Thalassemia and the hemoglobinopathies

Hemoglobin is composed of a porphyrin compound (heme) and globin. Normal adult hemoglobin (Hb A) consists of globin containing two pairs of chains of amino acids, of which the alpha chain consists of 141 amino acids, the beta chain 146. (A chain of amino acids is called a peptide or, alternatively, when many amino acids make up the chain, a polypeptide.) A minor fraction of normal adult hemoglobin consists of hemoglobin A2, which contains alpha and delta chains. A different hemoglobin (Hb F) is present in fetal life and possesses a pair of the same alpha chains as does Hb A, but the second set is different (gamma chains). In normal hemoglobin the order in which the amino acids follow one another in the chain is always exactly the same. Studies by a number of investigators have now shown that qualitative and quantitative abnormalities in the globin chains can lead to disease.

In thalassemia it is thought that a primary genetic defect results in reduction in the rate at which alpha, beta, or delta chains are manufactured, the chains being otherwise normal. The relative deficiency of one pair of chains and the resultant imbalance of chain pairs results in ineffective production of red cells, deficient hemoglobin production, microcytosis (small cells), and hemolysis. In sickle-cell anemia and in other abnormalities affecting hemoglobin, the substitution of one amino acid for another at a particular site in the chain is the underlying fault. The substitution of valyl for glutamyl in the sixth position of the beta chain, for example, results in the formation of Hb S (the hemoglobin of sickle-cell disease) instead of Hb A. The defect is inherited as a Mendelian recessive. Thus, if only one parent transmits the abnormality, the offspring inherits the trait but is harmed relatively little; the red cells contain more Hb A than Hb S. If the trait is inherited from both parents, the predominant hemoglobin in the red cell is Hb S; the serious and sometimes fatal disease sickle-cell anemia is the consequence.

Since the first characterization of the nature of the abnormality in Hb S by Linus Pauling and his associates (1949), more than 100 abnormal hemoglobins have been identified, and other forms of “molecular disease” have been recognized as well. Fortunately, most abnormal hemoglobins are not sufficiently affected to alter their function, and therefore no observable illness occurs.

Sickle-cell anemia (Figure 1) occurs almost exclusively in blacks. In the United States at least 8 percent of blacks carry the sickle-cell trait. The actual disease, sickle-cell anemia, is less common (about 1 in 400 blacks). In this condition most of the red cells of a sample of fresh blood look normally shaped—discoidal—until deprived of oxygen, when the characteristic sickle- or crescent-shaped forms with threadlike extremities appear. Re-exposure to oxygen causes immediate reversion to the discoidal form. Sickle-cell anemia is characterized by severe chronic anemia, punctuated by painful crises, the latter being due to blockage of the capillary beds in various organs by masses of sickled red cells. This gives rise to fever and episodic pains in the chest, abdomen, or joints that are difficult to distinguish from the effects of other diseases. Death results from anemia, from infections, or, ultimately, from heart or kidney failure. While the many complications of the disease can be treated and pain relieved, there is no treatment to reverse or prevent the actual sickling process.

Thalassemia (Greek: “sea blood”) is so called because it was first discovered among peoples around the Mediterranean Sea, among whom its incidence is high. The thalassemias are another group of inherited disorders in which one or more of the hemoglobin subunits are synthesized defectively. This condition, when inherited from one parent, is called thalassemia minor; it causes serious disease only when inherited from both parents (thalassemia major, Cooley's anemia). Thalassemia now is known also to be common in Thailand and elsewhere in the Far East. The red cells in this condition are unusually flat with central staining areas and for this reason have been called target cells. In the mild form of thedisease, thalassemia minor, there is usually only slight or no anemia, and life expectancy is normal. Thalassemia major is characterized by severe anemia, great enlargement of the spleen, and body deformities associated with expansion of the bone marrow. The latter presumably represents a response to the need for greatly accelerated red cell production by genetically defective red cell precursors, which are relatively ineffective in producing maturered cells. Anemia is so severe that transfusions are often necessary; however, they are of only temporary value and lead to excessive iron in the tissues once the transfused red cells break down. The enlarged spleen may further aggravate the anemia by pooling and trapping the circulating red cells. Splenectomy may partially relieve the anemia but does not cure the disease.

The defect in thalassemia may involve the beta chains of globin (beta-thalassemia), the alpha chains (alpha-thalassemia), the delta chains (delta-thalassemia), or both delta- and beta-chain synthesis. In the last (delta–beta-thalassemia), Hb F concentrations usually are considerably elevated since the number of beta chains available to combine with alpha chains is limited and gamma chain synthesis is not impaired. Beta-thalassemia comprises the majority of all thalassemias. A number of genetic mechanisms account for impaired production of beta chains, all of which result in inadequate supplies of messenger RNA available for proper synthesis of the beta polypeptide at the ribosome. In some cases no messenger RNA is produced. Most defects have to do with production and processing of the RNA from the beta gene; in alpha thalassemia, by contrast, the gene itself is deleted. There are normally two pairs of alpha genes, and the severity of the anemia is determined by the number deleted. Since all normal hemoglobins contain alpha chains, there is no increase in F or A1. The extra non-alpha chains may combine into tetramers to form beta4 (hemoglobin H) or gamma4 (hemoglobin Barts). These tetramers are ineffective in delivering oxygen and are unstable. Inheritance of deficiency of a pair of genes from both parents results in intrauterine fetal death or severe disease of the newborn child (hydrops fetalis).

In most forms of hemoglobin abnormality only a single amino acid substitution occurs, but there may be combinations of hemoglobin abnormalities, or a hemoglobin abnormality may be inherited from one parent and thalassemia from the other. Thus, sickle-thalassemia and Hb E-thalassemia are relatively common.

A malfunction of the abnormal hemoglobin may result in erythrocythemia, or overproduction of red cells. In these cases there is increased oxygen affinity, limiting proper delivery of oxygen to tissues and thereby stimulating the bone marrow to increase red cell production. Inother cases the iron in heme may exist in the oxidized, or ferric (Fe3+), state and thus cannot combine with oxygen to carry it to tissues. This results in a bluish colour of the skin and mucous membranes (cyanosis). The abnormality in the globin molecule that accounts for this is usually in an area of the molecule called the heme pocket, which normally protects the iron against oxidation, despite the fact that oxygen is being carried at this site.

Disorders affecting red cells. Erythrocytosis

Erythrocytosis is an increase above normal in the number of red cells in the circulating blood, usually accompanied by an increase in the quantity of hemoglobin and in the volume of packed red cells. The increase may be either an actual rise in the total quantity of red blood cells in the circulation (absolute erythrocytosis), or it may be the result of a loss of blood plasma and thus a relative increase in the concentration of red cells in the circulating blood (relative erythrocytosis). The latter may be the consequence of abnormally lowered fluid intake or of marked loss of body fluid, such as occurs in persistent vomiting, severe diarrhea, or copious sweating or when water is caused to shift from the circulation into the tissue.

Absolute erythrocytosis occurs in response to some known stimulus for the production of red cells. This is in contrast to a disease called polycythemia vera, in which an increased amount of red cells are produced without a known cause. In polycythemia vera there is usually an increase in other blood elements as well.

Erythrocytosis is a response by the body to an increased demand for oxygen. It occurs when hemoglobin is not able to pick up large amounts of oxygen from the lungs; i.e., when it is not “saturated.” This may result from decreased atmospheric pressure, as at high altitudes, or from impaired pulmonary ventilation. The sustained increase in red cells in persons who reside permanently at high altitudes is a direct result of the diminished oxygen pressure in the environment. Chronic pulmonary disease (e.g., emphysema—abnormal distension of the lungs with air) may produce chronic hypoxemia (reduced oxygen tension in the blood) and lead to erythrocytosis. Extreme obesity also may severely impair pulmonary ventilation and thereby cause erythrocytosis (Pickwickian syndrome).

Congenital heart disorders that permit shunting of blood from its normal path through the pulmonary circuit, thereby preventing adequate aeration of the blood, can also cause erythrocytosis, as can a defect in the circulating hemoglobin. The latter defect may be congenital because of an enzymatic or a hemoglobin abnormality, as mentioned above; or it may be acquired as the result of the excessive use of coal-tar derivatives, such as phenacetin, which convert hemoglobin to pigments incapable of carrying oxygen (methemoglobin, sulfhemoglobin). Lastly, erythrocytosis can develop in the presence of certain types of tumours and as the result of the action of adrenocortical secretions. Treatment of erythrocytosis due to any of these causes involves the correction or alleviation of the primary abnormality.

In polycythemia vera, the numbers of red cells, and often also the numbers of white cells and platelets, are increased and the spleen usually is enlarged. In this disease the stem cell precursor of the bone marrow cells produces excessive progeny. Afflicted persons have an exceptionally ruddy complexion and may complain of headaches, dizziness, a feeling of fullness, and other symptoms. Because of the excessive quantities of red cells, the blood is usually thick, and its flow is retarded; it sometimes clots in the blood vessels (thrombosis) ofthe heart, the brain, or the extremities with serious consequences. One of the simplest methods of treatment is to remove the blood, one pint at a time, from a vein until the cellular level approaches normal and the symptoms disappear. Occasionally it may be necessary to use drugs or radiation, in the form of radioactive phosphorus, to restrain the overactivity of the marrow cells. These treatments, however, must be avoided when possible because of their potential complications.

Maxwell M. Wintrobe

Jane F. Desforges