Inherited Hemoglobin Disorders Research Articles

Therapeutic Value of Silymarin as Iron Chelator in Children with Beta Thalassemia with Iron Overload

Beta thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia. The most common treatment for thalassemia is blood transfusion which is necessary to provide the patients with healthy red blood cells containing normal hemoglobin. Repeated blood transfusion leads to iron overload. Excess iron is deposited in body organs as liver, heart and endocrine glands causing organ damage. Iron chelation therapy is the main way to treat iron overload in beta thalassemia major. Silymarin and its biologically active component Silybin are strong antioxidant and have documented iron chelating activities in patients with beta-thalassemia major. The aim of this review was to spotlight on the therapeutic value of silymarin as iron chelator in children with beta thalassemia major with iron overload.

Therapeutic value of combined therapy with deferasirox and silymarin on iron overload in children with Beta thalassemia.

BackgroundBeta thalassemia is an inherited hemoglobin disorder resulting in a severe, chronic anemia requiring life-long blood transfusion that induces iron overload. Silymarin is a flavonoid complex isolated from Silybin marianum with a strong antioxidant activity, inducing an hepatoprotective action, and probably, a protective effect on iron overload. The aim of this work was to determine the silymarin value in improving iron chelation in thalassemic patients with iron overload treated with Deferasirox.Patients and MethodsThis study was conducted on 40 children with beta thalassemia major under follow-up at Hematology Unit, Pediatric Department, Tanta University Hospital with serum ferritin level more than 1000 ng/ml and was divided into two groups. Group IA: Received oral Deferasirox (Exjade) and silymarin for 6 months. Group IB: Received oral Deferasirox (Exjade) and placebo for 6 months and 20 healthy children serving as a control group in the period between April 2011 and August 2012 and was performed after approval from research ethical committee center in Tanta University Hospital and obtaining an informed written parental consent from all participants in this study.ResultsSerum ferritin levels were markedly decreased in group IA cases compared with group IB (P= 0.001).ConclusionFrom this study we concluded that, silymarin in combination with Exjade can be safely used in the treatment of iron-loaded thalassemic patients as it showed good iron chelation with no sign of toxicity.RecommendationsWe recommend extensive multicenter studies in a large number of patients with longer duration of follow-up and more advanced techniques of assessment of iron status in order to clarify the exact role of silymarin in reducing iron overload in children with beta thalassemia.

Carrier screening for inherited haemoglobin disorders among secondary school students and young adults in Latium, Italy

To reduce the incidence of β-thalassaemia major and other severe haemoglobin-related disorders by the early identification of healthy carriers, the Centro Studi Microcitemie Roma has been organising since 1975 a prevention programme in Latium, an Italian central region. This programme entails two different types of carrier screening on a voluntary basis: a universal screening offered to secondary school students and a screening offered to young adults. In 36years of scholastic screening (from 1975 until 2011), 1,466,100 students have been examined and 26,786 (1.8%) carriers of non-α thalassaemia have been identified. In the extra-scholastic screening, 388,690 adult subjects (including the carriers' relatives) have been examined and a total of 38,457 (9.9%) carriers of non-α thalassaemia have been detected. These results demonstrate that the precocious identification of healthy carriers allowed the identification of at-risk couples and reduced to zero the birth of affected babies in the Latium native population. This programme does not involve huge resources and is relatively inexpensive and, as such, it is essential to be offered to the total Latium scholastic and extra-scholastic population, which is epidemiologically changing due to migratory fluxes from countries in which haemoglobin disorders are common.

Endocrine complications in patients with thalassaemia major

Thalassemia major is an inherited hemoglobin disorder characterized by chronic anemia and iron overload due to transfusion therapy and gastrointestinal absorption. Iron overload causes severe endocrine complications in patients with multi-transfused thalassaemia major. Endocrine complications includes short stature, acquired hypothyroidism and hypoparathyroidism, hypogonadism, glucose intolerance and diabetes mellitus.

Myocardial iron overload in sickle/thalassemia patients of Italian origin

Purpose: Sickle-thalassemia is an inherited hemoglobin disorder resulting from the combined heterozygosity for sickle-cell and β-thalassemia genes. Myocardial iron overload in patients with sickle-thalassemia has been poorly studied; however, a report has shown no evidence of cardiac iron in a small group (n=10) of multitransfused Arab patients. The current study aims to further evaluate cardiac iron overload in a larger group of Italian patients using a T2* multislice approach and explore its correlation with transfusions, age and sex. Methods: Fifty-nine sickle-thalassemia patients (29 males, mean age 35.6±14.1 years), enrolled in the MIOT network were considered. Three parallel short-axis views of the left ventricle were acquired and analyzed with a dedicated software (HIPPO MIOT) providing the T2* value on each of 16 segments as well as the global T2* value averaged over all segmental T2* values and the T2* value in the mid-ventricular segment averaged over the mid-anterior and the mid-inferior septum. Results: We found 55 (93%) patients with all 16 segmental T2* values normal (>20 ms). Of the 4 patients with abnormal segmental T2* values, all showed an heterogeneous MIO (some segments with T2* values >20 ms and other segments with T2* values <20 ms) and none showed an homogeneous MIO (all segment with T2* values <20 ms). Out of the 4 patients with heterogeneous MIO, only one had a global T2* global <20 ms. The mean global heart T2* value was 34.4±6.2 ms. We did not find significant differences among sickle-thalassemia regularly (N=20), sporadically (N=32) and no transfused (N=7) in the T2* global value (33.4±7.3 ms versus 35.5±5.4 ms versus 32.4±6.3 ms; P=0.425). On linear regression analysis, there was a statistically significant positive correlation between global T2* and age but with poor linearity (R=0.368; P=0.004). The global T2* value was not significant different between males and females (35.6±4.9 ms versus 35.2±7.2 ms; P=0.118). Conclusions: In respect of myocardial iron deposition, the sickle/thalassemia patients are similar to patients with homozygous SCD for which iron overloading is relatively rare.

The Role of the Inherited Disorders of Hemoglobin, the First “Molecular Diseases,” in the Future of Human Genetics

Although the inherited hemoglobin disorders were the first genetic diseases to be explored at the molecular level, they still have important messages for the future of medical genetics. In particular, they can offer a better understanding of the evolutionary and population biology of genetic disease, the mechanisms that underlie the phenotypic diversity of monogenic disease, and how, by developing appropriate partnerships, richer countries can help low-income countries to evolve programs for the control and management of these diseases where, in many cases, they are particularly common.

Prevention of the Hemoglobinopathies

The inherited hemoglobin disorders not only cause suffering and unhappiness to the patients but they also absorb a large part of resources and human effort in several countries which harbor the deleterious genes [...]

Heart Failure with preserved ejection fraction (HFPEF) and pulmonary hypertension may complicate cases of Sickle Cell Disease in Saudi patients originally from the Eastern Province, Saudi Arabia

Sickle cell disease is an important chronic inherited haemoglobin disorder, associated with recurrent vaso-occlusive and haemolytic crises and chronic tissue ischemia which may adversely affect any organ system including the cardiovascular system. Our objectives were to evaluate the cardiac performance in general with concentration on LV diastolic function and pulmonary artery pressure in young adult and adult Saudi patients originally from the Eastern province of Saudi Arabia. Forty-five patients with sickle disease were recruited for echocardiographic study while 45 controls, matched for age and sex, served as controls. Left and right ventricular dimensions and wall thicknesses of the LV, LV mass, LV mass index and LV contractility variables were obtained. Left atrial dimension and volume and pulmonary artery systolic pressure were also estimated. We evaluated also parameters of LV diastolic function including early and late atrio-ventricular flow velocities (E and A wave, respectively), E/A ratio, deceleration time (DT), A wave duration (A Dur.), and LV isovolumic relaxation time (IVRT). Other parameters of LV diastolic function including evaluation of Tissue Doppler Velocities, such as lateral annular e′ wave, a′ wave, e′/a′ ratio and E/e′ ratio were evaluated. There were increases in the LV dimensions, LV volumes, stroke volume, and LV mass indexes of the SCD patients. The preload was increased (LV diastolic volume) and afterload was decreased (low diastolic blood pressure). The LV ejection fraction was equivalent. However, there were evidences of LV diastolic dysfunction in 24%, and PH in 40% of the SCD patients. The mean left atrial volume was also increased in the SCD patients. Left ventricular diastolic dysfunction (Heart Failure with Preserved Ejection Fraction – HFPEF) and pulmonary hypertension may complicate cases of the Arab-Indian haplotype of sickle cell disease.

World distribution, population genetics, and health burden of the hemoglobinopathies.

Although information about the precise world distribution and frequency of the inherited hemoglobin disorders is still limited, there is no doubt that they are going to pose an increasing burden on global health resources in the future. Their high frequency is a reflection of natural selection combined with a high frequency of consanguineous marriages in many countries, together with an epidemiological transition; whereby, as public health measures improve in the poorer countries of the world, more babies with these disorders are surviving to present for treatment.

Echocardiographic evaluation of left ventricular diastolic and systolic function in Saudi patients with sickle cell disease

Background and objectivesSickle cell disease (SCD) is a chronic, inherited haemoglobin disorder, associated with recurrent vaso-occlusive and haemolytic crises and chronic tissue ischemia which may adversely affect any organ system. Our objectives were to evaluate the left ventricular (LV) systolic and diastolic functions in Saudi patients with SCD originally from the Eastern Province of Saudi Arabia. Design and settingProspective hospital based echocardiography study on adolescent and adult patients with SCD. MethodsForty-five patients with SCD were recruited for echocardiographic study while 45 patients, matched for age and sex, served as controls. Left and right ventricular dimensions and LV wall thicknesses, LV mass index (LVMI) and LV contractility variables were obtained. Left atrial dimension and volume and pulmonary artery systolic pressure (PASP) were also estimated. We also evaluated parameters of LV diastolic function, including early and late mitral flow velocities (E and A wave respectively), E/A ratio, deceleration time (MVDT), A wave duration (MVA D), LV isovolumic relaxation time (IVRT), and tissue Doppler velocities, such as lateral annular e‘ wave, a‘ wave, e‘/a‘ ratio and E/e‘ ratio. ResultsThere were increases in the LV dimensions, LV volumes, stroke volume, and LVMI of the SCD patients. The preload was increased (LV diastolic volume) and afterload was decreased (low diastolic blood pressure). The LVEF was equivalent, though there was evidence of LV diastolic dysfunction in 24%, and pulmonary hypertension (PH) in 40% of the SCD patients. The mean left atrial volume (LAV) was also increased in the SCD patients. ConclusionLV diastolic dysfunction (heart failure with preserved ejection fraction) and PH may complicate cases of the Arab-Indian haplotype of SCD.

Advances in the treatment of alpha-thalassemia

Alpha (α)-thalassemia represents a group of recessively inherited hemoglobin disorders marked by deficient or absent synthesis of 1 to all 4 of the α-globin genes. Inactivation of 3 α-globin genes – either by deletional or nondeletional mutations – results in hemoglobin H (Hb H) disease. Patients with Hb H disease produce hemoglobin composed of all beta chains and have moderate to severe hemolytic anemia, a variable degree of ineffective erythropoiesis, and splenomegaly. Transfusion requirements vary depending on the mutation and clinical severity. Treatment for deletional Hb H disease is primarily preventative and transfusions are uncommon. Patients with nondeletional Hb H disease (e.g., Hb H Constant Spring) typically have more severe anemia, and approximately one-third require regular transfusions. These patients often require comprehensive, multidisciplinary care. This chapter focuses on screening, diagnosis, and treatment approaches for patients with Hb H disease.

Hemoglobin Showa-Yakushiji: A Common β Thalassemia Mutation Among the Agri Community from Western India

β thalassemia is one of the commonest inherited hemoglobin disorders. The prevalence of β thalassemia varies between 3% and 17% in various caste groups found in India. Hemoglobin Hb Showa Yakushiji results from a single nucleotide change at codon 110(CTG→CCG) in β globin gene. From earlier investigations, it was observed that Hb Showa Yakushiji was present in four Agri families who were referred for prenatal diagnosis. There are no reports on the prevalence of β thalassemia mutations from the Agri community. To find out the prevalence of β Thalassemia and Hb Showa Yakushiji among the Agri community. Testing was conducted in the Agri dominated area around Navi Mumbai. Seven hundred ninety-five blood samples from unrelated Agri individuals were collected. Carrier detection for β thalassemia was done by using standard hematological procedures followed by characterization of mutations. The prevalence of β thalassemia among Agris was found to be 3.64%. Prevalence of Hb Showa Yakushiji among β thalassemia carriers was 24.13%. Among Agris we reported only four β thalassemia mutations. This study has helped us in establishing an algorithm for identifying β thalassemia mutations among Agris that is cost effective and will be useful for offering prenatal diagnosis.

Inherited hemoglobin disorders in an Afro-Amazonian community: Saracura

The most common hemoglobinopathies, viz, hemoglobins S and C, and α- and β-thalassemias, were investigated through the molecular screening of 116 subjects from the community of Saracura, comprising fugitive African slaves from farms of the municipality of Santarém, in the west of Pará State, Brazilian Amazon. The observed frequency of the HBB*S gene (0.9%) was significantly lower than that encountered in other Afro-derived communities in the region. Concomitantly, the absence of the HBB*C allele has been reported for most of the Afro-Amazonian communities thus far studied. As remnant populations of quilombos are generally small, the heterogeneous distribution of HBB*S and HBB*C alleles among them is probably due to genetic drift and/or founder effect. The observed frequency of 3.7 kb deletion in Saracura (8.5%) was consistent with the African origin of the population, with a certain degree of local differentiation and admixture with individuals of Caucasian ancestry, placed in evidence by the occurrence of - -(MED) deletion (1.2%), a common mutation in Mediterranean regions. As regards β-thalassemia, among the seven different mutations found in Saracura, three βo and two β+ mutations were of Mediterranean origin, and two β+ of African. Thus, only 28% of the local β-thalassemia mutations found in Saracura were of African origin.

Using the Cascade Model to Improve Antenatal Screening for the Hemoglobin Disorders

The inherited hemoglobin disorders constitute a major public health problem. Facilitators (experienced hemoglobin counselors) were trained to deliver knowledge and skills to "frontline" practitioners to enable them to support parents during antenatal screening via a cascade (train-the-trainer) model. Objectives of evaluation were to explore the extent that the cascade model was perceived to be embedded in practice, identify enablers and barriers to effective cascading, assess the feasibility of incorporating e-learning into the model, and obtain the facilitators' perceptions of the change process. Focus groups and interviews were undertaken with 50 facilitators. Data were analyzed thematically. Cascading was influenced by contextual factors operating in the work environment, especially workload, existing roles and responsibilities and adequate preparation. Facilitators' confidence and perceptions of success varied for individuals in the same workplace exposed to the same opportunities to receive and deliver training. Cascading could by enhanced by carefully selecting potential facilitators, training needs assessment to identify the knowledge and skills required by individuals, and follow-up to offer ongoing support. Evaluation demonstrated the importance of contextual and individual factors to successful cascading and the feasibility of combining it with e-learning. Future evaluations should consider the perspectives of all stakeholders, namely managers, recipients of cascading and clients, and cost-effectiveness.

Components of an Effective Large Scale Program for the Prevention of Inherited Hemoglobin Disorders; the Paradigm of Greece

Large scale prevention programs for Thalassemia major or Sickle cell disease have already been set up in several places with high frequency of the deleterious genes. The Greek health authorities realized the magnitude of the problem and allowed the creation of a National Thalassemia Center in 1972. The incidence of thalassemia in Greece varies from 1–2 per cent up to 15%, the mean being around 8 per cent. With an annual number of births around 100,000, if no prevention measures are taken, the expected yearly number of newborns with thalassemia major in Greece should be of the order of 100–120. To these one should add a few decades of sickle cell patients, homozygotes or compound HbS/β-thalassemia heterozygotes. The total number of patients with thalassemia major now surviving is estimated at 4000 plus another 600–800 patients with sickle cell disease. The National Thalassemia Center Center defined a network of peripheral Thalassemia Units in the major regional hospitals of the country, let them provide free carrier identification to couples requesting the test. When both partners were identified as carriers, they were given preliminary information locally and were referred to the Central Laboratory in Athens for further genetic counselling and, if so decided, prenatal diagnosis. Prenatal diagnosis was provided initially by fetoscopy and fetal blood biosynthesis; this approach was soon replaced by chorionic villi sampling and molecular techniques. The number of prenatal diagnoses carried out yearly over the last decade appears to cover the needs; the number of positive diagnoses is very close to the expected 25%, which also excludes overdiagnosis. The overall evaluation of the the program is reflected in the number of infants who were admitted to the pediatric clinics of the country in need of transfusion over the years the program was functioning. In fact, over the past years this number has steadily decreased to approximately 10 missed diagnoses annually, but has not reached zero as expected, after all this effort. The function of a comprehensive program for the prevention of thalassemia and HbS disease in Greece over the last 25 years has helped enormously in (a) avoiding birth of several hundreds of children with thalassemia major, thus (b) securing the use of the available resources for the optimal care of the patients who are living to-day, and (c) allowing thousands of couples at risk to give birth to healthy children.

Elevated Hemoglobin A2 as a Marker for .BETA.-Thalassemia Trait in Pregnant Women

β-thalassemia is one of the most prevalent inherited hemoglobin disorders. Compound heterozygotes or homozygous mutations of the β-globin chain gene account for severe cases of β-thalassemia that require lifelong transfusion, and make it necessary to identify β-thalassemia carries for prenatal diagnosis. The increase in hemoglobin A2 (HbA2) level is the most significant parameter in the identification of β-thalassemia carriers. HbA2, composing of two α chains and two δ chains, is a minor component of the hemoglobin present in normal adult red blood cells, accounting for about 2.5% of the total hemoglobin in healthy individuals. However, HbA2 level is also elevated in some pregnant women. This study aimed to evaluate the value of HbA2 level in the screening of pregnant women with β-thalassemia trait. Pregnant and non-pregnant women were randomly recruited who attended the prenatal care or diagnosis at our hospital located in Guangdong, a province in South China. Hemoglobin capillary electrophoresis was performed on high performance liquid chromatography to measure HbA2 levels in blood. The β-globin gene mutations were detected by the PCR-reverse dot-blot assay, and some were verified by direct sequencing. Pregnant women (n = 96) and non-pregnant women (n = 114) with normal HbA2 level (< 3.5%) had no β-thalassemia mutation. In contrast, pregnant women (n = 55) and non-pregnant women (n = 85) with elevated HbA2 level (≥ 3.5%) are β-thalassemia carriers. In conclusion, HbA2 level is a good marker for screening β-thalassemia trait in pregnant women in South China population.

Percutaneous aortic valve replacement in a 65-year old patient with thalassemia intermedia: A case report

Thalassaemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia. Organ damage caused by iron overload represents the major cause of illness and the heart complications secondary to extensive myocardial iron overload are the leading cause of mortality. These patients are generally not considered as candidates for heart transplantation. We report a case of a patient with thalassemia intermedia (TI) with severe cardiac dysfunction and severe aortic stenosis who underwent percutaneous aortic valve replacement (PARV). PARV was a safe and a valid therapeutic approach dramatically to improve the clinical evolution of cardiomyopathies in our patient.

Large scale screening for haemoglobin disorders in southern Vietnam: implications for avoidance and management

In order to obtain an approximate assessment of the public health burden that will be posed by the inherited disorders of haemoglobin in southern Vietnam, several thousand individuals were screened for these conditions. A smaller sample was screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The important haemoglobin disorders identified were beta thalassaemia, haemoglobin E and a variety of different forms of alpha thalassaemia. There were sufficient G6PD-deficient individuals to materially affect malaria control programme design. The most remarkable finding was wide variation in the gene frequencies of these conditions among the ethnic groups sampled. The approximate number of babies expected to be born with clinically significant haemoglobin disorders in Vietnam was estimated from the gene-frequency data. This study emphasizes the importance of wide-scale population screening, including ethnic subgroups, to establish the requirements for inherited haemoglobin disorder programmes in resource-limited settings.

The inherited diseases of hemoglobin are an emerging global health burden

AbstractIt is estimated that in excess of 300 000 children are born each year with a severe inherited disorder of hemoglobin and that approximately 80% of these births occur in low- or middle-income countries. As these countries go through an epidemiologic transition, with a reduction in childhood and infant mortality due to improved public health measures, babies who would have previously died of these diseases before they were recognized are now surviving to present for diagnosis and treatment. Hence, they are presenting an increasing global health burden. Because of their uneven distribution in high-frequency populations, reflecting their complex population genetics, the true magnitude of this burden is still unknown. In many poor countries there are virtually no facilities for the diagnosis and management of these conditions, and even in richer countries there are limited data about their frequency, clinical course, or mortality. Without this information, it will be impossible to persuade governments about the increasing importance of these diseases. The situation will only be improved by concerted action on the part of the hematology community of the richer countries together with input from the major international health organizations and funding agencies.

A new α 0-thalassemia deletion found in a Dutch family (-- AW)

Alpha-thalassemia is an inherited hemoglobin disorder characterized by a microcytic hypochromic anemia caused by a quantitative reduction of the α-globin chain. The majority of the α-thalassemias is caused by deletions in the α-globin gene cluster. A deletion in the α-globin gene cluster, which was found in a Dutch family, was characterized by MLPA, long-range PCR and direct sequencing. We describe the molecular characterization of a novel 8.2 kb deletion (-- AW), involving both α-globin genes in cis. The deletion is caused by a non-homologous recombination event between an Alu and an L1-repeat sequence. This deletion is the third example of a non-homologous recombination event involving an Alu and an L1 repeat, and the first described in the human α-globin gene cluster. Because of a 25% risk of Hb Bart's with hydrops foetalis in the offspring when in combination with another α 0-thalassemia allele, it is important to diagnose this deletion.