Iron deficiency anemia arises when the balance of iron intake, iron stores, and the body's loss of iron are insufficient to fully support production of erythrocytes. Iron deficiency anemia rarely causes death, but the impact on human health is significant. In the developed world, this disease is easily identified and treated, but frequently overlooked by physicians. In contrast, it is a health problem that affects major portions of the population in underdeveloped countries. Overall, the prevention and successful treatment for iron deficiency anemia remains woefully insufficient worldwide, especially among underprivileged women and children. Here, clinical and laboratory features of the disease are discussed, and then focus is placed on relevant economic, environmental, infectious, and genetic factors that converge among global populations.

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Iron Deficiency Anemia: A Common and Curable Disease

More than 100 varieties of α-thalassemia have been identified. Their geographic distribution and the challenges associated with screening, diagnosis, and management suggest that α-thalassemias should have a higher priority on global public health agendas.

The α-Thalassemias

The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and β-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and β-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.

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The Switch from Fetal to Adult Hemoglobin

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.

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

As discussed by Williams and Weatherall (2012), HbE occurs at an extremely high frequency in many countries in Asia. Because there is also a high frequency of different β-thalassemia alleles in these populations, the coinheritance of HbE and β thalassemia, HbE β thalassemia, occurs very frequently. Similarly, because different forms of α thalassemia are also very common in these countries, HbE also occurs together with them, producing a complex series of phenotypes.

The first description of HbE β thalassemia appeared in a paper by Minnich and her colleagues in 1954 under what, at the time, was the rather surprising title “Mediterranean Anaemia: A study of 32 cases in Thailand” (Minnich et al. 1954). In the same year, the first electrophoretic identification of HbE was reported independently (Itano et al. 1954). The first detailed clinical description of HbE β thalassemia was reported in 1956 by Chernoff and colleagues (1956). Much later, groups in Thailand began a detailed analysis of the interaction of the various forms of α thalassemia with HbE, which result in a complex series of phenotypes, most of which are much milder than HbE β thalassemia (Wasi et al. 1969).

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The Hemoglobin E Thalassemias

Hemoglobinopathies are a heterogeneous group of monogenic disorders widespread overall. They are commonly subdivided into three partially overlapping subgroups: structural variants which comprise the sickle cell anemia syndrome; thalassemias, characterized by a reduced rate of synthesis of one or more globin chains of hemoglobin; conditions of high persistence of fetal hemoglobin in adulthood (HPFH) (Weatherall & Clegg, 2001). As a group, they are the commonest monogenic disorders in the world population. It is thought that the high prevalence of these defects could be due to selective advantage of the carrier state to malaria infection. However, in spite of epidemiological evidences supporting this hypothesis as well as of extensive hematological studies, the mechanisms underlying this protection still remain unknown. It is, however, evident that as a consequence of this positive selection, these diseases are mostly common in geographic areas extending from the Mediterranean region through tropical countries including Sub-Saharian Africa, the Middle East, India, Southeast Asia and Indonesia, where malaria was or still is endemic (Weatherall & Clegg, 2001). In many of these areas the estimated frequencies of these disorders range from 3 to 10 percent, even though in some specific areas the carrier frequencies may be higher, reaching 80-90% in some tribal populations in India (Harteveld & Higgs, 2010). Because of their high frequencies, different hemoglobin defects may be co-inherited, giving rise to an extremely complex series of genotypes and clinical phenotypes. In fact, in many regions thalassemic defects coexist with structural Hb variants; it is also quite common for individuals from areas at high frequency of thalassemic defects to inherit genes for more than one type of thalassemia. Furthermore, some Hb variants are synthesized at reduced rate or are highly instable, leading both to functional and structural deficiency of the affected globin chain, thus resulting in a thalassemic condition, generally showing dominant inheritance. These complex interactions contribute to generate a wide range of clinical disorders that, taken together, constitute the thalassemic syndromes (Weatherall, 2001). The complex and heterogeneous spectrum of molecular defects underlying these inherited conditions is regionally specific and in most cases the geographic and ethnic distributions have been determined, providing support for prevention programs based on screening, genetic counselling and prenatal diagnosis in couples at risk.

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Molecular Basis of Thalassemia

During development the human β-globin gene cluster undergoes two switching processes at the embryo-fetal and fetal-adult stages, respectively, involving changes in chromatin remodeling and in transcriptional regulatory networks. In particular, during the perinatal period, the switch from fetal-to-adult globin gene expression leads to fetal globin genes silencing and progressive decline of fetal hemoglobin (HbF). Impaired hemoglobin switching is associated with hereditary persistence of HbF (HPFH), a condition in which the fetal globin genes fail to be completely silenced in adult red blood cells. This condition, when co-inherited with hemoglobinopathies, has great therapeutic potential because elevated HbF levels can ameliorate β-thalassemia and sickle cell anemia. Therefore, there is a growing interest about the complex network of factors that regulate fetal globin genes expression. Here we discuss the activity of transcriptional repressors of fetal globin genes and their potential role as novel therapeutic targets in β-thalassemia.

https://www.intechopen.com/citation-pdf-url/70744

Transcriptional Repressors of Fetal Globin Genes as Novel Therapeutic Targets in Beta-Thalassemia

In this cross-sectional study we assessed the vascular alterations in retinal and choriocapillaris perfusion in patients affected by β-thalassemia, by means of optical coherence tomography angiography (OCTA) A total of 124 eyes of 62 patients (mean age 4474 ± 579 years old) affected by β-thalassemia (transfusion dependent thalassemia (TDT), non-transfusion dependent thalassemia (NTDT) and minor) were compared to 40 eyes of twenty healthy subjects We evaluated the vessel density (VD) in superficial capillary plexus, deep capillary plexus, radial peripapillary capillary, choriocapillaris and the foveal avascular zone area The TDT group showed a statistically significant reduction in retinal and choriocapillaris VD respect to controls and the other groups (p < 005) No statistically significant difference was found in OCTA parameters between β-thalassemia minor and controls The NTDT group showed a significant reduction in VD in deep capillary plexus respect to controls and β-thalassemia minor Significant negative correlations were shown in TDT group between foveal avascular zone and hemoglobin (r = -0437, p = 0044) and between ferritin levels and VD of choriocapillaris (r = -0431, p = 0038) The OCTA parameters provided a deeper understanding on retinal and choriocapillaris vascular impairment affected by tissue hypoxia levels and the oxidative stress in different clinical phenotypes of the β-thalassemia

Retinal and Choriocapillaris Vascular Changes in Patients Affected by Different Clinical Phenotypes of β-Thalassemia: An Optical Coherence Tomography Angiography Study.

Background: We performed counselling for prenatal diagnosis (PD) of haemoglobinopathies in 372 couples. Thirty-four out of 372 (9.1%) did not undergo PD: six due to spontaneous abortion; nine because it was too difficult to make a decision if PD was positive; 18 because counselling excluded the carrier status of one or both parents; and one because parental mutations were mild. Methods: Eleven out of 338 (3.3%) couples underwent PD because they had a thalassaemic child; 106 (31.4%) were found to be at high risk during pre-conceptional screening; 221 (65.4%) because of familiarity. Of 523 PDs in 486 (92.9%), including six dichorionic twin pregnancies, PD was performed on DNA from chorionic villi (CV), and in 37 from amniocytes (7.1%). In 1/523 cases, PD was not completed because DNA from CV was not sufficient; in two cases single tandem repeat analysis revealed maternal contamination of foetal DNA; in 7/522 (1.3%) cases PD revealed non-paternity. In 435/522 (83.3%) cases, PD was performed using reverse dot-blot and ARMS; 34/522 (6.5%) required sequencing. In 53/522 (10.2%) cases it was necessary to test globin loci for large rearrangements. Results: One hundred and twenty out of 522 (23.0%) PDs revealed an affected foetus. In all but two cases the couple interrupted pregnancy. In the six twin pregnancies PD revealed a normal and a carrier foetus (two cases), carrier status in both foetuses (two cases) and a carrier and an affected foetus (two cases). In these latter cases the couple planned selective interruption. Conclusions: Our PD procedure is successful and reliable, and is useful in high-risk areas characterised by molecular heterogeneity.

Prenatal diagnosis of haemoglobinopathies: our experience of 523 cases.

We describe a novel deletion causing heterozygous eγδβ-thalassemia (eγδβ-thal) across three generations of a Greek family. The Greek deletion is about 72 kb in length, spanning from the hypersensitive site 4 (HS4) in the locus control region (LCR) to the 3' end of the β-globin gene, thus encompassing the entire β-globin gene cluster. The deletion caused severe but transient neonatal anemia and a non transfusion-dependent chronic hemolytic anemia state later in life, resembling mild β-thalassemia intermedia (β-TI) rather than β-thalassemia (β-thal) trait, as had been previously reported. Apart from the presentation of clinical and laboratory characteristics, the challenges involving clinical management are also discussed.

A Novel εγδβ-Thalassemia Deletion Associated with Severe Anemia at Birth and a β-Thalassemia Intermedia Phenotype Later in Life in Three Generations of a Greek Family.

Maria Rosaria Storino

Papers

Molecular Basis of Thalassemia

Transcriptional Repressors of Fetal Globin Genes as Novel Therapeutic Targets in Beta-Thalassemia

Retinal and Choriocapillaris Vascular Changes in Patients Affected by Different Clinical Phenotypes of β-Thalassemia: An Optical Coherence Tomography Angiography Study.

Prenatal diagnosis of haemoglobinopathies: our experience of 523 cases.

A Novel εγδβ-Thalassemia Deletion Associated with Severe Anemia at Birth and a β-Thalassemia Intermedia Phenotype Later in Life in Three Generations of a Greek Family.