A few years ago, an eminent British professor of medicine, while reviewing a new edition of a well-known textbook of medicine, suggested that works of this type were becoming valueless because they were already out of date by the time they were published. His derogatory comments went further: Having taken the trouble to weigh the book, he suggested that volumes of this type would suffer the same fate as dinosaurs and become extinct by collapsing under their excessive weight. Even allowing for this bizarre and completely erroneous view of the biological fate of the dinosaurs, does this argument carry any weight beyond its metaphorical context?

Undoubtedly, there is feeling rife among medical publishers that the day of the major monograph in the biological sciences may be coming to an end. They argue that there is so much information online that the need for works of this type is becoming increasingly limited. Is this really the case? Although it is impossible to deny that the long gestation of monographs of this type may lead to the omission of the occasional “breakthrough” in a field, it seems very important that in any rapidly moving area of the biomedical sciences there is a regular and broad critical review of where it has got to and how it has been modified by recent advances. Not uncommonly in medical research and practice, today's breakthrough is tomorrow's breakdown.

Is the hemoglobin field moving rapidly? This was another question that had to be considered by the editors of this new edition.

It is now widely accepted that the hemoglobinopathies are the most common monogenic diseases in humans. In this chapter we discuss the possible reasons for their very high frequency and uneven distribution among the world's population and describe recent attempts to determine their global health burden and how this might be managed.

FREQUENCY AND DISTRIBUTION

Frequency

A number of attempts have been made to review or determine the global frequency and annual birth rates of homozygotes or compound heterozygotes for the important inherited disorders of hemoglobin. Composite data from these reports for the frequency and distribution by World Health Organization (WHO) regions are summarized in Table 26.1 and similar data for the estimated annual birth rate of severe forms of hemoglobinopathy are summarized in Figure 26.1. As we will discuss later in this chapter, such summaries are based on imperfect data and should be viewed with some caution; nevertheless, it is now generally acknowledged that as a group the hemoglobinopathies represent the most common monogenic diseases of humans.

Any explanation for the extremely high gene frequencies of the inherited disorders of hemoglobin must take into account a number of unusual features about their world distribution. The high-frequency regions stretch across the tropical belt of the Old World or areas into which there has been a high rate of migration from this region.

INTRODUCTION

Clinically, either alone or through their interactions with β-globin structural hemoglobin variants, the β thalassemias are by far the most important forms of thalassemia. Their control and management will pose a major drain on health care resources in the new millennium, particularly in emerging countries in which improvements in sanitation and public health measures have dramatically reduced the number of infant deaths from malnutrition and infection, and hence in which babies with these forms of thalassemia increasingly will survive long enough to present for diagnosis and treatment.

In this chapter we describe the clinical and laboratory features of the severe, transfusion-dependent forms of β thalassemia and their carrier states, and discuss what is known of the diverse family of disorders that fall between these extremes, the β thalassemia intermedias. Readers who wish to learn more about the historical development of this field are referred to the monograph of Weatherall and Clegg. The public health and economic aspects of the thalassemias in the developing countries are discussed in detail by Weatherall et al.

CLASSIFICATION, NOMENCLATURE, AND GENOTYPE/PHENOTYPE RELATIONSHIPS

Despite our increasing knowledge of the molecular pathology of the β thalassemias, it is still useful to retain a broad classification based on their clinical manifestations. The severe, transfusion-dependent forms are designated β thalassemia major, or Cooley anemia, and the symptomless carrier states, thalassemia minor.

INTRODUCTION

Before describing the various ways in which α-globin expression may be downregulated in patients with α thalassemia, it is worth briefly reviewing the normal structure of the human α-globin cluster and how the genes are expressed throughout erythroid differentiation and development.

The α-globin cluster is located in a gene dense region of the genome close to the telomere of chromosome 16 (16p13.3). The genes are arranged along the chromosome in the order, telomere-ς-ψς-αD-ψα1-α2-α1-θ-centromere (Fig. 13.1). Upstream of the α cluster there are four highly conserved, noncoding sequences multispecies conserved sequences called MCS-R1–R4 that are thought to be important in the regulation of the α-like globin genes. They correspond to previously identified erythroid-specific DNase l hypersensitive sites (DHS) referred to as HS-48, HS-40, HS-33, and HS-10, the coordinates referring to their positions (kb) with respect to the ς-globin mRNA cap site. Of these elements, only MCS-R2 (HS-40) has been shown to be essential for α globin expression (summarized in Higgs et al.). The role(s) of the other MCS sequences are as yet unclear.

It has been shown that as progenitors commit to the erythroid lineage and differentiate to form mature red cells, a subset of the key erythroid transcription factors and cofactors (Chapter 4) progressively bind the upstream elements and the promoters of the α-like globin genes. Finally, RNA polymerase II is recruited to both the upstream regions and the globin promoters as transcription starts in early and intermediate erythroblasts.

Over the years, study of the thalassemia syndromes has served as a paradigm for gaining insights into the factors that can regulate or disrupt normal gene expression. The thalassemias constitute a heterogeneous group of naturally occurring, inherited mutations characterized by abnormal globin gene expression resulting in total absence or quantitative reduction of α- or β-globin chain synthesis in human erythroid cells. α Thalassemia is associated with absent or decreased production of α-chains, whereas in the β thalassemias, there is absent or decreased production of β-chains. In those cases in which some of the affected globin chain is synthesized, early studies demonstrated no evidence of an amino acid substitution. In all cases in which genetic evidence was available, the thalassemia gene appeared to be allelic with the structural gene encoding α- or β-globin. The elucidation of the nature of the various molecular lesions in thalassemia has been a fascinating process, and full of surprises. Increase in our knowledge of the molecular basis of β thalassemia has closely followed and depended on progress and technical breakthroughs in the fields of biochemistry and molecular biology. In particular, recombinant DNA and polymerase chain reaction–based technologies have contributed to a virtual explosion of new information on the precise molecular basis of most forms of thalassemia. The accrual of this knowledge has, to a great degree, paralleled the acquisition of new, detailed information on the structure, organization, and function of the normal human globin genes, as described in the preceding chapters.

Over the past 30 years we have become familiar with the way in which different types of hemoglobin are expressed at different stages of development. In the human embryo the main hemoglobins include Hb Portland (ζ2γ2), Hb Gower I (ζ2ε2), and Gower II (α2ε2). In the fetus, HbF (α2γ2) predominates and in the adult, HbA (α2β2) makes up the majority of hemoglobin in red cells. These simple facts belie the complexity of the cellular and molecular processes that bring about these beautifully coordinated changes in the patterns of globin gene expression throughout development.

To understand these phenomena we have to consider the individual components including 1) the origins of erythroid cells in development, 2) the processes by which erythroid cells differentiate to mature red cells at each developmental stage, and 3) the molecular events that produce the patterns of gene expression we observe.

Two different types of erythroid cells are observed during development. The first erythroid cells to be seen in the developing embryo are located in the blood islands of the yolk sac. These primitive erythroid cells are morphologically different from the definitive erythroid cells made in the fetal liver and bone marrow and contain predominantly embryonic hemoglobins. Somewhat later during embryonic development, definitive erythroid and other hematopoietic cells originate from multipotent cells identified in a part of the embryo that lies near the dorsal aorta, in the region close to where the kidneys first develop: the so-called aorta-gonads-mesonephros (AGM) region.

INTRODUCTION

Hemoglobin E (HbE) is the most common abnormal hemoglobin in Southeast Asians, especially among the Khmer, Laotians, and Mon/Khmer speaking people, the Zhuang in Guangxi, People's Republic of China, and in India, Bangladesh, and Sri Lanka. The occurrence of HbE is most concentrated at the border of Thailand, Laos, and Cambodia, an area dubbed the HbE triangle. The gene frequency of HbE is between 0.05 and 0.10, reaching 0.5 in certain parts of Cambodia and the northeast of Thailand. It is estimated that 30 million Southeast Asians are heterozygous for HbE and 1 million are homozygous. The maintenance of so high a gene frequency indicates that the HbE variant somehow improves fitness. Correlation of HbE frequency with the incidence of malaria has been noted, suggesting the action of a balanced polymorphism. Studies of malaria and HbE are detailed in Chapter 26.

CLASSIFICATION OF HbE DISORDERS

In 1954, HbE became the fourth abnormal hemoglobin to be identified by electrophoresis, and a substitution of lysine for glutamic acid at position 26 of the β-globin chain was found in 1961. Many different syndromes are observed when HbE is variously combined with different α and β thalassemias and with other abnormal hemoglobins (Fig. 18.1). They can be classified into asymptomatic and symptomatic forms (Table 18.1).

Asymptomatic Forms

HbE Heterozygotes. HbE heterozygotes are clinically normal with minimal changes in blood counts and erythrocyte indices.

The treatment of hemoglobin disorders is evolving and clinical trials of many new agents are underway. Hydroxyurea is used to increase fetal hemoglobin (HbF) levels, stem cell transplantation has the potential for cure, and a larger repertory of iron chelators might make long-term transfusion more feasible. In this section of five chapters, three cover clinically available treatments, discussing in detail aspects of HbF induction, blood transfusion with iron chelation, and stem cell transplantation. One chapter focuses on innovative treatment approaches that remain, at the time of writing, investigative. Treatments include antioxidants, statins, antiinflammatory agents, transport channel inhibitors, antiadhesive agents, and therapeutic methods of increasing nitric oxide bioavailability. The first patients have been treated in a gene therapy trial in which lentiviral vectors containing therapeutic β-like globin genes are used to counter the results of the sickle or β thalassemia mutation, and a final chapter brings this field up to date.

Transfusions are not innocuous and are complicated by alloimmunization, the transmission of unsuspected viral diseases, and iron overload. Controlled, randomized trials of the utility of transfusions for specific complications are sparse. When transfusion is contemplated, expert opinion, with its pitfalls, is relied on in most instances. Usually, it is unclear if simple transfusion or exchange transfusion yields superior results for sickle cell disease complications such as stroke in children or the acute chest syndrome. Strong personal feelings among clinicians regarding the method of transfusion make the chance of definitive clinical trials dim.