Page 644 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 40

THALASSEMIA SYNDROMES

John Chapin and Patricia J. Giardina

The thalassemia syndromes are a heterogeneous group of inherited sickle cell anemia), which are characterized by the production of
anemias characterized by defects in the synthesis of one or more of normal amounts of mutant globin chains having deranged physical
the globin chain subunits of the hemoglobin (Hb) tetramer. The or chemical properties, the thalassemias are quantitative disorders: the
clinical syndromes associated with thalassemia arise from the com- primary lesion lies in the amount of globin produced. However, some
bined consequences of inadequate Hb production and imbalanced rare forms of thalassemia are characterized by the production of
accumulation of globin subunits. The former causes hypochromia structurally abnormal globin chains in reduced amounts, which are
and microcytosis; the latter leads to ineffective erythropoiesis (IE) and described in more detail in this chapter. These thalassemic hemoglo-
hemolytic anemia. Clinical manifestations are diverse, ranging from binopathies share features of thalassemia as well as those of structural
asymptomatic hypochromia and microcytosis to profound anemia, hemoglobinopathies. 6
which can be fatal in utero or in early childhood if untreated. This Some mutations alter the patterns of fetal to adult Hb switching.
heterogeneity arises from the variable severities of the primary bio- These conditions, called hereditary persistence of fetal Hemoglobin, are
synthetic defects and coinherited modifying factors, such as increased not generally associated with clinical symptoms; nonetheless, they
synthesis of fetal globin subunits or diminished or increased synthesis merit consideration in this chapter. Their importance lies in their role
of α-globin subunits. Palliative treatment of the severe forms by as modulating factors when coinherited with other hemoglobinopa-
blood transfusion is eventually compromised by the concomitant thies. They are also useful models for investigating the molecular basis
problems of iron overload, alloimmunization, and bloodborne for globin gene regulation during human development and as para-
infections. digms for rational therapy for the major β-chain hemoglobinopathies,
As a group, the thalassemias represent the most common single namely, sickle cell anemia and β-thalassemia.
genetic disorder known. In many parts of the world, they constitute
major public health problems. Laboratory analysis of these disorders
has been one of the most productive and enlightening endeavors of ETIOLOGY, EPIDEMIOLOGY, AND PATHOPHYSIOLOGY
biomedical research. Study of the molecular defects underlying the
thalassemia syndromes has led to fundamental advances in our Thalassemias have been encountered in virtually every ethnic group
understanding of eukaryotic gene structure and function. For each of and geographic location. Thalassemia carriers affect 1.5% of the
these reasons, a thorough understanding of thalassemia and its related world population. They are most common in the Mediterranean
disorders is essential to hematologists. This chapter reviews the major basin and tropical or subtropical regions of Asia and Africa. The
features of these syndromes. Readers wanting more detailed informa- “thalassemia belt” extends along the shores of the Mediterranean and
tion than can be included here are referred to more comprehensive throughout the Arabian peninsula, Turkey, Iran, India, southeastern
monographs elsewhere. 1,2 Asia, especially Thailand, Cambodia, and southern China. 7–10 The
The classification, genetic basis, and pathophysiology of the prevalence of carriers of thalassemia in these regions is in the range
thalassemia syndromes are based on a thorough understanding of the of 2.5% to 15%. Similar to sickle cell anemia, thalassemia is most
human Hbs, their biosynthesis, their encoding globin gene families, common in areas historically affected by endemic malaria. Malaria
and their roles as soluble oxygen-carrying molecules. Therefore, seems to have conferred selective survival advantage to thalassemia
readers of this chapter should first familiarize themselves with the heterozygotes in which infection with the malarial parasite is believed
material presented in Chapter 31. The material presented in this to result in milder disease and less impact on reproductive fitness. 1,2,11
chapter is also substantially clarified by prior reading of Chapters 33 Therefore, the gene frequency for thalassemia has become fixed and
and 34 because the principles underlying the pathophysiology of and high in populations exposed to malaria over many centuries.
therapy for thalassemia draw heavily on knowledge of iron
metabolism.
PATHOPHYSIOLOGY: GENERAL PRINCIPLES
DEFINITIONS AND NOMENCLATURE The primary lesion in all forms of thalassemia is reduced or absent
production of one or more globin chains. For all practical purposes,
The term thalassemia is derived from a Greek term that roughly the major impact on clinical well-being occurs only when these
1
means “the sea” (Mediterranean) in the blood. It was first applied lesions affect the α- or β-globin chains necessary for the synthesis of
to the anemias frequently encountered in people from the Italian and adult hemoglobin (Hb A), with a normal structure of α 2 β 2 . Severe
3–5
Greek coasts and nearby islands. The term is now used to refer to impairment of γ-, ε-, or ζ-globin production is presumably lethal in
inherited defects in globin-chain biosynthesis. Individual syndromes utero, and has not been observed in human biology. One consequence
are named according to the globin chain whose synthesis is adversely of reduced globin-chain production is immediately apparent: reduced
affected. Thus, α-globin chains are absent or reduced in patients production of functioning Hb tetramers. As a result, hypochromia
with α-thalassemia, β-globin chains in patients with β-thalassemia, and microcytosis are characteristic of virtually all patients with thalas-
δ-globin and β-globin chains in patients δβ-thalassemia, and so forth. semia. In the milder forms of the disease, this phenomenon may be
In some contexts, it is also useful to subclassify the syndromes accord- barely detectable.
ing to whether synthesis of the affected globin chain is totally absent The second consequence of impaired globin biosynthesis is unbal-
+
(e.g., β°-thalassemia) or only partially reduced (e.g., β -thalassemia). anced synthesis of the individual α- and β-subunits. Hb tetramers
The most common forms of thalassemia arise from total absence are highly soluble and have reversible oxygen-carrying properties
of structurally normal globin chains or a partial reduction in their exquisitely adapted for oxygen transport and delivery under physio-
synthesis. In contrast to the “structural” hemoglobinopathies (e.g., logic conditions. Free or “unpaired” α-, β-, and γ-globin chains are

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