The different patterns of insulin response during Oral Glucose Tolerance Test (OGTT) in transfused young patients with ß-Thalassemia.

BACKGROUND AND AIM: Dysregulation of glucose metabolism is a common complication of transfusions in Transfusion Dependent Thalassemia (TDT) patients. For early diagnosis of glucose disturbances, screening is recommended. The age of starting and the type of screening vary; the more common methods are assessment of RPG, FPG, 2h PG and 2 hours OGTT. The combined assessment of glucose tolerance and insulin response during OGTT is rarely recommended. The main objective of the study is the evaluation of simultaneous assessment of Glucose Tolerance (GT) and Insulin Response (IR) during OGTT in patients with TDT. METHODS: 43 TDT patients aged 12-28years, without clinical evidence of glucose disturbances, were randomly selected for the study. The 2-hour OGTT in 30 minutes intervals was applied. Plasma glucose and insulin were assessed in all samples using routine laboratory methods. RESULTS: Of 43 patients 31(72%) had Normal GT; of them 9 (29%) had normal insulin response  (NIR), 14 (45%) high IR and 8(26%) delayed peak IR. Delayed peak IR was found in 8 of the 9 patients with Impaired GT and in 2 of the 3 with diabetic GT. Deficient IR (hypoinsulinemia) was found in two patients. CONCLUSIONS: Simultaneous assessment of GT and IR during OGTT in TDT patients, seems to be a most sensitive and creditable screening test for early diagnosis of glucose disturbances. High IR and delayed peak IR in normoglycemic patients are valuable indices for diagnosis of the pre-diabetic state that precede the development of glucose disturbances in TDT patients and start proper follow and management.

Evaluation of endocrine complications in beta-thalassemia intermedia (ß-TI): a cross-sectional multicenter study.

BACKGROUND: Data on the prevalence and type of endocrine disorders in ß-thalassemia intermedia (ß-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of ß-TI patients. METHODS: In this cross-sectional multicenter study, 726 ß-TI patients, aged 2.5-80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5-80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. RESULTS: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729-13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944-13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217-140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012-2.977, P = 0.045). Hydroxyurea was identified as a "protective factor" for NIDDM (Odds ratio: 0.259, 95% CI: 0.074-0.902, P = 0.034). CONCLUSIONS: To the best of our knowledge, this is the largest cohort of ß-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with ß-TI compared with ß-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in ß-TI patients.

Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries.

BACKGROUND: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. AIMS OF THE STUDY: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. RESULTS: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with ß- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other "general medical and non-medical conditions". CONCLUSIONS: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care.

An ICET-A survey on occult and emerging endocrine complications in patients with ß-thalassemia major: Conclusions and recommendations.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the  reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of  physicians' current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended.

Thirty-year experience in preventing haemoglobinopathies in Greece: achievements and potentials for optimisation.

OBJECTIVES: Beta thalassaemia major (ß-TM) and sickle-cell disease (SCD) are severe haemogobinopathies requiring life-lasting, advanced medical management. In the Mediterranean region, both conditions occur with high frequency. We assessed the efficacy of the National Program for the Prevention of Haemoglobinopathies in Greece during the last 30 yrs. METHODS: Data of affected births between 01/01/1980 and 31/12/2009 were collected in a nationwide scale, and expected vs. observed rates of new births were calculated and compared. In a subpopulation of affected births of Greek origin, the causes for occurrence of the new affected birth were also collected and analysed. RESULTS: Overall, the reduction in new cases was 81.1% and 84.6% for ß-TM and SCD, respectively. For ß-TM, a constant declining trend was recorded over the 30-yr period, whereas for SCD, a transient reversal was observed in the mid-1990s probably due to the significant influx of immigrants of African origin. Programme failure was 2.2 times more common among new ß-TM births of Greek origin compared to new SCD cases (P < 0.001). Unawareness and parental choice were more frequent in SCD compared to ß-TM (unawareness: OR = 1.4, P = 0.05, parental choice: OR = 1.9, P = 0.01). The main cause for programme failure was carrier misidentification and incorrect genetic advice for ß-TM and SCD, respectively. CONCLUSIONS: The ß-TM and SCD prevention programme in Greece has significantly reduced the numbers of new affected births. The outcomes could be optimised in groups of non-Greek origin, in carrier identification and by offering specialised genetic counselling.

Impact of magnetic resonance imaging on cardiac mortality in thalassemia major.

PURPOSE: To evaluate whether the introduction of magnetic resonance imaging (MRI) in the management of thalassemia major (TM) patients has affected the risk of cardiac death. MATERIALS AND METHODS: In all, 804 TM patients from two large reference units were included and the risk of dying of cardiac causes, before and after their first MRI, was assessed by a Cox proportional hazards model with time-dependent covariates. RESULTS: Adding information from MRI reduced the risk of cardiac death from 6.0 deaths/1000 patient-years to 3.9 deaths/1000 patient-years (P = 0.22). The risk of cardiac death before having an MRI study was 82% higher compared to the risk observed after the first MRI. CONCLUSION: MRI has become a vital component of ongoing management and seems to have a beneficial effect on cardiac mortality in TM.

Natural and vaccine-induced immunity to Neisseria meningitidis serogroup C in asplenic patients with ß-thalassemia.

Natural and vaccine-induced immunity to meningococcus C (MenC) was evaluated in asplenic adolescents and adults with ß-thalassemia. At baseline 19.3% of patients and 22.8% age-matched controls had positive (>2 µg/ml) naturally acquired Men C- specific IgG antibodies; patients had a lower probability of having protective SBA compared to controls (OR=21, p=0.012). MenC conjugate vaccine (MCC) induced protective IgG concentrations in 63% of patients and 90.1% of controls. SBA increased significantly post vaccination and there were no differences between patients and controls; however patients had significantly lower IgG concentrations post vaccination compared to controls (4.52 vs 10.94 µg/ml, p<0.001, respectively). A second dose of MCC given to 11 patients who had received MCC in the past induced higher IgG compared to primary response (p=0.001). Naturally- and vaccine-induced immunity to MenC is impaired in asplenic ß-thalassemics; a second dose of MCC improves vaccine immunogenicity and is essential for their optimal protection.

Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population.

BACKGROUND: With transfusions and chelation therapy, the prognosis for transfusion-dependent beta thalassaemia has changed from being fatal in early childhood to a chronic disorder with prolonged survival. DESIGN AND METHODS: In this historical prospective study, we present survival, causes of death and mortality ratios compared to the general population in 1044 Greek patients with transfusion-dependent beta thalassaemia. RESULTS: At the age of 50years, the overall survival was 65.0%, while the cardiac death-free survival was 77%. Birth cohort had a significant effect on survival (P<0.001) with a negative trend towards past decades. The standardised mortality ratio (standardised for sex and ages 20-40years) compared to the general population improved significantly from 28.9 in 1990-1999 to 13.5 in 2000-2008, while the standardised cardiac mortality ratio reduced from 322.9 to 106.6, respectively. CONCLUSIONS: Survival in thalassaemia has dramatically improved over the last twenty years but mortality remains significantly increased, compared to the general population.

Deferasirox administration for the treatment of non-transfusional iron overload in patients with thalassaemia intermedia.

Abnormal iron regulation in patients with thalassaemia intermedia may lead to iron overload even in the absence of transfusions. There are limited data on iron chelator use in patients with thalassaemia intermedia and no guidelines exist for the management of iron overload. We present data from 11 patients with thalassaemia intermedia treated with deferasirox (Exjade(®) , 10-20 mg/kg/d) for 24 months. Liver iron concentration and serum ferritin levels significantly decreased over the first 12 months (P = 0·005) and continued to decrease over the remainder of the study (P = 0·005). This small-scale study indicated that deferasirox may be suitable for controlling iron levels in patients with thalassaemia intermedia.

Cardiac magnetic resonance in transfusion dependent thalassaemia: assessment of iron load and relationship to left ventricular ejection fraction.

Cardiac Magnetic Resonance (CMR) has replaced all other surrogate measurements in the determination of transfusional cardiac iron overload in patients with thalassaemia major. We aimed to determine the diagnostic value of CMR T2* with respect to cardiac dysfunction (CD) as determined by CMR-derived left ventricular ejection fraction (LVEF). Cardiac T2* values and LVEF measured by CMR were recorded in 303 patients with thalassaemia major, at the time of their first CMR. T2* was correlated with LVEF (regression coefficient: 0·57, P<0·001). The prevalence of CD was 32·9% in patients with T2*≤8 ms, 12·5% in patients with T2*>8 ms and ≤14 ms and reduced to 9·1% in patients with T2* between 14-20 ms. As the probability of CD is progressively, and not suddenly, reduced with increasing values of T2*, CMR has a limited diagnostic value for CD (Receiver operating characteristic analysis, area under the curve = 0·68). Patients with cardiac T2*≤8 ms require careful and intensive management. This risk decreases with increasing values of T2* but even in mildly loaded patients the probability of impaired LVEF is not negligible.

A rare thalassemic syndrome caused by interaction of Hb Adana [alpha59(E8)Gly-->Asp] with an alpha+-thalassemia deletion: clinical aspects in two cases.

Hb Adana is a highly unstable and rare alpha-globin hemoglobin (Hb) variant, to date described in only three families, in interaction with other alpha-thalassemia (alpha-thal) deletions. We describe the clinical and hematological findings in two cases from independent families of Albanian origin, who have an interaction of the codon 59 (Gly-->Asp) alpha2-globin gene variant in trans to a 3.7 kb alpha(+)-thal deletion (alpha(codon 59)alpha/-alpha). We report their presenting symptoms and laboratory findings as well as complications and differences in their clinical management. Both cases can be characterized as thalassemia intermedia and illustrate the problems associated with selecting the most appropriate options for patient management, especially in cases with rare underlying genotypes.

Study of bone density by pQCT analysis in healthy adults and patients with B-thalassemia major and intermedia.

BACKGROUND: Bone changes are a prominent symptom of beta-thalassemias, related to expansion of bone marrow and reduction of bone density. Conventional treatment ameliorates bone changes and improves survival, thus increasing the morbidity of bone diseases in adulthood. Peripheral quantitative computer tomography (pQCT) was used recently to assess the changes in volumetric bone mineral density (vBMD) in various bone compartments. OBJECTIVES: Assessment of indices of bone density and structure in patients with thalassemia major (thal-major) and intermedia (thal-interm) on conventional therapy and in healthy adults. MATERIAL AND METHODS: 45 patients with thal-major, 27 with thal-interm and 32 healthy individuals aged 21-42 years were studied by pQCT analysis. The vBMD total (tot), trabecular (trab) and cortical (cort), the bone mineral content (BMC), the cross sectional area (CSA), the cortical thickness (CRTHK) and the stress strain index (SSI) were assessed at the 4% site of the distal radius. RESULTS: Tot, trab, and cort vBMD, BMC, and cortical thickness showed statistically significant differences among the three groups with significant reduction in thalassemics. No significant differences were found in the three groups with CSA and SSI. Impairment of bone density and structure in Greek thalassemics on proper treatment was not as severe as expected. A significant proportion of patients had bone density indices within the normal range and above the 10th percentile of normal. CONCLUSIONS: Peripheral QCT analysis is a convenient method to study the regional changes of bone density in patients with thalassemia. These changes affect mainly the cortical compartment and are more pronounced in thalassemia intermedia.

Quantification of siderophages in bronchoalveolar fluid in transfusional and primary pulmonary hemosiderosis.

Transfusional iron overload may occur in the lungs. We hypothesized that quantitating siderophages in the bronchoalveolar fluid (BALF) of heavily transfused patients may prove to be a useful tool in determining lung iron overload in transfusion-dependent patients. The study included six patients (7-20 years) with thalassemia major (TM) who had received multiple blood transfusions, one with hereditary spherocytosis (four blood transfusions) and one with sickle cell disease (never transfused); they were compared to three children with idiopathic pulmonary hemosiderosis (IPH) (2.5-7.0 years) as positive controls. Fiberoptic bronchoscopy with bronchoalveolar lavage was performed in seven patients under general anesthesia for elective surgery and the rest were bronchoscoped electively under sedation. Spirometry was also performed in eight patients. There was no significant difference between children with TM and IPH in siderophages as percentage of total count (95% CI -31.0 to 1.5, P = 0.068). There were positive relationships between both mean serum ferritin values during the preceding year and the total number of units of transfused blood, and percent siderophage count among multiply transfused patients (P = 0.010, P = 0.052, respectively); similar findings were noted for the Golde score (P = 0.001, P = 0.031, respectively). None of the patients showed lung function impairment. In conclusion, in this small study, we found that the BALF of multiply transfused patients with benign hematological disorders contain similar numbers of siderophages to that of patients with IPH; this is strongly suggestive of secondary pulmonary hemosiderosis. The correlation between the patients' serum ferritin, and the BALF siderophages suggests that the later may serve as a marker of pulmonary iron overload in patients requiring blood transfusion and appear to be more sensitive than standard pulmonary function tests.

The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major.

Hepcidin production is homeostatically regulated by iron stores, anemia and hypoxia. We evaluated the effect of iron overload and of ineffective erythropoeisis on hepcidin expression in patients with thalassemia major. Liver hepcidin mRNA levels correlated with hemoglobin concentration and inversely correlated with serum transferrin receptor, erythropoietin and non-transferrin-bound iron. They did not correlate with indices of iron load. Urinary hepcidin levels were disproportionably suppressed in regards to iron burden. We conclude that hepcidin expression is regulated mainly by increased erythropoietic activity rather than by iron load and that hepcidin plays a central regulatory role in iron circulation and iron toxicity in patients with thalassemia.

Longitudinal study of survival and causes of death in patients with thalassemia major in Greece.

Iron-induced organ degeneration is the main factor of mortality in patients with thalassemia major. Since chelation therapy is at a turning point, from the laborious parenteral route to the use of new promising oral agents, we investigated the current status of survival of these patients to present reliable data that will be useful in future comparative studies. Survival probabilities were estimated by the Kaplan-Meier method, and results were compared by the log-rank test in a total of 647 thalassemic patients (pts) (52% males) born between 1/1/58 and 1/2/04. Terminal follow-up was 1/12/04. All transfusion-dependent pts monitored in our center, or in frequent contact if they had moved elsewhere, were strictly selected, excluding all rarely transfused or intermediate cases. Pts born before 1/1/75 were classified in group A (n = 366), while pts born later were included in group B (n = 281). According to the last 5 years' mean serum ferritin level, pts were divided into three hemosiderosis groups: (1) mild (<2000 microg/L) 49%, (2) moderate (2000-4000 microg/L) 28%, and (3) severe (>4000 microg/L) 23%. Of the 647 pts, 115 died (mean age: 22.6 +/- 6.2 years), most frequently by heart failure (71.3%) followed by sepsis (7.8%). Life expectancy in the entire population was up to 59% at 46 years. Survival was higher for pts born after 1975 than those before (P < .001). Statistically significantly different survival probabilities were found between groups with mild, moderate, or severe hemosiderosis (P < .001). Effective management with improved chelation therapy could lead to better results.

Echocardiographic and electrocardiographic prognostic factors of heart failure in young patients with beta-thalassemia major: a 10-year (1995--2004) follow-up.

Despite intense iron-chelation therapy, the life expectancy of patients with beta-thalassemia major (beta-TM) is still limited by the occurrence of heart failure. In the present study, we sought to evaluate the prognostic significance of several clinical factors on the outcome of heart failure or arrhythmias in patients with beta-TM. The study group consisted of 131 consecutive young patients with beta-TM (71 men aged 21+/-4 years, 60 women aged 22+/-5 years) who were initially examined during 1995. The clinical and vital statuses of all patients were biannually reviewed from 1995 to 2004. Cox proportional hazards models were used to evaluate the association of the occurrence of death or nonfatal events due to heart failure or arrhythmias with clinical factors (systolic and diastolic blood pressures), echocardiographic factors (left and right ventricular diameters, left atrial and aortic root dimensions, left ventricular ejection fraction), electrocardiographic factors (T-wave inversion in leads V1-V3, QRS duration, heart rate), and serum ferritin levels, after controlling for age, sex, and body mass index. During the follow-up, 11 men (16%) and 5 women (8%) had an event (men versus women, P = .212). The age-adjusted event rate was 16 events per 913 person-years (2%). The presence of T-wave inversion in right precordial leads (hazard ratio = 3.06; 95% confidence interval [CI], 1.1-8.8), increased heart rate (hazard ratio = 1.28; 95% CI, 1.03-1.58), decreased aortic root diameter (hazard ratio = 0.84; 95% CI, 0.73-0.96), and decreased ejection fraction (hazard ratio per 1% change = 0.95; 95% CI, 0.91-0.99) were associated with a higher risk for a cardiac event. We revealed that the presence of T-wave inversions, increased heart rate, low ejection fraction of the left ventricle, and decreased aortic root diameter appear to confer higher risk for cardiac events in young patients with beta-TM.

Evolution of glucose intolerance and diabetes in transfused patients with thalassemia.

OBJECTIVE: To study the evolution of glucose disturbances (GD) in patients with thalassemia aged 11-30 years. DESIGN AND METHODS: A total of 263 patients, classified into three groups on the basis of age, and period of follow-up ranging from 2-10 years, were studied. Evolution of GD was assessed through serial oral glucose tolerance tests (OGTT), based on WHO criteria. RESULTS: At baseline (11-14 years of age) evaluation of OGTT disclosed a prevalence of 16.3% of impaired glucose tolerance (IGT), and zero for diabetic tolerance (DT). Prevalence of IGT increased progressively up to 39% in the following 4 years, but remained constant during the last 6 years of observation. In contrast, DT had a very low prevalence, beginning with 0.5% at 13-16 years, increasing to 2.4% by the age of 21-24 years. CONCLUSIONS: During puberty and early adolescence impaired glucose tolerance (IGT) was found in a considerable proportion of thalassemics. In contrast, DT was infrequent and progression to DM was slow. Only 12.4% of patients with IGT developed DT within a period of 10 years. Further studies are necessary to identify all of the factors contributing to abnormalities of glucose metabolism in thalassemic patients.

Bone density study at the distal radius, using pQCT analysis, in Greek thalassemic patients.

BACKGROUND: Expansion of marrow spaces in thalassemia patients contributes to reduced bone density and increased risk of fractures. Peripheral quantitative computed tomography (pQCT) measures the volumetric bone mineral density (vBMD) independently in different compartments. OBJECTIVE AND METHODS: To study the regional bone structure in thalassemia, we performed pQCT (XCT-2000 Scanner, Stratec Inc.) in 57 young adult patients with beta-thalassemia major, aged 21-44 years (32 females). The vBMDs (total, trabecular, cortical + subcortical), Stress-Strain Index (SSI) and the cross-sectional area (CSA) were determined at the "4% site" of the distal radius; data were compared to reference values. RESULTS: Total vBMD, trabecular, cortical plus subcortical vBMD in thalassemics were significantly lower than in healthy adults (p<0.005). Thalassemic males had significant higher values of vBMD, SSI and CSA than females (p<0.005). CONCLUSIONS: In Greek thalassemic patients a significant reduction in bone density, associated with increased morbidity and risk of fractures, has been detected on pQCT examination.