Main Article Content
Abstract. Backgrond: β-thalassemia intermedia (TI) spans a wide spectrum of severity and carries higher morbidity than previously recognized, including extramedullary hematopoeisis, leg ulcers, gallstones, thrombosis, secondary heart failure, pulmonary hypertension, skeletal deformity, growth retardation and endocrine abnormalities, such as diabetes mellitus, hypothyroidism, osteoporosis, and hypogonadism.
Objectives: To evaluate the final height and the endocrine complications encountered in young adult patients with TI followed at Hematology Section, Doha (Qatar) in relation to liver iron content in non-transfused versus infrequently transfused TI patients.
Patients and Methods: This retrospective cohort study was performed on 28 young adults with TI who were randomly selected from the Hematology Clinic of the Hematology Section, National Centre for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar).
Eligibility criteria for this retrospective analysis included TI patients diagnosed by complete blood count, hemoglobin electrophoresis and young adult age ( ≥ 18 years).
Group 1 included 9 patients who did not receive any blood transfusion and Group 2 included 19 patients who infrequently received blood transfusion.
Data recorded from charts included demographic characteristics (gender, date of birth, ethnicity), disease and treatment characteristics (e.g., transfusion frequency, history of chelation therapy, and splenectomy), auxological and pubertal data [growth percentiles and pubertal stages, and body mass index (BMI)], laboratory data and target organ complications (including endocrinopathies and liver disease). Iron overload was assessed by direct (liver iron content; LIC) and indirect methods (SF), and bone mass index (BMA) by dual-energy X-ray absorptiometry (DXA).
Results: Short stature [Final Height (Ht) SDS < -2] occurred in 25% of patients with no difference between the two groups of patients. Insulin growth factor 1 (IGF-1) SDS was low in 35.7 % of patients with no statistical difference among the two groups. Impaired fasting blood glucose occurred in 17.8% of patients, diabetes mellitus in 25% and hypogonadotropic hypogonadism in 10.7% of them. Morning cortisol was low in one patient. No thyroid or hypoparathyroid abnormalities were detected in any patient. Liver iron content (LIC) > 15 mg/g dry weight and SF > 2,000 ng/mL were detected in 75% of the patients. The values resulted significantly higher in the transfused group (Group 2). High liver enzyme level (ALT) was detected in 42.8 % of patients and the values were significantly higher in the transfused group (Group 2).Total and fetal Hb was significantly higher in group 1 versus group 2. Osteopenia was diagnosed in 14.3% of patients. Females had significantly better final height SDS, higher IGF-1 SDS, lower LIC and fasting blood glucose level compared to males. Ht-SDS was correlated significantly with IGF-1 SDS. LIC was correlated significantly with SF level. ALT concentrations were correlated significantly with LIC and SF levels. Total and fetal Hb did not correlate significantly with Ht-SDS or IGF-1 level.
Conclusions: A significant number of TI patients have high LIC, short stature and endocrine disorders. Patients who require occasional transfusions have more liver iron overload and higher hepatic dysfunction. Females appear to attain better final adult height and have higher IGF1- SDS versus males. Our data emphasize the need for long term surveillance for identification of organ-specific risk factors and early disease manifestations.We also recommend a close monitoring of endocrine and other complications, according to the international guidelines.
Downloads month by month
1. Taher AT, Temraz S, Cappellini MD. Deferasirox for the treatment of iron overload in non-transfusion-dependent thalassemia. Expert Rev Hematol. 2013;6:495-509.
2. Cappellini MD, Musallam Khaled M, Taher Ali T. Insight onto the pathophysiology and clinical complications of thalassemia intermedia. Hemoglobin. 2009;33:S145–59.
3. Galanello R, Cao A. Relationship between genotype and phenotype. Thalassemia intermedia. Ann NY Acad Sci.1998; 850: 325–333.
4. Karimi M, Cohan N, De Sanctis V, Mallat NS, Taher A. Guidelines for diagnosis and management of Beta-thalassemia intermedia. Pediatr Hematol Oncol. 2014;31:583-596.
5. Taher A, Hershko C, Cappellini MD. Iron overload in thalassaemia intermedia: Reassessment of iron chelation strategies. Br J Haematol.2009; 147: 634–640.
6. De Sanctis V, Tangerini A, Testa MR, Lauriola AL, Gamberini MR, Cavallini AR, Rigolin F. Final height and endocrine function in thalassaemia intermedia. J Pediatr Endocrinol Metab. 1998;11 (Suppl 3):965-971.
7. 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, Kilinc Y, 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, Jaouni SA, Di Maio S, Wali Y, Elhakim IZ, Kattamis C. An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Major and Intermedia: A preliminary report. Acta Biomed. 2018;88:435-444.
8. Inati A, Noureldine MA, Mansour A, Abbas HA. Endocrine and bone complications in β-thalassemia intermedia: current understanding and treatment.Biomed Res Int. 2015; :813098. doi: 10.1155/2015/813098.
9. Taher AT., Musallam KM., Karimi M, El-Beshlawy A, Belhoul K, Daar S, Saned MS, El-Chafic AH, Fasulo MR, Cappellini MD. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the optimal care study. Blood. 2010;115:1886–1892
10. De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, Karimi M, Yassin MA, El Awwa A, Stoeva I, Raiola G, Galati MC, Bedair EM, Fiscina B, El Kholy M. Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab. 2013;17:8-18.
11. WHO Multicenter Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr. 2006; 450 (Suppl):76-85.
12. Soliman AT, Al Yafei F, Al-Naimi L, Almarri N, Sabt A, Yassin M, De Sanctis V. Longitudinal study on thyroid function in patients with thalassemia major: High incidence of central hypothyroidism by 18 years. Indian J Endocrinol Metab. 2013; 17:1090-1095.
13. Puavilai G, Chanprasertyotin S, Sriphrapradaeng A. Diagnostic criteria for diabetes mellitus and other categories of glucose intolerance: 1997 criteria by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (ADA), 1998 WHO consultation criteria, and 1985 WHO criteria. World Health Organization. Diabetes Res Clin Pract. 1999;44:21-26.
14. Bondanelli M, Ambrosio MR, Cavazzini L, Bertocchi A, Zatelli MC, Carli A, Valle D, Basaglia N, Uberti EC. Anterior pituitary function may predict functional and cognitive outcome in patients with traumatic brain injury undergoing rehabilitation. J Neurotrauma. 2007;24:1687–1697.
15. Alberti C1, Chevenne D, Mercat I, Josserand E, Armoogum-Boizeau P, Tichet J, Léger J.Serum concentrations of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio, and markers of bone turnover: reference values for French children and adolescents and z-score comparability with other references. Clin Chem. 2011; 57:1424-1435.
16. Kanbour I, Chandra P, Soliman A, De Sanctis V, Nashwan A, Abusamaan S, Moustafa A, Yassin MA.Severe liver iron concentrations (LIC) in 24 patients with β-thalassemia major: correlations with serum ferritin, liver enzymes, and endocrine complications. Mediterr J Hematol Infect Dis 2018, 10(1): e2018062, DOI: http://dx.doi.org/10.4084/MJHID.2018.062
17. Verlhac S, Morel M, Bernaudin F, Béchet S, Jung C, Vasile M. Liver iron overload assessment by MRI R2* relaxometry in highly transfused pediatric patients: an agreement and reproducibility study. Diagn Interv Imaging. 2015;96:259-264.
18.St Pierre TG, El-Beshlawy A, Elalfy M, Al Jefri A, Al Zir K, Daar S, Habr D, Kriemler-Krahn U, Taher A. Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration. Magn Reson Med. 2014;71:2215-2223.
19. Orvieto R, Leichter I, Rachmilewitz EA, Margulies JY. Bone density, mineral content, and cortical index in patients with thalassemia major and the correlation to their bone fractures, blood transfusions, and treatment with desferrioxamine. Calcif Tissue Int. 1992;50: 397–399.
20. Taher A, Isma'eel H, Cappellini MD. Thalassaemia intermedia: revisited. Blood Cells Mol Dis. 2006;37:12-20.
21.Fiorelli G, Fragion S, Piperno A, Battafarano N, Cappellini MD. Iron metabolism in thalassemia intermedia. Haematologica. 1990;75:89–95.
22.Pippard MJ, Warner GT, Callender ST, Weatherall DJ. Iron absorption and loading in β-thalassaemia intermedia. Lancet. 1979;2:819–821.
23.Celada. Iron overload in non-transfused patient with thalassemia intermedia. Scand J Haematol 1982, 28:169–174
24.Shah R, Trehan A, Das R, Marwaha RK. Serum ferritin in thalassemia intermedia. Indian J Hematol Blood Transfus. 2013;30:281-285.
25. Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamim H, Taher AT. Elevated liver iron concentration is a marker of increased morbidity in patients with β thalassemia intermedia. Haematologica. 2011;96:1605-1612.
26. Taher A, El Rassi F, Isma'eel H, Koussa S, Inati A. Correlation of serum ferritin levels and liver iron concentration determined by R2* MRI in patients with thalassemia intermedia. Blood. 2007;110:3818.
27.Taher AT, Musallam KM, Saliba AN, Garziadei G, Cappellini MD. Hemoglobin level
and morbidity in non-transfusion-dependent thalassemia. Blood Cells Mol Dis. 2015; 55 :108–109.
28. Karamifar H, Karimi M, Amirhakimi GH, Badiei M. Endocrine function in thalassemia intermedia. Int J Biomed Sci. 2006,2:236-240.
29. Musallam KM, Sankaran VG, Cappellini MD, Duca L, Nathan DG, Taher AT. Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia. Blood. 2012;119:364-367.
30. Soliman AT, De Sanctis V, Kalra S. Anemia and growth.Indian J Endocrinol Metab. 2014;18 (Suppl 1):S1-5.
31. Soliman AT, De Sanctis V, Yassin M, Adel A. Growth and Growth hormone - Insulin Like Growth Factor -I (GH-IGF-I) Axis in Chronic Anemias. Acta Biomed. 2017;88:101-111.
32. Soliman AT, De Sanctis V, Elalaily R, Yassin M. Insulin-like growth factor- I and factors affecting it in thalassemia major. Indian J Endocrinol Metab. 2015;19:245-251.
33. De Sanctis V, Soliman AT, Candini G, Yassin M, Raiola G, Galati MC, Elalaily R, Elsedfy H, Skordis N, Garofalo P, Anastasi S, Campisi S, Karimi M, Kattamis C, Canatan D, Kilinc Y, Sobti P, Fiscina B, El Kholy M. Insulin-like Growth Factor-1 (IGF-1): Demographic, Clinical and Laboratory Data in 120 Consecutive Adult Patients with Thalassaemia Major. Mediterr J Hematol Infect Dis. 2014 Nov 1;6(1):e2014074. doi: 10.4084/MJHID.2014.074.
34.Fung EB, Xu Y, Trachtenberg F, Odame I, Kwiatkowski JL, Neufeld EJ, Thompson AA, Boudreaux J, Quinn CT, Vichinsky EP; Thalassemia Clinical Research Network. Inadequate dietary intake in patients with thalassemia. J Acad Nutr Diet. 2012;112:980-90.
35. Flatau E, Resnitzky P, Kauffman N, Harpaz S, Kohn D. Iron loading and endocrine functions in nontransfused patients with beta-thalassemia intermedia or sickle-cell thalassemia. Isr J Med Sci. 1981;17:22-27.
36.Karimi M, Zarei T, Haghpanah S, Azarkeivan A, Kattamis C, Ladis V, Kattamis A, Kilinc Y, Daar S, Alyaarubi S, Yasseen D, Yassin M, Soliman AT, Canatan D, Obiedat M, Al-Rimawi H, Mariannis D, Christodoulides C, Christou S, Tzoulis P, De Sanctis V . Evaluation of endocrine complications in beta-thalassemia intermedia patients: A cross-sectional multicenter study. ASH annual meeting December 2018, Abstract 2343.
37. Baldini M, Marcon A, Cassin R, Ulivieri FM, Spinelli D, Cappellini MD, Graziadei G. Beta-thalassaemia intermedia: evaluation of endocrine and bone complications. Biomed Res Int. 2014;2014:174581. doi: 10.1155/2014/174581.
38.Chouliaras G, Yiannoutsos CT, Berdoukas V, Ladis V. Cardiac related death in thalassaemia major: time trend and risk factors in a large Greek Unit. Eur J Haematol. 2009;82:381–387.
39. Taher AT, Porter J, Viprakasit V, et al. Deferasirox reduces iron overload
significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012;120:970-977.
40. Saliba AN, Musallam KM, Cappellini MD, et al. Serum ferritin values between 300 and 800 ng/mL in nontransfusion-dependent thalassemia: A probability curve to guide clinical decision making when MRI is unavailable. Am J Hematol. 2017;92:E35-E37.
41. Taher AT, Porter JB, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, Siritanaratkul N, Galanello R, Karakas Z, Lawniczek T, Habr D, Ros J, Zhu Z, Cappellini MD. Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study. Ann Hematol. 2013;92:1485-1493.
42. Fortin PM, Fisher SA, Madgwick KV, Trivella M, Hopewell S, Doree C, Estcourt LJ. Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia. Cochrane Database Syst Rev. 2018 May 8;5:CD012349. doi: 10.1002/14651858.CD012349.pub2.
43. Yassin MA, Soliman AT, De Sanctis V, Hussein RM, Al-Okka R, Kassem N, Ghasoub R, Basha A, Nashwan AJ, Adel AM. Jadenu® Substituting Exjade® in Iron Overloaded β-Thalassemia Major (BTM) Patients: A Preliminary Report of the Effects on the Tolerability, Serum Ferritin Level, Liver Iron Concentration and Biochemical Profiles. Mediterr J Hematol Infect Dis. 2018 Nov 1;10(1):e2018064. doi: 10.4084/MJHID.2018.064. eCollection 2018.
44.Chowdhury P, Saha M, Chowdhury D. Correlation of serum ferritin with hepatic iron overload among non-transfusion dependent beta thalassaemia with haemoglobin E disease patients from Eastern India. J Mol Biomark Diagn.2015; 6: 231. doi: 10.4172/2155-9929.1000231.
45. Taher A, Vichinsky E, Musallam K, Cappellini MD, Viprakasit V. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT); Thalassemia International Federation: Nicosia, Cyprus, 2013.