The thalassemia syndromes are hemoglobin disorders that result from significantly reduced or absent synthesis of either the α- or β-globin chains. The result is a chronic hemolytic anemia with ineffective erythropoiesis and bone marrow overstimulation. This article reviews current diagnostic approaches, complications, and disease management of thalassemia.
Key points
- •
The thalassemia syndromes are a heterogeneous group of disorders characterized by variable degrees of hemolysis, chronic anemia, and ineffective erythropoiesis.
- •
Because more patients are living longer, disease- and treatment-related complications are becoming more common.
- •
Optimal and safe transfusion support, iron chelation, noninvasive iron assessments, and stem cell therapies provide new tools for effective management of thalassemia.
Introduction/history
The thalassemia syndromes are a group of inherited hemoglobinopathies that result from significantly reduced or absent synthesis of normal hemoglobin. The type of thalassemia is based on the defective globin gene involved; patients with affected β-globin genes have β-thalassemia, and those with affected α-globin genes have α-thalassemia. Patients with thalassemia have widely variable clinical presentations, ranging from nearly asymptomatic to severe anemia requiring lifelong blood transfusions with complications in multiple organ systems. The mainstay of therapy for thalassemia remains red blood cell transfusion, which then necessitates iron chelation. This article focuses on the diagnosis and clinical manifestations of thalassemia.
Introduction/history
The thalassemia syndromes are a group of inherited hemoglobinopathies that result from significantly reduced or absent synthesis of normal hemoglobin. The type of thalassemia is based on the defective globin gene involved; patients with affected β-globin genes have β-thalassemia, and those with affected α-globin genes have α-thalassemia. Patients with thalassemia have widely variable clinical presentations, ranging from nearly asymptomatic to severe anemia requiring lifelong blood transfusions with complications in multiple organ systems. The mainstay of therapy for thalassemia remains red blood cell transfusion, which then necessitates iron chelation. This article focuses on the diagnosis and clinical manifestations of thalassemia.
Epidemiology
Although thalassemia is rare in the United States, an estimated 5% of the world’s populations carry at least one variant globin allele. In general, these conditions are inherited in an autosomal recessive pattern. Numerous studies have confirmed that red blood cells in thalassemia carriers are less susceptible to invasion by Plasmodium falciparum , thus conferring a survival advantage in malaria-endemic regions. The prevalence of thalassemia is highest in geographic regions that historically were most affected by malaria, including the Mediterranean, sub-Saharan Africa, the Middle East, the Asian-Indian subcontinent, and Southeast Asia. Resources available in many regions have substantially improved patient survival over time. In 1973, fewer than 2% of patients with thalassemia were older than 25 years; today that cohort represents 36% of patients with thalassemia in the United States. Immigration has also contributed to the ethnic diversity of the thalassemia population in the United States.
α-Thalassemia
α-Thalassemia is caused by absent or decreased production of α-globin chains. The α gene locus contains paired alleles (αα/αα) on chromosome 16. Clinical severity varies based on the number of alleles affected and also on the type of genetic mutation. Deletional defects involving the α-globin gene locus can be from nonhomologous recombination or other mechanisms that either completely or at least partially delete both α-globin chains. Nondeletional mutations result in reduced production of α-globin and, in some cases, varying amounts of structurally aberrant α-globins that are associated with a more severe clinical phenotype.
Persons with one mutated allele are silent carriers (αα/α-). Patients with α-thalassemia trait have 2 deletions (αα/–) on the same chromosome ( cis ) or on opposite (α-/α-) chromosomes ( trans .). The arrangement of these anomalies have important implications on reproduction. Inheritance of 2 mutant α alleles in cis from one parent, combined with a single mutation from a parent who is a silent carrier, may result in a clinically significant condition involving 3 of 4 genes in the offspring. α-Thalassemia involving all 4 α genes typically has a severe clinical phenotype, often causing intrauterine anemia and hydrops fetalis.
Hemoglobin H (HbH) disease is caused by mutations of 3 of the 4 alleles, with compound heterozygosity for α + and α 0 mutations. In fetal development, the excess γ chains form homotetramers (γ 4 ), also called Hb Bart’s , which are detectable transiently at birth. Later, excess β-globin chains form β 4 homotetramers (HbH), which are unstable and precipitate in developing red cells. The globin chain imbalance contributes to ineffective erythropoiesis and local intracellular oxidative damage in circulating red blood cells and shortened red cell life span. Most patients with HbH disease are not transfusion-dependent but may require transfusion support for infections and other oxidative stresses.
The most common nondeletional form of HbH disease is HbH Constant Spring. The Constant Spring α-globin mutation results in the elongation of 3′ mRNA sequences, abnormally elongated α-globin chains, and reduced globin production from the unaffected allele. Intracellular precipitation of oxidized chains of hemoglobin Constant Spring damages red cell membranes, which causes hemolysis and a more severe anemia. Unlike most other forms of HbH disease, patients with HbH Constant Spring are often transfusion-dependent.
β-Thalassemia
The β-globin locus on chromosome 11 includes genes that encode γ-, δ-, and β-globins, which pair with α-globin chains to create fetal hemoglobin (HbF), hemoglobin A 2 , and normal adult hemoglobin (HbA), respectively. Hundreds of β-globin gene mutations cause β-thalassemia, involving both coding and intervening (noncoding) DNA sequences. The disease severity, or degree of transfusion dependence, correlates with the degree of α-globin chain excess. Patients usually present with anemia as early as the first 6 months of life when HbF production declines, or they can present in early childhood with symptoms such as abdominal distention, hepatosplenomegaly from extramedullary hematopoiesis, irritability, jaundice, and poor growth.
Operationally, β-thalassemia can be described based on blood transfusion requirements. Thalassemia major describes patients who require regular blood transfusions, usually more than 8 to 12 times per year. Thalassemia intermedi a describes patients who can, under normal circumstances, maintain an adequate hemoglobin concentration and require red cell transfusions fewer than 8 times per year, or only in times of physiologic stress.
Hemoglobin E (HbE)/β-thalassemia is a β-thalassemia subtype that deserves special mention. It has been estimated that half of all patients worldwide with clinically severe thalassemia actually have the HbE/β-thalassemia genotype. It is also the most common form of β-thalassemia now detected on newborn screening in some parts of the United States. HbE is a structural β-globin variant that results in both decreased β-globin chain synthesis and production of a structurally abnormal β E -globin that has impaired interactions with α-globin. When coinherited with a β-thalassemia mutation, HbE/β-thalassemia results in a phenotype that is extremely variable, ranging from full transfusion dependence to only requiring occasional transfusions during times of physiologic stress, such as during acute febrile illnesses.
Pathophysiology
Normally, α-globin production begins during fetal development and is constant throughout later life. γ-Globin is turned on during early embryonic development to create HbF (α 2 γ 2 ), which typically declines in the first 6 months after birth. β-Globin production begins in late gestation to create HbA (α 2 β 2 ), which reaches adult levels by 1 year of life.
The fundamental derangement that underpins thalassemia syndromes is globin synthesis imbalance, and often it is the relative excess of a given chain that is most destructive. In β-thalassemia, the reduced production of β-globin chains leads to decreased amounts of HbA per cell, and interaction of the relative excess α-globin chains with the red cell membrane causes hemolysis and premature intramedullary cell death. This ineffective erythropoiesis is compounded by sequestration of defective red cells in the spleen. In the absence of transfusion therapy, severe anemia over time contributes to growth retardation and high-output cardiac failure in thalassemia, and tissue hypoxia stimulates increased erythropoietin production and marrow expansion that causes bony deformities and fractures. Increased intestinal iron absorption and regular red cell transfusions contribute to parenchymal iron deposition. Excess tissue iron causes cirrhosis, cardiac dysfunction, and endocrinopathies.
Diagnosis of thalassemia
The complete blood cell (CBC) count, including hemoglobin and red cell indices, and reticulocyte count are useful screening studies for thalassemia. Most patients with thalassemia will have microcytosis and hypochromia. The red blood cell count may be relatively elevated. The peripheral blood smear shows many bizarrely shaped, fragmented, microcytic red cells and may reveal red blood cell inclusion bodies (globin chains) after supravital staining.
Hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) can be diagnostic for β-thalassemia, with predominant HbF, low or absent HbA, and elevated HbA 2 . HbE may also be detected in patients with HbE/β-thalassemia. For patients with HbH disease or other forms of α-thalassemia, HPLC can detect elevated Hb Bart’s at birth, HbH later in life, and Hb Constant Spring variants. In general, DNA-based testing is essential for a definitive diagnosis of α-thalassemia, and should be used for confirmatory testing in patients with suspected β-thalassemia.
Complications of thalassemia
Growth Impairment
Children with thalassemia are at risk for growth failure from chronic anemia, and a hypermetabolic state from high-volume ineffective erythropoiesis. Nutritional deficiencies, chelation toxicity, and iron-induced endocrinopathies also contribute to suboptimal linear growth and weight gain. Pubertal development may also be delayed because of iron loading and/or severe anemia.
Bone Abnormalities
Marked erythroid expansion can cause significant bony abnormalities in patients with thalassemia, particularly those with β-thalassemia. Radiographic abnormalities in untreated patients can become marked after the first year of age. Long bones show cortical thinning with expansion of the medullary space, and become prone to pathologic fractures. Skull findings are classic, with marked widening of the diploic space and a resultant “hair on end” appearance ( Fig. 1 ). Other skeletal findings include failed pneumatization of maxillary sinuses and maxillary overgrowth that contributes to the classic thalassemic facies, widening of the ribs, and squared vertebral bodies.
Full access? Get Clinical Tree
