical Investigation, 76, 1463–1470.
3. Cabantchik, Z.I., Breuer, W., Zanninelli, G. & Cianciulli, P. (2005) LPI-labile plasma iron in iron overload. Best Practice & Research. Clinical Haematology, 18, 277–287.
4. Dussiot, M., Maciel, T.T., Fricot, A., Chartier, C., Negre, O., Veiga, J., Grapton, D., Paubelle, E., Payen, E., Beuzard, Y., Leboulch, P., Ribeil, J.A., Arlet, J.B., Cote, F., Courtois, G., Ginzburg, Y.Z., Daniel, T.O., Chopra, R., Sung, V., Hermine, O. & Moura, I.C. (2014) An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nature Medicine, 20, 398–407.
5. Esposito, B.P., Breuer, W., Sirankapracha, P., Pootrakul, P., Hershko, C. & Cabantchik, Z.I. (2003) Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood, 102, 2670–2677.
6. Fucharoen, S. & Viprakasit, V. (2009) Hb H disease: clinical course and disease modifiers. Hematology the Education Program of the American Society of Hematology, 26–34.
7. Fucharoen, S. & Weatherall, D.J. (2012) The hemoglobin E thalassemias. Cold Spring Harbor Perspectives in Medicine, 2, a011734.
8. Galanello, R. & Origa, R. (2010) Beta-thalassemia. Orphanet Journal of Rare Diseases, 5, 11.
9. Galanello, R., Barella, S., Turco, M.P., Giagu, N., Cao, A., Dore, F., Liberato, N.L., Guarnone, R. & Barosi, G. (1994) Serum erythropoietin and erythropoiesis in high- and low-fetal hemoglobin beta-thalassemia intermedia patients. Blood, 83, 561–565.
10. Gardenghi, S., Grady, R.W. & Rivella, S. (2010) Anemia, ineffective erythropoiesis, and hepcidin: interacting factors in abnormal iron metabolism leading to iron overload in beta-thalassemia. Hematology/Oncology Clinics of North America, 24, 1089–1107.
11. Harteveld, C.L. & Higgs, D.R. (2010) Alpha-thalassaemia. Orphanet Journal of Rare Diseases, 5, 13.
12. Kautz, L., Jung, G., Valore, E.V., Rivella, S., Nemeth, E. & Ganz, T. (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nature Genetics, 46, 678–684.
13. Lal, A., Goldrich, M.L., Haines, D.A., Azimi, M., Singer, S.T. & Vichinsky, E.P. (2011) Heterogeneity of hemoglobin H disease in childhood. New England Journal of Medicine, 364, 710–718.
14. Lal, A., Porter, J., Sweeters, N., Ng, V., Evans, P., Neumayr, L., Kurio, G., Harmatz, P. & Vichinsky, E. (2013) Combined chelation therapy with deferasirox and deferoxamine in thalassemia. Blood Cells, Molecules, & Diseases, 50, 99–104.
15. Loreal, O., Gosriwatana, I., Guyader, D., Porter, J., Brissot, P. & Hider, R.C. (2000) Determination of non-transferrin-bound iron in genetic hemochromatosis using a new HPLC-based method. Journal of Hepatology, 32, 727–733.
16. Musallam, K.M., Cappellini, M.D., Wood, J.C., Motta, I., Graziadei, G., Tamim, H. & Taher, A.T. (2011) Elevated liver iron concentration is a marker of increased morbidity in patients with b-thalassemia intermedia. Haematologica, 96, 1605–1612.
17. Musallam, K.M., Taher, A.T. & Rachmilewitz, E.A. (2012) beta-thalassemia intermedia: a clinical perspective. Cold Spring Harbor Perspectives in Medicine, 2, a013482.
18. Musallam, K.M., Cappellini, M.D. & Taher, A.T. (2013) Evaluation of the 5 mg/g liver iron concentration threshold and its association with morbidity in patients with beta-thalassemia intermedia. Blood Cells, Molecules, & Diseases, 51, 35–38.
19. Musallam, K.M., Cappellini, M.D., Daar, S., Kairmi, M., El-Beshlawy, A., Graziadei, G., Magestro, M., Wulff, J., Pietri, G. & Taher, A.T. (2014) Serum ferritin level and morbidity risk in transfusion-independent patients with beta-thalassemia intermedia: the ORIENT study. Haematologica, 99, e218–e221.
20. O'Donnell, A., Premawardhena, A., Arambepola, M., Allen, S.J., Peto, T.E., Fisher, C.A., Rees, D.C., Olivieri, N.F. & Weatherall, D.J. (2007) Age-related changes in adaptation to severe anemia in childhood in developing countries. Proceedings of the National Academy of Sciences of the United States of America, 104, 9440–9444.
21. Origa, R., Galanello, R., Ganz, T., Giagu, N., Maccioni, L., Faa, G. & Nemeth, E. (2007) Liver iron concentrations and urinary hepcidin in b-thalassemia. Haematologica, 92, 583–588.
22. Pakbaz, Z., Fischer, R., Fung, E., Nielsen, P., Harmatz, P. & Vichinsky, E. (2007) Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatric Blood & Cancer, 49, 329–332.
23. Pasricha, S.R., Frazer, D.M., Bowden, D.K. & Anderson, G.J. (2013) Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with beta-thalassemia major: a longitudinal study. Blood, 122, 124–133.
24. Pippard, M.J., Callender, S.T., Warner, G.T. & Weatherall, D.J. (1979) Iron absorption and loading in b-thalassaemia intermedia. Lancet, 2, 819–821.
25. Pootrakul, P., Huebers, H.A., Finch, C.A., Pippard, M.J. & Cazzola, M. (1988) Iron metabolism in thalassemia. Birth Defects Original Article Series, 23, 3–8.
26. Porter, J.B., Walter, P.B., Neumayr, L.D., Evans, P., Bansal, S., Garbowski, M., Weyhmiller, M.G., Harmatz, P.R., Wood, J.C., Miller, J.L., Byrnes, C., Weiss, G., Seifert, M., Grosse, R., Grabowski, D., Schmidt, A., Fischer, R., Nielsen, P., Niemeyer, C. & Vichinsky, E. (2014) Mechanisms of plasma non-transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients. British Journal of Haematology, 167, 692–696.
27. Premawardhena, A., Fisher, C.A., Olivieri, N.F., de Silva, S., Arambepola, M., Perera, W., O'Donnell, A., Peto, T.E., Viprakasit, V., Merson, L., Muraca, G. & Weatherall, D.J. (2005) Haemoglobin E b thalassaemia in Sri Lanka. Lancet, 366, 1467–1470.
28. Rees, D.C., Porter, J.B., Clegg, J.B. & Weatherall, D.J. (1999) Why are hemoglobin F levels increased in HbE/beta thalassemia? Blood, 94, 3199–3204.
29. Ricchi, P., Ammirabile, M., Costantini, S., Di, M.T., Verna, R., Diano, A., Foglia, M.C., Spasiano, A., Cinque, P. & Prossomariti, L. (2012) A useful relationship between the presence of extramedullary erythropoeisis and the level of the soluble form of the transferrin receptor in a large cohort of adult patients with thalassemia intermedia: a prospective study. Annals of Hematology, 91, 905–909.
30. St Pierre, T.G., Clark, P.R., Chua-anusorn, W., Fleming, A.J., Jeffrey, G.P., Olynyk, J.K., Pootrakul, P., Robins, E. & Lindeman, R. (2005) Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood, 105, 855–861.
31. Taher, A., El Rassi, F., Isma'eel, H., Koussa, S., Inati, A. & Cappellini, M.D. (2008) Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia. Haematologica, 93, 1584–1586.
32. Taher, A., Hershko, C. & Cappellini, M.D. (2009a) Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies. British Journal of Haematology, 147, 634–640.
33. Taher, A., Musallam, K.M., El, R.F., Duca, L., Inati, A., Koussa, S. & Cappellini, M.D. (2009b) Levels of non-transferrin-bound iron as an index of iron overload in patients with thalassaemia intermedia. British Journal of Haematology, 146, 569–572.
34. Taher, A.T., Musallam, K.M., Cappellini, M.D. & Weatherall, D.J. (2011) Optimal management of b-thalassaemia intermedia. British Journal of Haematology, 152, 512–523.
35. Taher, A.T., Porter, J., Viprakasit, V., Kattamis, A., Chuncharunee, S., Sutcharitchan, P., Siritanaratkul, N., Galanello, R., Karakas, Z., Lawniczek, T., Ros, J., Zhang, Y., Habr, D. & Cappellini, M.D. (2012) Deferasirox significantly reduces iron overload in non-transfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood, 120, 970–977.
36. Taher, A.T., Porter, J.B., Viprakasit, V., Kattamis, A., Chuncharunee, S., Sutcharitchan, P., Siritanaratkul, N., Origa, R., Karakas, Z., Habr, D., Zhu, Z. & Cappellini, M.D. (2015) Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia. British Journal of Haematology, 168, 284–290.
37. Tanno, T. & Miller, J.L. (2010) Iron loading and overloading due to ineffective erythropoiesis. Advances in Hematology, 2010, 358283.
38. Tanno, T., Bhanu, N.V., Oneal, P.A., Goh, S.-H., Staker, P., Lee, Y.T., Moroney, J.W., Reed, C.H., Luban, N.L., Wang, R.-H., Eling, T.E., Childs, R., Ganz, T., Leitman, S.F., Fucharoen, S. & Miller, J.L. (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nature Medicine, 13, 1096–1101.
39. Vichinsky, E. (2007) Hemoglobin E syndromes. Hematology/the Education Program of the American Society of Hematology, 79–83.
40. Vichinsky, E.P. (2013) Clinical manifestations of alpha-thalassemia. Cold Spring Harbor Perspectives in Medicine, 3, a011742.
41. Walter, P.B., Macklin, E.A., Porter, J., Evans, P., Kwiatkowski, J.L., Neufeld, E.J., Coates, T., Giardina, P.J., Vichinsky, E., Olivieri, N., Alberti, D., Holland, J. & Harmatz, P. (2008) Inflammation and oxidant-stress in beta-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial. Haematologica, 93, 817–825.
42. Weatherall, D.J. (2012) The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Reviews, 26, S3–S6.
43. Worwood, M., Cragg, S.J., Wagstaff, M. & Jacobs, A. (1979) Binding of human serum ferritin to concanavalin A. Clinical Science (Lond), 56, 83–87.