GROWTH AND ENDOCRINE FUNCTION IN TUNISIAN THALASSEMIA MAJOR PATIENTS
Main Article Content
Keywords
Thalassemic Syndromes, endocrine disorders
Abstract
Beta-thalassemia major (TM) is among prevalent hereditary disorders imposing high expenses on health-care system worldwide. The patient’s survival is dependent on lifetime blood transfusion which leads to iron overload and its toxicity on various organs including endocrine glands. This article provides an overview of endocrine disorders in beta-TM patients. This single center investigation enrolled 28 beta-TM patients (16 males, 12 females) regularly transfused with packed red cell since early years of life. For each patient were determined: age, sex, number of transfusions received, history of splenectomy and anthropometric parameters. Evaluation for hormonal status including growth, gonadal, thyroid, adrenal cortex, and parathyroid glands was done for all patients. Dual energy X-ray absorptiometry was used to diagnose osteoporosis. Assessment of iron overload status was performed by measuring the serum ferritin concentration and the results of magnetic resonance imaging T2*. Growth retardation was found in 16 of the 28 studied patients (57 %).Thirteen among them had delayed puberty. Spontaneous puberty was achieved in 16 cases. Growth hormone (GH) deficiency was found in 10 cases (35 %). Seventeen among the studied patients (60 %) developed disorders of glucose homeostasis. Subclinical hypothyroidism was found in six patients (21 %). Intensive chelation therapy had allowed the reversibility of this complication in five cases. Adrenal Insufficiency was found in 9 cases (32%). Hypoparathyroidism has occurred in one case. Ten of the 28 studied patients had osteoporosis (35%). Twenty-three of the 28 studied patients (82%) had at least one endocrine complication.
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References
1. Telfer PT,Warburton F, Christou S, Hadjigavriel M, Sitarou M, Kolnagou A, Angastiniotis M . Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone. Haematologica 2009; 94 (12):1777-1778.
http://dx.doi.org/ 10.3324/haematol.2009.009118
PMid: 19815834
2. De Sanctis V, Roos M, Gasser T, Fortini M, Raiola G, Galati MC. Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia. JPediatr EndocrinolMetab 2006 ;19(4):471-480.
PMID:16759032
3. Sempé. Sempé M, Pédron G, Roy-Pernot MP .Auxologie méthode et séquences. Théraplix. Paris; 1979.
4. Tanner J.M. Growth at adolescence. 2nd Edition Blackwell Scientific Publications ;1962 .
5. Diagnosis and classification of diabetes mellitus. American diabetes association. Diabetes Care 2010 ; 33: 62-69. http://dx.doi.org/10.2337/dc10-S062
PMid: 20042775
6. Brabant G, von zur Mühlen A, Wüster C, Ranke MB, Kratzsch J, Kiess W, Ketelslegers JM, Wilhelmsen L, Hulthén L, Saller B, Mattsson A, Wilde J, Schemer R, Kann P. German KIMS Board. Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study. Horm Res 2003; 60:53-60. http://dx.doi.org/ 10.1159/000071871
PMid: 12876414
7. Greulich WW, pyle SI. Radiographic atlas of skeletal development of the hand and wrist . 2nd Ed. Stanford University Press; 1959.
8. Fernandes JL, Sampaio EF, Verissimo M, Pereira FB, da Silva JA, de Figueiredo GS, Kalaf JM, Coelho OR . Heart and liver T2 assessment for iron overload using different software programs. Eur Radiol 2011 ; 21(12):2503–2510. http://dx.doi.org/ 10.1007/s00330-011-2208-1
PMid:21842212
9. Carpenter JP, He T, Kirk P, Roughton M, Anderson LJ, de Noronha SV, Sheppard MN, Porter JB, Walker JM, Wood JC, Galanello R, Forni G, Catani G, Matta G, Fucharoen S, Fleming A, House MJ, Black G, Firmin DN, St Pierre TG, Pennell DJ. On T2* magnetic resonance and cardiac iron. Circulation 2011 ;123(14):1519–1528. http://dx.doi.org/10.1161/CIRCULATIONAHA.110.007641
PMid:21444881
10. Hankins JS, Mccarville MB, Loeffler RB et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood 2009 ; 113(20):4853–4855. http://dx.doi.org/ 10.1182/blood-2008-12-191643
PMid:19264677
11. Di Tucci AA, Matta G, Deplano S, Gabbas A, Depau C, Derudas D, Caocci G, Agus A, Angelucci E. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica 2008 ; 93(9):1385–1388. http://dx.doi.org/ 10.3324/haematol.12759
PMid:18603557
12. Ouederni M , Ben Khaled M , Mellouli F , Ben Fraj E , Dhouib N , Yakoub IB , Abbes S , Mnif N , Bejaoui M .Myocardial and liver iron overload, assessed using T2* magnetic resonance imaging with an excel spreadsheet for post processing in Tunisian thalassemia major patients. Ann Hematol 2017 ; 96(1):133-139. http://dx.doi.org/ 10.1007/s 00277-016-2841-5
PMid:27730342
13. Soliman A T, Khalafallah H, Ashour R. Growth and factors affecting it in thalassemia major. Hemoglobin 2009 ; 33(S1):S116–S126. http://dx.doi.org/ 10.3109/03630260903347781 PMid:20001614
14. Skordis N, Kyriakou A. The multifactorial origin of growth failure in thalassaemia. Pediatr Endocrinol Rev 2011 ; 8 Suppl 2:271-277.
PMid:21705977
15. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010;5:11. http://dx.doi: 10.1186/1750-1172-5-11
PMID: 20492708
16. Kyriakou A, Skordis N.Thalassaemia and Aberrations of Growth and Puberty. Mediterr J Hematol Infect Dis. 2009; 1(1): e2009003.
PMID: 21415985
17. De Sanctis V, Skordis N, Galati MC, Raiola G, Giovannini M, Candini G, Kaffe K, Savvides I, Christou S . Growth hormone and adrenal response to intramuscular glucagon test and its relationship to IGF-1 production and left ventricular ejection fraction in adult B-thalassemia major patients. PediatrEndocrinol Rev 2011 ; 8 Suppl 2:290-294.
PMid:21705980
18. Pincelli AI, Masera N, Tavecchia L, Perotti M, Perra S, Mariani R, Piperno A, Mancia G, Grassi G, Masera G. GH deficiency in adult B-thalassemia major patients and its relationship with IGF-1 production. Pediatr Endocrinol Rev 2011 ; 8 Suppl 2:284-289.
PMid:21705979
19. De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Pepe A, Kattamis C, Soliman NA, Elalaily R, El Kholy M, Yassin M. Acquired hypogonadotropic hypogonadism (AHH) in thalassaemia major patients: An underdiagnosed condition? Mediterr J Hematol Infect Dis 2016, 8(1): e2016001.http://dx.doi.org/10.4084/MJHID.2016.001
20. De Sanctis V, Soliman AT, Elsedfy H, Albu A, Al Jaouni S, Anastasi S, Bisconte MG, Canatan D, Christou S, Daar S, Di Maio S, El Kholy M, Khater D, Elshinawy M, Kilinc Y, Mattei R, Mosli HH, Quota A, Roberti MG, Sobti P, AL Yaarubi S, Canpisi S, Kattamis C. Review and recommendations on management of adult female thalassemia patients with hypogonadism based on literature review and experience of ICET-A network specialists. Mediterr J Hematol Infect Dis 2017, 9(1): e2017001. http://dx.doi.org/10.4084/MJHID.2017.001
21. Borgna-Pignatti C, De Stefano ?, Zonta ?, Vullo C, De Sanctis V, Melevendi C, Naselle A, Masera G, Terzoli S, Gabitti V, Piga A.Growth and sexual maturation in thalassemia major. J Pediatr 1985 ; 106: 150-156.
PMid:3965675
22. Bejaoui M, Guirat N. Beta thalassemia major in a developing country: epidemiological, clinical and evolutionary aspects. Mediterr J Hematol Infect Dis 2013;5(1):e2013002. http://dx.doi.org/ 10.4084/MJHID.2013.002
PMid:23350015
23. Thuret I, Pondarré C, Loundou A, Steschenko D, Girot R, Bachir D, Rose C, Barlogis V, Donadieu J, De Montalembert M, Hagege I, Pegourie B, Berger C, Micheau M, Bernaudin F, Leblanc T, Lutz L, Galactéros F, Siméoni MC, Badens C. Complications and treatment of patients with ?-thalassemia in France: results of the National Registry. Haematologica 2010 ; 95(5):724-729. http://dx.doi.org/ 10.3324/haematol.2009.018051
PMid: 20007138
24. Toumba M, Sergis A, Kanaris C, Skordis N . Endocrine complications in patients with thalassaemia major.Pediatr Endocrinol Rev 2007; 5: 642-648.
PMId:18084158
25. Gamberini MR, Fortini M, De Sanctis V, Gilli G, Testa MR.. Diabetes mellitus and impaired glucose tolerance in thalassaemia major: incidence, prevalence, risk factors and survival in patients followed in the Ferrara Center.Pediatr Endocrinol Rev 2004 ; 2 (Suppl 2): 285-291.
PMid:16462713
26. Au WY, Lam WW, Chu W, Tam S, Wong WK, Liang R, Ha SY . A T2* magnetic resonance imaging study of pancreatic iron overload in thalassemia major. Haematologica 2008 ; 93:116-119. http://dx.doi.org/ 10.3324/haematol.11768
PMid:18166794
27. Bas M, Gumruk F, Gonc N, et al. Biochemical markers of glucose metabolism may be used to estimate the degree and progression of iron overload in the liver and pancreas of patients with ?-thalassemia major. Ann Hematol 2015;94:1099-2104. http://dx.doi.org/10.1007/s00277-015-2342-y
PMid:25740381
28. Phenekos C, Karamerou A, Pipis P, Constantoulakis M, Lasaridis J, Detsi S, Politou K. Thyroid function in patients with homozygous ?-thalassemia. Clin Endocrinol (Oxf) 1984; 20:445–450.
PMid:6424976
29. Magro S, Puzzanio P, Consarino C, Galati MC, Morgione S, Porcelli D, Grimaldi S, Tancre D, Arcuri V, De Santis V. Hypothyroidism in patients with thalassemia syndromes. Acta Haematol (Basel) 1990 ; 84:72–76. http://dx.doi.org/ 10.1159/000205032
PMid:2120889
30. Depaz G, Deville A, Coussement N, Manassero J, Mariani R. Thyroid function in thalassemia major. Ann Pediatr (Paris) 1985 ; 32:809–811.
PMid:4091451
31. Landau H, Matoth I, Landau-Cordova Z, Goldfarb A, Rachmilewitz EA, Glaser B. Cross-sectional and longitudinal study of the pituitary-thyroid axis in patients with thalassaemia major. Clin Endocrinol (Oxf) 1993 ; 38:55–61.
PMid:8435886
32. De Sanctis V, Elsedfy H , Soliman AT., Elhakim IZ , Kattamis C, Soliman NA, Elalaily R.
Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy. Mediterr J Hematol Infect Dis 2016; 8(1): e2016022. http://dx.doi.org/ 10.4084/MJHID.2016.022
PMid: 27158435
33. Huang KE , Mittelman SD, Coates TD, Geffner ME, Wood JC. A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing. J Pediatr Hematol Oncol. 2015 ;37(1):54-59. http://dx.doi.org/ 10.1097/MPH.0000000000000199
PMid:24942024
34. De Sanctis V , Soliman AT, Canatan D , Elsedfy H, Karimi M , Daar S , Rimawi H , Christou S, Skordis N , Tzoulis P, Sobti P, Kakkar S, KilincY, Khater D, Alyaarubi SA, Kaleva V, Lum SH, Yassin MA, Saki F, Obiedat M, Anastasi S, Galati MC, Raiola G, Campisi S , Soliman N, Elshinawy M, Al Jaouni S, Di Maio S, Wali Y, Elhakim IZ, Kattamis C. An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Majorand Intermedia: A preliminary report. Acta Biomed 2018; 16;88(4):435-444. http://dx.doi.org/10.23750/abm.v88i4.6837
PMid:29350657
35. Casale M, Citarella S, Filosa A, De Michele E, Palmieri F, Ragozzino A, Amendola G, Pugliese U, Tartaglione I, Della Rocca F, Cinque P, Nobili B, Perrotta S. Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with ?-thalassemia major. Am J Hematol 2014; 89(12):1102-1106. http://dx.doi.org/ 10.1002/ajh.23844
PMid:25197009
http://dx.doi.org/ 10.3324/haematol.2009.009118
PMid: 19815834
2. De Sanctis V, Roos M, Gasser T, Fortini M, Raiola G, Galati MC. Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia. JPediatr EndocrinolMetab 2006 ;19(4):471-480.
PMID:16759032
3. Sempé. Sempé M, Pédron G, Roy-Pernot MP .Auxologie méthode et séquences. Théraplix. Paris; 1979.
4. Tanner J.M. Growth at adolescence. 2nd Edition Blackwell Scientific Publications ;1962 .
5. Diagnosis and classification of diabetes mellitus. American diabetes association. Diabetes Care 2010 ; 33: 62-69. http://dx.doi.org/10.2337/dc10-S062
PMid: 20042775
6. Brabant G, von zur Mühlen A, Wüster C, Ranke MB, Kratzsch J, Kiess W, Ketelslegers JM, Wilhelmsen L, Hulthén L, Saller B, Mattsson A, Wilde J, Schemer R, Kann P. German KIMS Board. Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study. Horm Res 2003; 60:53-60. http://dx.doi.org/ 10.1159/000071871
PMid: 12876414
7. Greulich WW, pyle SI. Radiographic atlas of skeletal development of the hand and wrist . 2nd Ed. Stanford University Press; 1959.
8. Fernandes JL, Sampaio EF, Verissimo M, Pereira FB, da Silva JA, de Figueiredo GS, Kalaf JM, Coelho OR . Heart and liver T2 assessment for iron overload using different software programs. Eur Radiol 2011 ; 21(12):2503–2510. http://dx.doi.org/ 10.1007/s00330-011-2208-1
PMid:21842212
9. Carpenter JP, He T, Kirk P, Roughton M, Anderson LJ, de Noronha SV, Sheppard MN, Porter JB, Walker JM, Wood JC, Galanello R, Forni G, Catani G, Matta G, Fucharoen S, Fleming A, House MJ, Black G, Firmin DN, St Pierre TG, Pennell DJ. On T2* magnetic resonance and cardiac iron. Circulation 2011 ;123(14):1519–1528. http://dx.doi.org/10.1161/CIRCULATIONAHA.110.007641
PMid:21444881
10. Hankins JS, Mccarville MB, Loeffler RB et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood 2009 ; 113(20):4853–4855. http://dx.doi.org/ 10.1182/blood-2008-12-191643
PMid:19264677
11. Di Tucci AA, Matta G, Deplano S, Gabbas A, Depau C, Derudas D, Caocci G, Agus A, Angelucci E. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica 2008 ; 93(9):1385–1388. http://dx.doi.org/ 10.3324/haematol.12759
PMid:18603557
12. Ouederni M , Ben Khaled M , Mellouli F , Ben Fraj E , Dhouib N , Yakoub IB , Abbes S , Mnif N , Bejaoui M .Myocardial and liver iron overload, assessed using T2* magnetic resonance imaging with an excel spreadsheet for post processing in Tunisian thalassemia major patients. Ann Hematol 2017 ; 96(1):133-139. http://dx.doi.org/ 10.1007/s 00277-016-2841-5
PMid:27730342
13. Soliman A T, Khalafallah H, Ashour R. Growth and factors affecting it in thalassemia major. Hemoglobin 2009 ; 33(S1):S116–S126. http://dx.doi.org/ 10.3109/03630260903347781 PMid:20001614
14. Skordis N, Kyriakou A. The multifactorial origin of growth failure in thalassaemia. Pediatr Endocrinol Rev 2011 ; 8 Suppl 2:271-277.
PMid:21705977
15. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010;5:11. http://dx.doi: 10.1186/1750-1172-5-11
PMID: 20492708
16. Kyriakou A, Skordis N.Thalassaemia and Aberrations of Growth and Puberty. Mediterr J Hematol Infect Dis. 2009; 1(1): e2009003.
PMID: 21415985
17. De Sanctis V, Skordis N, Galati MC, Raiola G, Giovannini M, Candini G, Kaffe K, Savvides I, Christou S . Growth hormone and adrenal response to intramuscular glucagon test and its relationship to IGF-1 production and left ventricular ejection fraction in adult B-thalassemia major patients. PediatrEndocrinol Rev 2011 ; 8 Suppl 2:290-294.
PMid:21705980
18. Pincelli AI, Masera N, Tavecchia L, Perotti M, Perra S, Mariani R, Piperno A, Mancia G, Grassi G, Masera G. GH deficiency in adult B-thalassemia major patients and its relationship with IGF-1 production. Pediatr Endocrinol Rev 2011 ; 8 Suppl 2:284-289.
PMid:21705979
19. De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Pepe A, Kattamis C, Soliman NA, Elalaily R, El Kholy M, Yassin M. Acquired hypogonadotropic hypogonadism (AHH) in thalassaemia major patients: An underdiagnosed condition? Mediterr J Hematol Infect Dis 2016, 8(1): e2016001.http://dx.doi.org/10.4084/MJHID.2016.001
20. De Sanctis V, Soliman AT, Elsedfy H, Albu A, Al Jaouni S, Anastasi S, Bisconte MG, Canatan D, Christou S, Daar S, Di Maio S, El Kholy M, Khater D, Elshinawy M, Kilinc Y, Mattei R, Mosli HH, Quota A, Roberti MG, Sobti P, AL Yaarubi S, Canpisi S, Kattamis C. Review and recommendations on management of adult female thalassemia patients with hypogonadism based on literature review and experience of ICET-A network specialists. Mediterr J Hematol Infect Dis 2017, 9(1): e2017001. http://dx.doi.org/10.4084/MJHID.2017.001
21. Borgna-Pignatti C, De Stefano ?, Zonta ?, Vullo C, De Sanctis V, Melevendi C, Naselle A, Masera G, Terzoli S, Gabitti V, Piga A.Growth and sexual maturation in thalassemia major. J Pediatr 1985 ; 106: 150-156.
PMid:3965675
22. Bejaoui M, Guirat N. Beta thalassemia major in a developing country: epidemiological, clinical and evolutionary aspects. Mediterr J Hematol Infect Dis 2013;5(1):e2013002. http://dx.doi.org/ 10.4084/MJHID.2013.002
PMid:23350015
23. Thuret I, Pondarré C, Loundou A, Steschenko D, Girot R, Bachir D, Rose C, Barlogis V, Donadieu J, De Montalembert M, Hagege I, Pegourie B, Berger C, Micheau M, Bernaudin F, Leblanc T, Lutz L, Galactéros F, Siméoni MC, Badens C. Complications and treatment of patients with ?-thalassemia in France: results of the National Registry. Haematologica 2010 ; 95(5):724-729. http://dx.doi.org/ 10.3324/haematol.2009.018051
PMid: 20007138
24. Toumba M, Sergis A, Kanaris C, Skordis N . Endocrine complications in patients with thalassaemia major.Pediatr Endocrinol Rev 2007; 5: 642-648.
PMId:18084158
25. Gamberini MR, Fortini M, De Sanctis V, Gilli G, Testa MR.. Diabetes mellitus and impaired glucose tolerance in thalassaemia major: incidence, prevalence, risk factors and survival in patients followed in the Ferrara Center.Pediatr Endocrinol Rev 2004 ; 2 (Suppl 2): 285-291.
PMid:16462713
26. Au WY, Lam WW, Chu W, Tam S, Wong WK, Liang R, Ha SY . A T2* magnetic resonance imaging study of pancreatic iron overload in thalassemia major. Haematologica 2008 ; 93:116-119. http://dx.doi.org/ 10.3324/haematol.11768
PMid:18166794
27. Bas M, Gumruk F, Gonc N, et al. Biochemical markers of glucose metabolism may be used to estimate the degree and progression of iron overload in the liver and pancreas of patients with ?-thalassemia major. Ann Hematol 2015;94:1099-2104. http://dx.doi.org/10.1007/s00277-015-2342-y
PMid:25740381
28. Phenekos C, Karamerou A, Pipis P, Constantoulakis M, Lasaridis J, Detsi S, Politou K. Thyroid function in patients with homozygous ?-thalassemia. Clin Endocrinol (Oxf) 1984; 20:445–450.
PMid:6424976
29. Magro S, Puzzanio P, Consarino C, Galati MC, Morgione S, Porcelli D, Grimaldi S, Tancre D, Arcuri V, De Santis V. Hypothyroidism in patients with thalassemia syndromes. Acta Haematol (Basel) 1990 ; 84:72–76. http://dx.doi.org/ 10.1159/000205032
PMid:2120889
30. Depaz G, Deville A, Coussement N, Manassero J, Mariani R. Thyroid function in thalassemia major. Ann Pediatr (Paris) 1985 ; 32:809–811.
PMid:4091451
31. Landau H, Matoth I, Landau-Cordova Z, Goldfarb A, Rachmilewitz EA, Glaser B. Cross-sectional and longitudinal study of the pituitary-thyroid axis in patients with thalassaemia major. Clin Endocrinol (Oxf) 1993 ; 38:55–61.
PMid:8435886
32. De Sanctis V, Elsedfy H , Soliman AT., Elhakim IZ , Kattamis C, Soliman NA, Elalaily R.
Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy. Mediterr J Hematol Infect Dis 2016; 8(1): e2016022. http://dx.doi.org/ 10.4084/MJHID.2016.022
PMid: 27158435
33. Huang KE , Mittelman SD, Coates TD, Geffner ME, Wood JC. A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing. J Pediatr Hematol Oncol. 2015 ;37(1):54-59. http://dx.doi.org/ 10.1097/MPH.0000000000000199
PMid:24942024
34. De Sanctis V , Soliman AT, Canatan D , Elsedfy H, Karimi M , Daar S , Rimawi H , Christou S, Skordis N , Tzoulis P, Sobti P, Kakkar S, KilincY, Khater D, Alyaarubi SA, Kaleva V, Lum SH, Yassin MA, Saki F, Obiedat M, Anastasi S, Galati MC, Raiola G, Campisi S , Soliman N, Elshinawy M, Al Jaouni S, Di Maio S, Wali Y, Elhakim IZ, Kattamis C. An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Majorand Intermedia: A preliminary report. Acta Biomed 2018; 16;88(4):435-444. http://dx.doi.org/10.23750/abm.v88i4.6837
PMid:29350657
35. Casale M, Citarella S, Filosa A, De Michele E, Palmieri F, Ragozzino A, Amendola G, Pugliese U, Tartaglione I, Della Rocca F, Cinque P, Nobili B, Perrotta S. Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with ?-thalassemia major. Am J Hematol 2014; 89(12):1102-1106. http://dx.doi.org/ 10.1002/ajh.23844
PMid:25197009