AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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 a₂-globin or a₁-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 a₂-globin and a₁-globin genes are deleted on the same chromosome (--/aa) or the trans form if the 2 a₂-globin genes of both alleles of chromosome 16 are deleted but the a₁-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 (b₄) 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 (g₄) 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 (g₄). 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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Autoimmune hemolytic anemia
Nonimmune hemolytic anemia
Iron deficiency anemia
Hydrops fetalis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• CBC and reticulocyte counts: Moderately severe hemolytic anemia is present, with hypochromia and microcytosis. Often, mild-to-moderate reticulocytosis is present. The higher the reticulocyte count, the more severe the hemolysis.
• Hb electrophoresis: Results indicate the presence of HbH, as well as typical findings of adult HbA, HbA₂, and HbF concentrations.
• Serum iron, total iron binding capacity, and ferritin analysis: Exclude iron deficiency, since it may be present in patients with thalassemia. In the setting of undiagnosed disease, iron deficiency also can cause microcytosis, which must be excluded. In older patients or in individuals who have received transfusions, monitor ferritin levels closely. Once the ferritin level is greater than 1000 ng/mL, consider beginning chelation therapy with deferoxamine. Iron deficiency may result in a misleading hemoglobin electropheresis finding due to suppression of hemoglobin production.
• Newer DNA-based techniques using polymerase chain reaction (PCR) may be used for globin-chain analysis. The techniques can be helpful in some cases in which both the patient's and parents' a-chain configurations are elucidated exactly, which can be useful in predicting the risk that a couple's future offspring will be affected.

Imaging Studies

• Ultrasound: Sonographs of the liver, gallbladder, and spleen frequently detect gallstones, which consist of pigment resulting from hemolysis. Hepatomegaly was present in 70% of 502 patients in Thailand, 60% of 153 patients in Sardinia, and 14% of 88 patients in Taiwan. Splenomegaly is also common in HbH disease and was found in 79% of patients in Thailand, 60% in Sardinia, and 47% in Taiwan.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

• General supportive care: Transfusions may be needed periodically or in periods of severe anemia, such as during parvovirus infections. Usually, patients with HbH disease live fairly normal lives and require few transfusions. Hb levels usually range from 7-10 g/dL. Transfusion therapy is reserved for patients with severe anemia (usually <7 g/dL) and symptomatic anemia. Hemolytic episodes may be triggered either by drug use or by infection. The use of special red blood cell units (eg, washed, irradiated, leucocyte depleted) usually is not required.
• Carefully document iron deficiency with laboratory testing prior to the administration of supplemental iron. Many patients with apparent iron deficiency can have iron overload (hemachromatosis), the effects of which can contribute to morbidity and mortality.
• In very severe cases, allogeneic bone marrow transplantation may be considered, which is curative, since the hematopoietic system of the patient is replaced by that of the donor. A sibling who is fully matched for human leukocyte antigen (HLA) and who is, at most, a carrier for a-thalassemia (deletion of 2 a-globin genes) is the most suitable donor. However, because of the toxicity of the procedure, bone marrow transplantation should be limited to the most severely affected patients.

Surgical Care

Splenectomy may be beneficial in some patients. Usually, splenectomy is reserved for patients with symptoms of hypersplenism, as reflected by leukopenia, thrombocytopenia, and worsening anemia or, in patients who were previously stable, development of a transfusion requirement.

Consultations

Patients with HbH disease usually undergo close follow-up monitoring by a hematologist who can coordinate care and treat the patient during acute hemolytic and anemic episodes.

Diet

In patients with elevated ferritin levels, the diet should be low in iron.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

In general, no medications are needed; however, if the reticulocyte count is elevated, supplement the diet with folic acid. If a patient has an elevated ferritin level, consider chelation therapy with deferoxamine.

Drug Category: Vitamins

This is a supplement with folic acid, a vitamin necessary for red blood cell production.

Drug Category: Chelation agents

Iron overload (usually from multiple transfusions) may require chelation therapy, which usually begins when the ferritin level is greater than 1000 ng/mL.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Outpatient Care

• Pay close attention to iron overload in patients. Even patients who have not received a large number of transfusions may have elevated total body iron loads and may require chelation therapy.

Deterrence/Prevention

• Prenatal testing is available for families at risk (eg, parents are members of ethnic groups with the highest carrier rates). Globin-chain analysis can be performed by means of PCR testing.
• Although neonatal screening is not sufficient in the diagnosis HbH disease, patients with the disease at birth have large amounts of Hb Bart (g₄), which is detectable with neonatal screening.

Prognosis

• The risk of severe anemia and the need for transfusions are lifelong.

Patient Education

• Educate patients and their parents regarding HbH disease.
• Genetic counseling is important for parents of a child with HbH disease. Parents must understand the risk that future children may have HbH disease and other, possibly more severe, thalassemia syndromes.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to recognize this type of anemia as a genetic condition and to properly inform parents and patients of the potential to have children with HbH disease or other thalassemia syndromes
• Failure to confirm iron deficiency anemia using laboratory testing in a patient with HbH disease may lead to continuation of supplemental iron therapy for an extended period (usually >3 mo), which may lead to secondary hemachromatosis. If iron overload continues longer than 1-2 years, it can lead to damage in multiple organs, including cardiac, hepatic, and endocrine dysfunction.

Special Concerns

• Pregnancy: During pregnancy, iron and folic acid deficiencies can alter the mean corpuscular volume (MCV). As a result, thalassemia may be difficult to diagnose or exclude during pregnancy. If a strong suspicion exists and if a definitive answer is required, PCR should be performed for globin-chain analysis. Pregnant women with HbH disease require special care, because those women with severe anemia may have serious health problems during their pregnancy and this may adversely affect the health of their fetuses. The incidence of low birth weight is also high in women with HbH disease and severe anemia.
• Geriatric patients: A particularly severe acquired form of HbH disease may occur in elderly men with clonal myeloproliferative diseases. In these patients, HbH levels may be as high as 60%. Extremely low a-chain–b-chain synthetic ratios may be present, and low a-globin messenger RNA levels are found in bone marrow cells. Hemolytic disease caused by HbH disease may wax and wane with the course of the myeloproliferative disease.
• a-thalassemia/mental retardation (ATR) syndromes:
• • In the ATR-16 syndrome, affected children have chromosomal rearrangements involving the short arm of chromosome 16 telomere, which includes the a-globin complex. This results in monosomy for the 16p telomere, and the a-thalassemia phenotype. If an affected child also inherits a single a-globin gene deletion from the other parent, HbH disease results. These children may also have mental retardation and other congenital anomalies thought to be due to deletions of dose-sensitive genes on chromosome 16p.
  • The ATR-X syndrome is an X-linked disorder caused by mutations of the ATRX gene located on chromosome Xq13.3. It is more frequent than the ATR-16 syndrome. Males who are affected usually have severe intellectual and physical handicaps and other congenital anomalies. Skeletal deformities are present in up to 90% of patients. The a-thalassemia phenotype is variable, with HbH inclusion bodies found in 0-32% of circulating erythrocytes.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Afshin Ameri, MD to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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• Ko TM, Hwa HL, Liu CW, et al. Prevalence study and molecular characterization of alpha-thalassemia in Filipinos. Ann Hematol. Aug 1999;78(8):355-7. [Medline].
• Leder A, Wiener E, Lee MJ, et al. A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice. Proc Natl Acad Sci U S A. May 25 1999;96(11):6291-5. [Medline].
• Liu YT, Old JM, Miles K, et al. Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions. Br J Haematol. Feb 2000;108(2):295-9. [Medline].
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Article Last Updated: Jul 19, 2006