Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and β-cell secretion in eleven β-thalassemia major patients with mild iron overload
Low serum ferritin and glucose homeostasis in β-thalassemia major
Keywords:
β-thalassemia major, glucose tolerance, insulin sensitivity, β-cell secretion, serum ferritin, follow-up.Abstract
Background: Iron chelation therapy (ICT) is the gold standard for treating patients with iron overload, though its long-term effects are still under evaluation. According to current recommendations regarding transfusion-dependent (TD) β-thalassemia major (β-TM) patients, their serum ferritin (SF) levels should be maintained below 1,000 ng/mL and ICT should be discontinued when the levels are <500 ng/mL in two successive tests. Alternatively, the dose of chelator could be considerably reduced to maintain a balance between iron input and output of frequent transfusions. Study design: Due to the paucity of information on long-term effects of ICT in β-TM with low SF levels on glucose homeostasis, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) promoted a retrospective and an ongoing prospective observational study with the primary aim to address the long-term effects of ICT on glucose tolerance and metabolism (β-cell function and peripheral insulin sensitivity) in adult β-TM patients with persistent SF level below 800 ng/mL. Patients and Methods: 11 β-TM patients (mean age: 35.5 ± 5.5 years; SF range: 345-777 ng/mL) with normal glucose tolerance test (OGTT) or abnormal glucose tolerance (AGT) for a median of 5.3(1.1-8.3) years. Results: Abnormal glucose tolerance (AGT) was observed in 7 patients (63.6%) at first observation and ) persisted in 6 patients (54.5%) at last observation. None of them developed diabetes mellitus. AGT was reversed in two patients.
One patient with NGT developed early glucose intolerance (1-h PG ≥155 and 2-h PG <140 mg/dL). Three out of 5 patients with isolated impaired glucose tolerance presented a variation of ATG. Stabilization of low indices for β-cell function and insulin sensitivity/resistance was observed. One patient developed hypogonadotrophic hypogonadism. Three out of 6 patients with SF below 500 ng/dL had hypercalciuria. Conclusion: Despite low SF level, the burden of endocrine complications remains a challenge in β-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.
References
Farmakis D, Porter J, Taher A, Cappellini MD, 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.
Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia. Lancet. 2022;399(10343):2310-24. doi: 10.1016/S0140-6736(22)00536-0.
Wood JC. Estimating tissue iron burden: current status and future prospects. Br J Haematol. 2015;170(1):15-28. doi: 10.1111/bjh.13374.
Noetzli LJ, Carson SM, Nord AS, Coates TD, Wood JC. Longitudinal analysis of heart and liver iron in thalassemia major. Blood. 2008;112(7):2973-8. doi: 10.1182/blood-2008-04-148767.
Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl). 2006;84(5):349-64. doi: 10.1007/s00109-005-0029-x.
Berdoukas V, Nord A, Carson S, Puliyel M, Hofstra T, Wood J, Coates TD. Tissue iron evaluation in chronically transfused children shows significant levels of iron loading at a very young age. Am J Hematol. 2013;88:E283-285. doi:10.1002/ajh.23543.
De Sanctis V, Soliman A, Tzoulis P, et al. The Prevalence of glucose dysregulations (GDs) in patients with β-thalassemias in different countries: A preliminary ICET-A survey. Acta Biomed. 2021;92(3): e2021240.doi: 10.23750/ abm.v92i3.11733.
De Sanctis V, Soliman A, Tzoulis P, et al. The clinical characteristics, biochemical parameters and insulin response to oral glucose tolerance test (OGTT) in 25 transfusion dependent β-thalassemia (TDT) patients recently diagnosed with diabetes mellitus (DM). Acta Biomed. 2022 Jan 19;92(6):e2021488. doi: 10.23750/abm.v92i6.12366.
Sevimli C, Yilmaz Y, Bayramoglu Z, et al. Pancreatic MR imaging and endocrine complications in patients with beta-thalassemia: a single-center experience. Clin Exp Med.2022; 22:95–101.doi.org/10. 1007/s10238-021-00735-7.
De Sanctis V, Daar S, Soliman AT, et al. Screening for glucose dysregulation in β-thalassemia major (β-TM): An update of current evidences and personal experience. Acta Biomed. 2022;93(1):e2022158. doi: 10.23750/abm.v93i1.12802.
Spasiano A, Meloni A, Costantini S, et al. Setting for "Normal" Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia: Our Current Strategy. J Clin Med. 2021;10(24):5985. doi: 10.3390/ jcm10245985.
Pinto MV, Bacigalupo L, Gianesin B, et al. Lack of correlation between heart, liver and pancreas MRI 2*: Results from long-term follow-up in a cohort of adult β -thalassemia major patients. Am J Hematol. 2018;93 (3):E79-82. doi:10.1002/ajh.25009.
Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol. 2010;148(3):466-75.doi:10.1111/j.1365-2141.2009.07970.x.
De Sanctis V, Soliman A, Daar S, Tzoulis P, Di Maio S, Kattamis C. Glucose Homeostasis and Αssessment of β-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with β-Thalassemia Major with Serum Ferritin below 1,000 ng/dL: Results from a Single ICET-A Centre. Accepted for publication, Medit J Hemat Infect Dis. 2022.
, Kuo FY, Cheng KC, Li Y, Cheng JT. Oral glucose tolerance test in diabetes, the old method revisited. World J Diabetes. 2021;12(6):786-93. doi: 10.4239/wjd.v12.i6.786.
Klein KR, Walker CP, McFerren AL, Huffman H, Frohlich F, Buse JB. Carbohydrate Intake Prior to Oral Glucose Tolerance Testing. J Endocr Soc. 2021;5(5):bvab049. doi: 10.1210/jendso/bvab049.
American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl.1): S14-S31.https://doi.org/10.2337/dc20-S002.
De Sanctis V, Soliman A, Tzoulis P, Daar S, Pozzobon G, Kattamis C. A study of isolated hyperglycemia (blood glucose ≥155 mg/dL) at 1-hour of oral glucose tolerance test (OGTT) in patients with β-transfusion dependent thalassemia (β-TDT) followed for 12 years. Acta Biomed. 2021;92(4): e2021322. doi: 10.23750/abm.v92i4.11105.
Tschritter O, Fritsche A, Shirkavand F, Machicao F, Haring H, Stumvoll M. Assessing the shape of the glucose curve during an oral glucose tolerance test. Diabetes Care. 2003;26:1026–33.doi:10.2337/diacare. 26.4.1026.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462-70. doi:10.2337/ diacare. 22.9.1462.
Hanefeld M, Hanefeld M, Koehler C, et al.. Insulin secretion and insulin sensitivity pattern is different in isolated impaired glucose tolerance and impaired fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. Diabetes Care. 2003;26:868–74. doi:10.2337/diacare. 26.3.868.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9. doi:10.1007/BF00280883.
Hayashi T, Boyko EJ, Sato KK, et al. Patterns of insulin concentration during the OGTT predict the risk of type 2 diabetes in Japanese Americans. Diabetes Care. 2013;36(5):1229-35. doi:10.2337/dc12-0246.
Roth CL, Elfers C, Hampe CS. Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents. Nutr Diabetes. 2017;7(12):301.doi: 10.1038/ s41387-017-0004-y.
Utzschneider KM, Prigeon RL, Faulenbach MV, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009;32(2):335-41.doi:
2337/dc08-1478.
Fulwood R, Johnson CL, Bryner JD. Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80. Vital Health Stat.1982; 11:1-173.PMID: 7170776.
Alder R, Roesser EB. Introduction to probability and statistics. WH Freeman and Company Eds. Sixth Edition. San Francisco (USA), 1975.PMID:1674139.
De Sanctis V, Soliman AT, Daar S, Tzoulis P, Fiscina B, Kattamis C, International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A). Retrospective observational studies: Lights and shadows for medical writers. Acta Biomed [Internet]. [cited 2022 Oct. 20];93(5):e2022319.doi.org /10.23750/abm.v93i5.13179.
De Sanctis V, Gamberini MR, Borgatti L, Atti G, Vullo C, Bagni B. Alpha and beta cell evaluation in patients with thalassaemia intermedia and iron overload. Postgrad Med J.1985;61(721):963-7.doi: 10.1136/ pgmj.61.721.963.
Papakonstantinou O, Alexopoulou E, Economopoulos N, et al. Assessment of iron distribution between liver, spleen, pancreas, bone marrow, and myocardium by means of R2 relaxometry with mri in patients with β-thalassemia major. J Magn Reson Imaging. 2009;29(4):853–9. doi:10.1002/jmri.21707.
Coates TD. Physiology and pathophysiology of iron in hemoglobin-associated diseases. Free Radic Biol Med. 2014 Jul;72:23-40. doi: 10.1016/j.freeradbiomed.2014.03.039.
Cabantchik ZI. Labile iron in cells and body fluids: physiology, pathology, and pharmacology. Front Pharmacol. 2014;5:45. doi: 10.3389/fphar.2014.00045.
Noetzli LJ, Panigrahy A, Mittelman SD, et al. Pituitary iron and volume predict hypogonadism in transfusional iron overload. Am J Hematol. 2012;87(2):167–71. doi: 10.1002/ ajh.22247.
Scaramellini N, Arighi C, Marcon A, et al. Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials. Blood. 2019;134 (Supplement 1):3542. doi: https://doi.org/10.1182/blood-2019-130237.
Wong P, Polkinghorne K, Kerr PG, et al. Deferasirox at therapeutic doses is associated with dose‐dependent hypercalciuria. Bone. 2016;85:55–8. doi.org/10.1016/j.bone.2016.01.011
Quinn CT, Johnson VL, Kim HY, et al. Renal dysfunction in patients with thalassaemia. Br J Haematol. 2011;153(1):111-7. doi: 10.1111/j.1365-2141.2010.08477.x.
Tanous O, Azulay Y, Halevy R. et al. Renal function in β-thalassemia major patients treated with two different iron-chelation regimes. BMC Nephrol.2021;22:418. doi.org/10.1186/s12882-021-02630-5.
Quinn CT, St Pierre TG. MRI Measurements of Iron Load in Transfusion-Dependent Patients: Implementation, Challenges, and Pitfalls. Pediatr Blood Cancer. 2016;63(5):773-80. doi: 10.1002/ pbc.25882.
Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008;294:E15–E26. doi: 10.1152/ajpendo.00645.2007.
Conwell LS, Trost SG, Brown WJ, Batch JA. Indexes of insulin resistance and secretion in obese children and adolescents: a validation study. Diabetes Care.2004;27:314–319. doi: 10.2337/diacare.27.2.314.
Noetzli LJ, Papudesi J, Coates TD, Wood JC. Pancreatic iron loading predicts cardiac iron loading in thalassemia major. Blood. 2009;114(19):4021-6. doi: 10.1182/blood-2009-06-225615.
Berliner C, Wang ZJ, Singer ST, et al. Anterior Pituitary Volume in Patients with Transfusion Dependent Anemias: Volumetric Approaches and Relation to Pituitary MRI R2. Clin Neuroradiol. 2022;32(1):259-67. doi: 10.1007/s00062-021-01111-4.
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Vincenzo De Sanctis, Ashraf T Soliman, Shahina Daar, Ploutarchos Tzoulis, Salvatore Di Maio, Christos Kattamis
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
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.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.