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.

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National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy "Η" was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.

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.

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.

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2110 An important goal in iron chelation is preventing tissue iron overload by maintaining low levels of plasma non-transferrin bound iron (NTBI). This is important in periods between chelator administration, when the plasma iron might surpass not only transferrin- but also chelator-iron binding capacities, thereby raising plasma NTBI and exposing cells to infiltrating forms of iron. We aimed to assess the ability of different chelation protocols to maintain patients free of the redox active and chelatable component of NTBI referred to as labile plasma iron (LPI) and the correlation between LPI and eLPI (equivalent to NTBI including mobilizable and chelated iron) with respect to compliance. Patients & Methods: 49 TMps (23 M, 26 F, mean age 35.5±11 years were included. Patients received deferoxamine (DFO)=8–40 (mg/kg) and/or deferiprone (DFP)=74–100 and/or deferasirox (DFX)=7.6–25 for >3 years. Blood samples were drawn at trough levels (12 hr for DFP & 24 hr for DFO and/or DFX) and at peak plasma levels of chelator (2 hrs post DFP and/or DFX p/o). LPI and eLPI were determined with the FeROS™ assay (Aferrix, Israel). Stata 11.0 was used for statistical analysis. The numbers of patients receiving a particular regime were adequate for comparison in the two combination regimes that included deferiprone. Results: 28/49 (57%) of TMps had normal basal LPI (<0.45μM/l) and 90% (19/21) normalized within 2 h of chelation. Baseline eLPI and LPI were negatively related to compliance (Spearman's rho: −0.28, p=0.05 and Spearman's rho: −0.38, p=0.007, respectively). A total of 34 TM patients (23 on DFP+DFO, 11 on DFX+DFO) were included in the comparison analysis based on measurements presented in Table 1. The same trends were confirmed by analysis of the probability of increasing eLPI, reducing LPI and normalizing LPI. No differences were observed in the proportion of patients who increased their baseline eLPI between the two regimes (p>0.05). In contrast, patients on DFP+DFO were 11.0 times more likely to reduce their baseline LPI levels compared to DFP+DFX (exact logistic regression, odds ratio (OR)=11.0, 95% ci: 1.05 - +∞, p=0.045). Similarly, patients treated with DFP+DFO were 14.7 times more likely to normalize their baseline LPI levels compared to DFP+DFX (exact logistic regression, OR =14.7, 95% ci: 1.0 - +∞, p=0.05). Discussion: The DFP+DFO combination seems to be superior to DFP+DFX in reducing LPI despite the lower compliance with the former. As the DFP is in both regimes our results indicate that the DFP is more efficient in combination with DFO than with DFX. The concept of having chelator present in the circulation at all times is logical as it would protect from the infiltrating forms of iron and is attainable with the present repertoire of chelators. This preliminary study suggests that the measurement of LPI provides a convenient and immediate index of chelation efficacy, adequacy of doses of chelator prescribed, and patient compliance. Repeating such measurements every 3 months should be useful in guiding patient management. Disclosures: Berdoukas: Apopharma: Consultancy. Cabantchik:Aferrix: Consultancy.

Life-threatening sequelae in β-thalassemia major patients (TM), result from transfusion iron overload (Fe load). Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces a synergistic effect superior to either drug alone. Combination can place all TMp in negative net iron balance and effect significant reduction in Fe load. 50 TM (24 males, 26 females) aged 8–48 yrs, were switched from monotherapy with DFO, to an individually tailored regimen (DFO 40–60 mg/kg/day- DFP 75–100 mg/kg/day) for 5–6yrs. Fe load was evaluated by mean ferritin levels (MEIA) and non-invasive heart &hepatic iron quantification, by annual Signa-MRI 1.5 Tesla, multi-echo T2 sequences. The heart was evaluated by Echo Doppler. Endocrine function was assessed by:- thyroid: FT4, FT3 &TSH in TRH-test, - Gonads: estradiol, progesterone, testosterone, Free-testosterone levels &LHRH stimulation- Glucose tolerance: OGGT with glucose &insulin measurements at each time and area under the curve (AUC). Insulin sensitivity and beta-cell function were assessed by indices of homeostasis model assessment (ISIHOMA &SCHOMA). Subsequently, all patients survived, even though with DFO alone in the previous decade, mortality ranged from 13.3–14.3%. In patients who accepted the treatment well, a trend analysis (PROC MIXED in SAS), revealed a negative trend of ferritin over time (p<0.0001) with a rate of decline equal to −95 ng/ml/month and a cumulative decrease in 5 years. The mean Ferritin value at baseline, 3.421μg/L, decreased dramatically to 87μg/L. MRI measurements led to significant reduction (p<0.0001) of Fe load to virtually Fe free organs (T2Heart from 28,2msec to 38,1msec &T2Liver from 22,7msec to37,2msec). In 12/50 with pre-existing cardiac dysfunction on medication, symptoms reversed and heart medications were stopped. Ventricular dimensions and function normalized in Echo tests. Mean LVEF increased significantly (p<0.0001) from 54% to 72% with no new dysfunction nor deterioration of heart function. In 17/50 with hypothyroidism on replacement therapy, 7/17 (41%) discontinued therapy and their TSH, FT4 normalised and 4/17 reduced their thyroxin dose. Free thyroxin (FT4) was significantly increased in euthyroid patients. In 14/24 males who were initially on testosterone replacement therapy, 4/14(28.5%) discontinued therapy, whereas 10/24 increased their testosterone levels. In 19/26 females with secondary amenorrhea, 2 had spontaneous ovulation with subsequent normal births and 2 gave birth following in vitro fertilization. In 6/50 with Insulin-dependent Diabetes, insulin dose was reduced. Initially, 14/50 TMp had non- Insulin dependent Diabetes (glucose 0>126 mg/dl, 2h>200mg/dl), 16/50 had Impaired Glucose Tolerance (IGT: glucose 2h>140<200 mg/dl) and 3/50 had Impaired Fasting Glucose (glucose 0>100<126 mg/dl). Following intensive combined chelation, 9/14 (64%), 10/16 (67%) and 3/3 (100%) respectively, normalised their glucose metabolism (p <0.001). An improvement in the glucose AUC was also noted (ANOVA-GENERAL LINEAR MODEL: p<0.002) despite BMI increase (p<0,001). Additionally, insulin secretion increased (SCHOMA: p<0,05 and Friedman/Wilcoxon p<0,004) and insulin sensitivity reduced, (ISIHOMA: p<0,742). These results indicate that in our patient cohort, intensive combination dramatically improved survival and led to reversal of secondary iron overload sequelae.