Literature Publications

Read TIF’s publication:

The Impact of Migration on the Health Services for Rare Diseases in Europe: The example of Haemoglobin Disorders (2013)

Global epidemiology of haemoglobin disorders and derived service indicators, Modell B, Darlison M. (2008)

Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates, Piel FB1, Patil AP, et al(2013)

Sickle cell disease from Africa to Belgium, from neonatal screening to clinical management (2010)

Lê, P.Q., Ferster, A., Cotton, F., Vertongen, F., Vermylen, C., Vanderfaeillie, A., Dedeken, L., Heijmans, C., Ketelslegers, O., Dresse, M.F., & Gulbis, B.

AIM: To describe the severity of sickle cell disease (SCD) in newborns in Belgium and evaluate the impact of neonatal screening (NS) on clinical outcome.

METHODS: Universal NS of umbilical cord blood for hemoglobinopathy was progressively deployed in Brussels and Liège starting in 1994. No particular population was targeted. Samples were analyzed initially using the isoelectric focusing technique and since 2008 the capillary electrophoresis technique. If a hemoglobin variant was suspected, further analysis was carried out using high performance liquid chromatography. Children presenting major hemoglobinopathy, especially SCD, were referred to a specialized centre for comprehensive management. Preventive measures included antipneumococcal prophylaxis immunization/antibiotic therapy, parental training to recognize severe anemia and splenic sequestration, and transcranial ultrasound recording for early detection of intracranial stenosis. A database was set up in Belgium to collect clinical and laboratory data including parental phenotype, diagnostic technique (neonatal screening or not), major clinical events (episodes of dactylitis, acute chest syndrome, severe anemia, infection, etc), number and duration of required hospitalizations, and treatment used.

RESULTS: Screening of 222352 newborns in maternity units in Brussels led to diagnosis of SCD in 145 patients, Adequate data for analysis of clinical outcome was available for 96 of these children born before 2007. Median age in the study group was 4.2 years and the total duration of follow-up was 510 years. Most cases occurred in families from the Democratic Republic of Congo. (64/96 patients; 66.7%) and involved homozygous hemoglobin S disease (80/96 patients; 83.3%). Twenty-seven percent of patients (26/96) presented no severe clinical events during the study (17 SS, median age 2,1 years (0-13.1 years). Conversely 33% presented an episode of dactylitis and 47.9% (46/96) presented recurrent vasoocclusive crises. Severe anemia was observed in 39.6% (38/96) of cases. Six patients (6.3%) developed septicemia despite prophylactic antibiotic therapy and anti-pneumococcal immunization using heptavalent conjugate vaccine and polysaccharide vaccine, no penicillin-resistant strains were observed. The incidence of stroke was 2.1% (3/96). Two patients presenting homozygous hemoglobin S disease died due to septicemia due to non-compliance with antibiotic therapy in one case and severe anemia in one case. All episodes of septicemia and both deaths occurred at the beginning of the NS program. Hydroxyurea therapy was used in 30 patients (31.2%) including 7 in whom transcranial Doppler depicted blood flow abnormalities and 8 in whom allogeneic bone marrow transplantation was performed.

CONCLUSIONS: Sickle cell disease is still associated with high morbidity and mortality but clinical care has improved and no death has occurred in the last 10 years. NS is an effective tool for early detection and management of SCD. Neonates with SCD diagnosed by NS in Belgium presented severe manifestations, but clinical outcomes were improved by comprehensive management.

Med Trop (Mars). 2010 Dec;70(5-6):467-70

HbH disease: clinical course and disease modifiers, Fucharoen S., Viprakasit V.(2009)

Electrocardiographic consequences of cardiac iron overload in thalassemia major (2013)

Cardiac iron and cardiac disease in males and females with transfusion-dependent thalassemia major: a T2* magnetic resonance imaging study, Marsella M., Borgna-Pignatti C., (2011)

Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients, (2012)

Cassinerio E, Roghi A, Pedrotti P, Brevi F, Zanaboni L, Graziadei G, Pattoneri P, Milazzo A, Cappellini MD.

Heart failure due to myocardial iron overload remains the leading cause of morbidity and mortality in adult thalassemia major (TM) patients. We evaluated the removal of cardiac iron and the changes of cardiac function by different iron chelation in TM patients by T2* cardiac magnetic resonance (CMR). Sixty-seven TM patients (27 males/40 females; mean age, 35 ± 6 years) on different chelation regimens underwent T2* CMR at baseline (t (0)), after 6-14 months (t (1)) and after 32 ± 7 months (t (2)). Patients were divided in four groups according to chelation treatment: group A (deferasirox), group B (deferoxamine), group C (combined treatment, deferoxamine plus deferiprone) and group D (deferiprone alone). Myocardial T2* at t (0) was >10 ms in 8 patients, between 10 and 20 ms in 22 patients and ≥ 20 ms in 37 patients. Progressive changes in T2* were observed at t (1) and t (2). Ten patients (10/36, 27.8 %) in group A, three patients (3/15, 20 %) in group B and three patients (3/12, 25 %) in group C moved from an abnormal T2* to normal values. We observed an improvement of left ventricular ejection fraction and a reduction of end-systolic and end-diastolic left ventricular volumes only in patients in group A with baseline cardiac T2* between 10 and 20 ms. Rigorous compliance to any chelation therapy at proper doses significantly improve myocardial T2*. Treatment with deferasirox significantly improves left ventricular function. Combination therapy seems to ameliorate cardiac T2* in a shorter period of time in severe siderosis.

Ann Hematol. 2012 Sep;91(9):1443-9. doi: 10.1007/s00277-012-1480-8. Epub 2012 May 10

How Early Can Myocardial Iron Overload Occur in Beta Thalassemia Major?, Yang G, Liu R, Peng P, Long L, Zhang X, et al. (2014)

Endocrine and bone disease in appropriately treated adult patients with beta-thalassemia major (2010)

Baldini M, Forti S, Marcon A, Ulivieri FM, Orsatti A, Tampieri B, Airaghi L, Zanaboni L, Cappellini MD.

With the optimization of transfusional and chelation regimens, beta-thalassemia has changed from a pediatric disease with poor life expectancy into a chronic disease. Bone demineralization is an important cause of morbidity in older patients; the etiology is multifactorial and partially unknown. We examined, cross-sectionally, 111 adult patients with beta-thalassemia major (66 females and 45 males, 32.6 ± 6 years) who were regularly transfused, sufficiently chelated and replaced for endocrine defects. Bone demineralization was detected in 92.7% of patients with different severity according to gender and site: osteopenia was the prominent finding at the femur, osteoporosis at the lumbar spine (p < 0.001), more evident in males.

The femoral site was more influenced by biochemical and clinical factors; despite adequate replacement, the femoral T-score was lower in the hypogonadic group than in the eugonadic group (p = 0.047). A significant correlation was found between the bone mass and body mass index (BMI), alkaline phosphatase (ALP), and pre-transfusional Hb levels. The multivariate analysis indicated as significant regressors ALP, BMI and hypoparathyroidism (T-score, p = 0.005, 0.035, and 0.002; Z-score, 0.002, 0.009, and 0.003, respectively) at the femoral site; whereas, only ALP at the lumbar spine (p = 0.008 and 0.045 for T-and Z-scores, respectively). The statistical significance was reached more frequently by the T-score, while the Z-score seemed to be a less sensitive parameter. Despite best care facilities, bone demineralization in thalassemic patients remains a challenge. Further exploration of the relationships between bone loss and endocrine, biochemical and hematologic parameters is warranted to find effective measures to reduce the risk of fracture in this disease.

Ann Hematol. 2010 Dec;89(12):1207-13. doi: 10.1007/s00277-010-1007-0. Epub 2010 Jun 26

International network on endocrine complications in thalassaemia (I-CET): an opportunity to grow (2012)

De Sanctis V, Soliman AT, Angastiniotis M, Eleftheriou A, Kattamis Ch, Karimi M, El Kholy M, Elsedfy H, Yassin MA, El Awwa A, Stoeva I, Skordis N, Raiola G, Fiscina B.

Most of the endocrine complications in thalassaemia are attributable to iron overload which may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with the iron chelation therapy. The major difficulties reported by hematologists or pediatric endocrinologists experienced in thalassaemias or thalassaemia syndromes in following growth disorders and endocrine complications were: lack of familiarity with medical treatment of endocrine complications (40%), interpretation of endocrine tests (30%), costs (65%), absence of paediatric endocrinologist for consultation on growth disorders and endocrine complications (27%), facilities (27%), other (e.g. lack of collaboration and on-time consultation between thalassaemic Centers supervised by hematologists and endocrinologists) (17%).

Because any progress we make in research into growth disorders and endocrine complications in thalassaemia should be passed on to all those suffering from it, guaranteeing them the same therapeutic benefits and the same quality of life, on the 8th of May, 2009 in Ferrara (Italy), the International Network on Endocrine Complications in Thalassemia (I-CET) was founded. The I-CET group is planning to conduct, in Ferrara in May 2012, a workshop, "MRI and Endocrine Complications in Thalassaemia", and in Doha (Qatar) in September 2012, a 3-day intensive course entitled, "Growth disorders and Endocrine Complications in Thalassaemia", to provide interested pediatricians, physicians and hematologists from all over the world with an in-depth approach to the diagnosis and management of growth and endocrine disorders in thalassaemic patients.

Georgian Med News. 2012 Apr;(205):52-7

The multifactorial origin of growth failure in thalassaemia

Skordis, N., & Kyriakou, A.

Growth failure in thalassaemia major (TM) has been recognised for many years, and has persisted despite major therapeutic advances. The child with TM has a particular growth pattern, which is relatively normal until age 9-10 years; after this age a slowing down of growth velocity and reduced or absent pubertal growth spurt are observed. The pathogenesis of growth failure is multifactorial. The fundamental problem is the free iron and hemosiderosis-induced damage of the endocrine glands.

Additional factors may contribute to the aetiology of growth delay including chronic anaemia and hypoxia, chronic liver disease, zinc and folic acid and nutritional deficiencies, intensive use of chelating agents, emotional factors, endocrinopathies (hypogonadism, delayed puberty, hypothyroidism, disturbed calcium homeostasis and bone disease) and last but not least dysregulation of the GH-IGF-1 axis.Three phases of growth disturbances according to age of presentation are well recognised, and have different aetiologies: in the first phase growth disturbance is mainly due to hypoxia, anaemia, ineffective erythropoiesis and nutritional factors.

During late childhood (second phase), growth retardation is mainly due to iron overload affecting GH-IGF-1 axis and other potential endocrine complications. Although appropriate iron chelation therapy can improve growth and development, TM children and adolescents treated intensively with desferrioxamine remain short as well, showing body disproportion between the upper and lower body segment. After the age of 10-11 years (third phase), delayed or arrested puberty is an important contributing factor to growth failure in adolescent thalassaemics, who do not exhibit a normal growth spurt. During the last decades therapeutic progress and bone marrow transplantation resulted in a prolonged life expectancy in TM patients. Growth retardation, however, continues to be a significant challenge in these individuals, often affecting their social adjustment and quality of life.

Pediatr Endocrinol Rev. 2011 Mar;8 Suppl 2:271-7.

Longitudinal study on thyroid function in patients with thalassemia major: High incidence of central hypothyroidism by 18 years, Soliman A., Al Yafei F.,et al. (2013)

Nutritional deficiencies in iron overloaded patients with haemoglobinopathies (2009)

Inadequate dietary intake in patients with thalassemia (2012)

Fung EB, Xu Y, Trachtenberg F, Odame I, Kwiatkowski JL, Neufeld EJ, Thompson AA, Boudreaux J, Quinn CT, Vichinsky EP; Thalassemia Clinical Research Network.

BACKGROUND: Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.

OBJECTIVE: Our objective was to assess dietary intake in a large contemporary sample of subjects with thalassemia.

DESIGN: A prospective, longitudinal cohort study using a validated food frequency questionnaire was conducted.

PARTICIPANTS/SETTING: Two hundred and twenty-one subjects (19.7±11.3 years, 106 were female) were categorized into the following age groups: young children (3 to 7.9 years), older children/adolescents (8 to 18.9 years), and adults (19 years or older); 78.8% had β-thalassemia and 90% were chronically transfused. This study took place at 10 hematology outpatient clinics in the United States and Canada.

MAIN OUTCOME MEASURES: We conducted a comparison of intake with US Dietary Reference Intakes and correlated dietary intake of vitamin D with serum 25-OH vitamin D and dietary iron with total body iron stores.

STATISTICAL ANALYSES PERFORMED: Intake was defined as inadequate if it was less than the estimated average requirement. χ(2), Fisher's exact, and Student's t test were used to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, sex, and race.

RESULTS: More than 30% of subjects consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which >90% of subjects consumed adequate amounts were riboflavin, vitamin B-12, and selenium. Dietary inadequacy increased with increasing age group (P<0.01) for vitamins A, C, E, B-6, folate, thiamin, calcium, magnesium, and zinc. More than half of the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of subjects. Dietary iron intake was not related to total body iron stores.

CONCLUSIONS: Subjects with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy are concerning and support the need for nutritional monitoring to determine which subjects are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.

J Acad Nutr Diet. 2012 Jul;112(7):980-90.doi: 10.1016/j.jand.2012.01.017. Epub 2012 May 1

Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance (2008)

Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population (2011)

Ladis V, Chouliaras G, Berdoukas V, Chatziliami A, Fragodimitri C, Karabatsos F, Youssef J, Kattamis A, Karagiorga-Lagana M.

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 50 years, 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 standardized 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.

Eur J Haematol. 2011 Apr;86(4):332-8. doi: 10.1111/j.1600-0609.2011.01582.x.

Preimplantation genetic diagnosis for hemoglobinopathies (2011)

Kuliev A, Pakhalchuk T, Verlinsky O, Rechitsky S.

Hemoglobinopathies are the most frequent indications for preimplantation genetic diagnosis (PGD), allowing couples at-risk of bearing offspring with thalassemia and sickle cell disease to reproduce without fear of having an affected child. The present experience includes PGD for sickle cell disease, α- and β-thalassemia (α- and β-thal). We present here the results of the world's largest experience of over 395 PGD cycles for hemoglobin (Hb) disorders, resulting in the birth of 98 healthy, hemoglobinopathy-free children, with seven pregnancies still ongoing.

One-third of these cases were performed in combination with HLA typing, allowing the birth of unaffected children who were also HLA identical to the affected siblings with hemoglobinopathies in these families, with successful or pending stem cell transplantation in a dozen of them. The results show that PGD is presently a practical approach for prevention of hemoglobinopathies, gradually also becoming a useful approach to improving access to HLA-compatible stem cell transplantation for this group of diseases.

Hemoglobin. 2011;35(5-6):547-55. doi: 10.3109/03630269.2011.608457. Epub 2011 Sep 12

Preimplantation genetic diagnosis, an alternative to conventional prenatal diagnosis of the hemoglobinopathies., Traeger-Synodinos J. (2013)

Guidelines for the Clinical Management of Non-Transfusion Dependent Thalassaemias(2013)- Cappellini M D, Taher A, Musallam K (2013)

Iron overload in non-transfusion-dependent thalassemia: a clinical perspective (2012)

Musallam, K.M., Cappellini, M.D., Wood, J.C., & Taher, A.T.

Iron overload due to increased intestinal iron absorption represents an important clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), particularly as they advance in age. Current models for iron metabolism in patients with beta (β)-thalassemia intermedia (TI) suggest that suppression of serum hepcidin results in increased iron absorption and release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading.

The clinical consequences of iron overload in patients with NTDT are multifactorial and include endocrinopathy, bone disease, thromboembolism, pulmonary hypertension, cerebrovascular and neuronal damage, liver fibrosis or cirrhosis, and increased risk of hepatocellular carcinoma. Although serum ferritin levels correlate with liver iron concentration (LIC), they underestimate iron load in these patients compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended with chelation therapy as indicated.

Blood Rev. 2012 Apr;26 Suppl 1:S16-9. doi: 10.1016/S0268-960X(12)70006-1.

Recent advances in the molecular understanding of non-transfusion-dependent Thalassemia

Galanello, R.

Thalassemias are a group of inherited autosomal recessive hematologic disorders that occur because of defects in the alpha (α)- and beta (β)-globin genes of adult hemoglobin (Hb). An imbalance in the synthesis of one or more of the globin chains can result in a wide spectrum of phenotypes depending on the type and amount of globin synthesized and additional genetic modifiers. In patients with thalassemia intermedia, a condition known as non-transfusion-dependent thalassemia (NTDT), transfusion requirements are absent or episodic. Non-transfusion-dependent thalassemia includes β-thalassemia intermedia, HbE β-thalassemia, and α-thalassemia intermedia, also known as Hb H disease. This article focuses on the molecular features and genetic mutations specific to NTDT.

Blood Rev. 2012 Apr;26 Suppl 1:S7-S11. doi: 10.1016/S0268-960X(12)70004-8.

Recent advances in β-thalassemias (2011)