eMedicine Specialties > Pediatrics: General Medicine > Hematology
Hemoglobin H Disease
Updated: Jul 19, 2006
Introduction
Background
Thalassemia is one of the world's most common single-gene disorders. The hallmark of the thalassemia syndromes is decreased or absent synthesis of one or more globin chains. a -Thalassemia is the decreased production of a 2 -globin or a 1 -globin gene products. Individuals with thalassemia syndrome are most often of African, Asian, Mediterranean, or Middle Eastern descent. Mutations and gene deletions causing the thalassemia genotype have arisen independently in different populations but then have propagated by means of natural selection. Thus, the thalassemias are more prevalent in regions in which malaria is endemic because the red blood cell phenotype confers some protection against malaria. However, individuals with b -thalassemia syndromes have somewhat better protection against malaria.
Pathophysiology
The a -thalassemia syndromes are a group of hereditary anemias of varying clinical severity. They are caused by deficient expression in one or more of the two a -globin genes on chromosome 16 and are characterized by the absence or reduced synthesis of a -globin chains. Healthy individuals have 2 a -globin genes on each chromosome 16 (aa/aa).
The loss of one (-a) or both (--) of these cis- linked genes is the most common cause of the a -thalassemias. Patients with hemoglobin H (HbH) disease have lost 3 of the a -globin genes (--/-a), and these individuals have chronic hemolytic anemia of variable severity. Fetuses with hydrops fetalis (--/--) die either in utero or shortly after birth because of severe anemia. Individuals with 3 functional a -globin genes (-a/aa) are silent carriers and are clinically and hematologically healthy.
Two genotypes (--/aa and -a/-a) are associated with the a -thalassemia trait. The genotypes are termed either the cis form if both a 2 -globin and a 1 -globin genes are deleted on the same chromosome (--/aa) or the trans form if the 2 a 2 -globin genes of both alleles of chromosome 16 are deleted but the a 1 -globin genes are intact (-a/-a).
In both cases, 2 a -globin genes are inactivated. The (--SEA) type of a -thalassemia deletion removes both a -globin genes in cis, is common in Southeast Asia, and is the most common cause for HbH disease and hydrops fetalis in that part of the world. Nondeletional forms of a -thalassemia in which the a -globin genes are intact are caused by mutations similar to those causing b -thalassemia and are relatively uncommon.
HbH disease usually is observed in individuals from Southeast Asia who have deletions of both a -globin genes on one allele and a deletion of only one a -globin gene on the other allele. The deletions result in HbH (b 4) characterized by a high b -globin– a -globin synthetic ratio and a 2- to 5-fold excess in b -globin production. The excess b chains aggregate into tetramers, which account for 5-30% of the hemoglobin (Hb) level in patients with HbH disease.
HbH has a high affinity for oxygen and has no Bohr effect or heme-heme interaction; therefore, HbH ineffectively supplies oxygen to the tissues under physiologic conditions. Patients with significant amounts of HbH have a defect in oxygen-carrying capacity that is more severe than that expected on the basis of the Hb concentration. Red cells containing HbH are sensitive to oxidative stress; thus, they may be more susceptible to hemolysis when oxidants such as sulfonamides are administered. Aging erythrocytes contain more precipitated HbH than younger erythrocytes; therefore, aging erythrocytes are removed from the circulation prematurely. Thus, HbH disease is primarily a hemolytic disorder. When bone marrow cells are examined, HbH inclusions are rare, and erythropoiesis is apparently effective. Erythroid hyperplasia can result in typical structural bone abnormalities with marrow hyperplasia, bone thinning, maxillary hyperplasia, and pathologic fractures.
Frequency
United States
Frequency of a -thalassemia is low among Caucasians. Among African Americans, the frequency of the a -thalassemia trait is relatively high (20-30%), but the trait usually consists of the loss of only a single a -globin gene on each allele, and HbH disease is rare. In North America, many multicultural communities are growing, and these populations have increased frequencies of thalassemia syndromes.
In some ethnic groups, such as the Southeast Asian population, in particular, and Mediterranean populations, HbH and Hb Bart (g 4) disease are common because of the frequent co-inheritance of one allele lacking both a -globin genes and the other allele lacking one a -globin gene. The high frequency of Hb Constant Spring in the Southeast Asian population can lead to the HbH (--/-aCS) phenotype, which involves an elongated form of a -globin.
International
a -Thalassemia is perhaps the most common single-gene disorder in the world. The frequency of a -thalassemia alleles is 5-10% in persons from the Mediterranean basin, 20-30% in portions of West Africa, and as high as 60-80% in parts of Saudi Arabia, India, Thailand, Papua New Guinea, and Melanesia. In Thailand, which has a population of 62 million people, approximately 7000 infants are born each year with HbH disease. The frequency of heterozygote carrier status among the Chinese population has been reported to vary from 5-15%. The frequency of a -thalassemia is less than 0.01% in Great Britain, Iceland, and Japan.
Mortality/Morbidity
The degree of anemia varies, and morbidity and mortality are largely related to the degree. In some families, a syndrome of HbH disease and varying degrees of mental retardation has been reported. As a result of multiple blood transfusions, consequences of iron overload on the heart, liver, and other organs may be present, and these can contribute to morbidity and mortality.
Race
a -Thalassemia occurs in individuals of all ethnic backgrounds but particularly those of African, Asian, Central American, Mediterranean, and Middle Eastern descent. Emigration from regions in which carrier frequency is high increases the presence of thalassemia syndromes in other parts of the world. Indeed, the disorders are increasing in frequency in North America and Europe.
Sex
Males and females are affected equally.
Age
HbH disease occurs in persons of all ages. Neonates with HbH disease often have anemia, with severely hypochromic red blood cells, and high levels of Hb Bart (g 4). This is in contrast to neonates with b -chain disease, who often have no anemia, although they may have hypochromic red blood cells. This is because a -chains are required for production of all forms of Hb, while b -chains are found only in the adult form of Hb, hemoglobin A (HbA). In the fetus and neonate, most Hb is hemoglobin F (HbF), which is composed of 2 a - and 2 g -chains.
Clinical
History
Symptoms are consistent with a chronic hemolytic anemia and include episodes of severe pallor and anemia. Infections, fever, ingestion of oxidative compounds, or drug use may precipitate hemolytic episodes, and patients may require transfusions. Generally, HbH disease is thought to be a mild disorder. However, because of the marked variability in degree of anemia, patients may range from asymptomatic to needing periodic transfusions to having severe anemia with hepatomegaly and splenomegaly. Some patients may also suffer hydrops fetalis syndrome in utero. Pregnancy may also be a special circumstance, in which patients may develop severe anemia and require transfusions.
Physical
Findings at physical examination are consistent with those of chronic hemolytic anemia and include pallor, jaundice, hepatosplenomegaly, folic acid deficiency, pigment gallstones, leg ulcers, and increased susceptibility to infection.
Causes
The disorder is inherited in a complex autosomal recessive manner; therefore, males and females are affected equally. Individuals with deletions of one or two a -globin genes have no clinical manifestations, while individuals with deletions of all 4 a -globin genes usually die in utero of hydrops fetalis.
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| References |
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References
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Further Reading
Keywords
hemoglobin H disease, alpha-thalassemia syndrome, α-thalassemia syndrome, HbH disease, chronic hemolytic anemia, genetic disorder, thalassemia, anemia, alpha-globin gene, globin protein, malaria protection, alpha-globin chains, jaundice, hepatosplenomegaly, folic acid deficiency, iron deficiency
