Summary Cardiac and endocrine disorders are common sequelae of iron overload in transfused thalassaemia patients. Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces an additive/synergistic effect superior to either drug alone. 52 thalassaemia major patients were transitioned from DFO to combined chelation with DFO and DFP. Serum ferritin, cardiac and hepatic iron levels were monitored regularly for up to 7 years, as were cardiac and endocrine function. Patients’ iron load normalized, as judged by ferritin and cardiac and hepatic magnetic resonance imaging findings. In all 12 patients receiving treatment for cardiac dysfunction, symptoms reversed following combined chelation, enabling nine patients to discontinue heart medications. In the 39 patients with abnormal glucose metabolism, 44% normalized. In 18 requiring thyroxine supplementation for hypothyroidism, 10 were able to discontinue, and four reduced their thyroxine dose. In 14 hypogonadal males on testosterone therapy, seven stopped treatment. Of the 19 females, who were hypogonadal on DFO monotherapy, six were able to conceive. Moreover, no patients developed de novo cardiac or endocrine complications. These results suggest that intensive combined chelation normalized patients’ iron load and thereby prevented and reversed cardiac and multiple endocrine complications associated with transfusion iron overload.

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.

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Over the last 20 years, the management of thalassemia major has improved to the point where we predict that the patients' life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow organ-specific assessment of the degree of iron overload and improvement in the treatment of hepatitis. The ability to prescribe any of the three chelators, as well as their combinations, has led to a more effective reduction of the total body iron. The ability to determine the amount of iron in the liver and heart by MRI has allowed the prescription of the most appropriate chelation regime for the patient and has allowed the reconsideration of 'the comfort zones'. Thus, normalizing iron stores not only prevents new morbidities but also reverses many complications, such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance and Type 2 diabetes, therefore improving survival and patients' quality of life. Furthermore, outcomes should continue to improve in the future. Starting relatively intensive chelation in younger children may prevent short stature and abnormal pubertal maturation, as well as other iron-related morbidities. In addition, further information should become available on the use of other combinations in chelation treatment, some of which have only been used in a very limited fashion so far. New safe oral chelators may also become available that may offer additional ease of use. All these advances in management do require absolute cooperation and understanding on behalf of children's parents and subsequently the adult themself. Only with such cooperation can normal long-term survival be achieved as it is likely that adherence to treatment is the primary barrier to longevity.

Over the last 20 years, management for thalassemia major has improved to the point where we predict that patients’ life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow specific organ assessment of the degree of iron overload, and improvement in the treatment of hepatitis. In October 2011, the Food and Drug Administration licensed deferiprone, further increasing the available choices for iron chelation in the US. The ability to prescribe any of the three chelators as well as their combinations has led to more effective reduction of total body iron. The ability to determine the amount of iron in the liver and heart by magnetic resonance imaging allows the prescription of the most appropriate chelation regime for patients and to reconsider what our aims with respect to total body iron should be. Recent evidence from Europe has shown that by normalizing iron stores not only are new morbidities prevented but also reversal of many complications such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance, and type 2 diabetes can occur, improving survival and patients’ quality of life. The most effective way to achieve normal iron stores seems to be with the combination of deferoxamine and deferiprone. Furthermore, outcomes should continue to improve in the future. Starting relative intensive chelation in younger children may prevent short stature and abnormal pubertal maturation as well as other iron-related morbidities. Also, further information should become available on the use of other combinations in chelation treatment, some of which have been used only in a very limited fashion to date. All these advances in management require absolute cooperation and understanding of parents, children, and, subsequently, the patients themselves. Only with such cooperation can normal long-term survival be achieved, as adherence to treatment is now likely the primary barrier to longevity.

The marked improvement in survival and reduced morbidity in thalassemia major (TM) allows many patients to parent children (1, 2). For women, in many instances assisted reproduction methods in vitro fertilization (IVF) need to be used. In general, as pregnancies in TM patients are usually planned, iron chelation therapy is stopped before the patient enters the IVF programme (3). In the past, the impact of such cessation was not easily assessable except by serum ferritin levels. Liver biopsies, though valuable were relatively traumatic and had low acceptance from patients. With the advent of magnetic resonance imaging (MRI) techniques such assessments are more easily accessible (4). The patient, subject of this report was followed prospectively before and after a pregnancy to determine the impact of withholding chelation therapy for a period of 12 months. Patient informationThe patient is now 38 yr old. She commenced regular blood transfusion at 10 months of age and desferrioxamine iron chelation therapy at the age of 11 yr. In June 2001 with the availability of the oral chelator deferiprone, she commenced combination therapy with deferiprone at 60-80 mg ⁄ kg ⁄ d in three doses (25% in the morning, 25% in the afternoon and 50% at night) and desferrioxamine at 30-50 mg ⁄ kg ⁄ infusion ⁄ d. She was always very compliant with her chelation therapy. She AbstractIn general, in women with transfusion-dependent thalassemia, during pregnancy, iron chelation therapy is ceased. We report a splenectomized patient, who was an excellent complier with chelation therapy, who before embarking on a pregnancy showed no evidence of iron overload, with normal cardiac, thyroid function and glucose metabolism. Laboratory findings showed ferritin 67 lg ⁄ L, myocardial T 2 * of 34 ms and liver magnetic resonance imaging (MRI) liver iron concentration of 1 mg ⁄ g dry weight. She became pregnant by in vitro fertilization in October 2006, delivery occurred in June 2007. She breast fed for 2 months. After 12 months without iron chelation, ferritin was 1583 lg ⁄ L. Quantitative MRI showed myocardial T 2 * of 27 ms, that the liver iron concentration had increased to 11.3 mg ⁄ g dry weight, indicative of moderate to heavy iron load. This case demonstrates that iron overload can develop rapidly and that physicians caring for patients with transfusion-dependent thalassemia should be particularly alert to any discontinuation of chelation therapy over time.

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Thyroid dysfunction is known to occur frequently in β-Thalassemia major patients (TMps), but its prevalence and severity varies in different cohorts according to chelation regimens. Thyroid hormones are critical determinants of brain and somatic development in infants and of metabolic activity in adults affecting the function of virtually every organ system. Thyroid gland mainly secrets T4, whereas 80% of T3 is produced by de-iodination of T4 (liver, kidney, heart and other tissues) and is influenced by a variety of factors. Furthermore, T4 & T3 secretion is tightly regulated within narrow limits by a mechanism that involves the pituitary-secreted TSH which in turn is stimulated by the hypothalamic TRH. Thus, iron overload-related hypothyroidism may be either central (because of deposition in the pituitary or the hypothalamus) and usually associated with other endocrinopathies, or primary (by deposition in the thyroid gland or even other organs). Existing data suggest that the thyroid gland appears to fail before the central components of the axis. In all cases, symptoms occur slowly over time and may vary from subclinical to overt hypothyroidism which is associated with an increased risk of cardiovascular disease. The aim of this study was to investigate the effect of long-term intensive combined chelation therapy on thyroid function in TMps after they were all in negative iron balance. 51 TMps, 25 males 26 females, mean age 29.8±2.03, who were previously maintained on subcutaneous desferrioxamine monotherapy (DFO:40mg/kg, 3–6 days/week) switched to an intensive combined chelation with DFO (40–60mg/kg/d) and Deferiprone (DFP: 75–100mg/kg/d) adapted to individual needs. Thyroid function was assessed initially and after 6 years by TRH stimulation test and TSH, FT4 & FT3 screening. All patients on hormone replacement therapy stopped treatment at least 30 days before the test. This was approved by the Hospital Scientific Committee. Criteria for the diagnosis of subclinical or compensated hypothyroidism was an increase of the TSH levels during the test of more than 20 μIU/ml from the basal value or an elevated basal TSH concentration (>5 μIU/ml) and for overt hypothyroidism a further decrease in FT4 & FT3 levels. With DFO monotherapy 18 TMps were treated with thyroxin therapy. In these patients after combined chelation and an important decrease in iron overload (p<0.0001) as estimated by ferritin levels (2,737±473 vs 450±225mg/dl), MRI liver and heart iron quantification (T2*L & T2*H) and LIC calculated by Ferriscan (13±3 vs. 1.4±0.5mg/gdw), a significant increase was observed in mean FT4 (1.07±0.03 vs. 0.7±0.02ng/ml, p<0.0001) & mean FT3 (2.6±0.1 vs. 1.3± 0.1pg/ml, p<0.0001) and an additional significant decrease in the mean TSH quantitative secretion, calculated as the area under the curve (AUC=1,332±131 vs. 2,231±241, p<0.0001). These 10/18 (56%) TMps with subclinical or compensated hypothyroidism, who normalized TSH, FT4 & FT3 levels and had a normal TRH stimulation test discontinued thyroxin therapy, while another 4/18 (22%) reduced their thyroxin dose. The remaining 4/18 with overt hypothyroidism, while they all improved their TRH stimulation test, only 2 improved to compensated hypothyroidism with TSH levels 5–10mIU/ml and normal FT4 & FT3 levels. Critically, in the other 33/51 euthyroid TMps, no new cases of hypothyroidism were noted after combined chelation and a significant increase (p<0.0001) was observed in the mean FT4 & FT3 levels with a significant decrease (p<0.0001) in the mean TSH quantitative secretion (AUC). This study showed that intensive combined chelation associated with a significant decrease of iron overload may reverse some cases of primary hypothyroidism, either subclinical or compensated, and may prevent progression to overt hypothyroidism, thus influencing the decision to treat with thyroid hormone. It may also improve some cases of overt hypothyroidism suggesting that even iron-induced damage of the thyroid pituitary axis might be ameliorated.