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Etiology and Pathology

To understand the radiological findings in either sickle cell disease or thalassemia, it is
helpful to have an understanding of the underlying pathological processes. Hemoglobin is made up of four heme moieties and four chains of amino acids (the globin portion); each chain is a coiled string of 140 to 150 amino acids. The four amino acid chains are in identical pairs. The ratio of the pairs changes from embryonal through fetal to adult life under genetic control.

The normal globin chains and their controlling genes are identified by the Greek letters alpha to epsilon. The epsilon chains occur only in early fetal life and need not be further considered. Alpha chains are formed by the 10th week of gestation and continue throughout life. Gamma chains are also formed about the 10th week, but are suppressed by the beta and delta chains during the last month of intrauterine life.

Thus, at birth, the greater portion of hemoglobin is made up of two alpha and two gamma chains: this is fetal hemoglobin (hemoglobin F). By about 6 months of age, fetal hemoglobin forms less than 2% of the total. Two alpha and two beta chains now predominate: this is adult hemoglobin (hemoglobin A). There is a small proportion, less than 3.5%, that consists of two alpha and two delta chains: this is hemoglobin A2.

One gene controls the production of each globin chain and is inherited from each parent. If any gene is defective the quality of the relevant hemoglobin chain is less than normal. Variations in the alpha chain are clinically unimportant; variations in the beta chain include sickle cell disease (hemoglobin S) and hemoglobin C, D, E and O, all of which are clinically significant.

If the same abnormal genes are inherited from both parents, the offspring is a homozygote: e.g., hemoglobin SS, which produces sickle cell anemia. The gene responsible for hemoglobin S disease is inherited in an autosomal Mendelian pattern. If only one parental gene is a variant, the individual is a heterozygote: e.g., the inheritance of one sickle cell gene and one normal beta chain produces hemoglobin AS; the child is then said to have the "sickle cell trait" or be a "carrier". The severity of the sickle cell anemia will vary depending on the genes concerned; in decreasing severity are hemoglobin SO, hemoglobin SD, hemoglobin SC and hemoglobin S-thalassemia.

Cockshott and Middlemiss studied sickle cell disease at length in West Africa, especially the radiological manifestations, and presented a clear description of the multiple aspects of this intriguing disease in their 1979 text Clinical Radiology in the Tropics, from which we quote: "The immense variety of all proteins in nature is achieved with only about twenty amino acids as building blocks by varying the number and order of those that are built into the chains. While hemoglobin is being made in the young red cells, the amino acids are added on in the right order as prearranged by the individual's genetic constitution. But if there is a mutation in the genetic template at one point, it will mean that at just one particular point in the chain the wrong amino acid will be put in; this is what an abnormal hemoglobin is. For example in HbS, a single amino acid, valine, replaces the glutamic acid normally present in HbA in position six of the beta polypeptide chain, whereas in HbC the glutamic acid is replaced by lysine in that same position."

"But hemoglobin production can go wrong for other reasons than the incorporation of the wrong amino acids. The synthesising mechanism may be perfect but the genetic message may not come through to the site of synthesis so that there is a failure to produce, say, the alpha or beta-chains. This is the defect that underlies thalassemia, and if the defect is inherited in a homozygous manner, the result is more disastrous than if there is merely an aberrant hemoglobin, because the red cells lacking hemoglobin are non-viable and are liable to be destroyed as soon as formed. The marrow hypertrophies but its efforts at erythropoiesis are ineffective. Some of the hemoglobinopathies do not produce an anemia, but the common ones do so because the life span of the red cells containing the abnormal hemoglobin is reduced, often very drastically, from infancy and the bone marrow will hypertrophy to replace red cells at up to six to ten times the normal rate."

"In addition HbS causes red cells to become elongated and adopt a sickle shape at low oxygen tensions. In sickle cell anemia (homozygous SS disease) nearly all the individual's hemoglobin is HbS and sickling occurs quite readily in the capillaries and marrow sinusoids; but so long as the circulation is not blocked the cells can unsickle when they pass on to better oxygenated regions. In the heterozygous SC and S/thalassemia states when the proportion of HbS in the red cells may be over 50%, sickling may also occur readily; in SC disease there is also increased blood viscosity. In bone, in the marrow sinusoids where circulation may be slow and oxygen utilization high, all these factors may lead to packing of the sinusoids with sickled cells, further reduction of oxygen tension and more sickling, thus proceeding to thrombosis, infarction and necrosis. A further complication is that wherever typhoid/paratyphoid diseases are common, infarcts tend to become infected by these organisms and this leads to Salmonella osteitis (Bohrer 1971). The S gene is the only variant of adult hemoglobin to cause the sickling phenomenon and so is the only one to cause infarction."

The commonest form of thalassemia is due to a defective beta gene. If the individual is a homozygote (inheriting defective beta genes from both parents), he will have practically no adult hemoglobin A. Because fetal hemoglobin decreases after birth, severe anemia develops by the age of 6 months (thalassemia major). The red cells are markedly hypochromic and microcytic and, as a result, are fragile when in the circulation: hemolysis and splenomegaly occur. Homozygous thalassemia is recognized by discovering that the available hemoglobin is fetal hemoglobin F with a small proportion of hemoglobin A2 and practically no adult hemoglobin A.

If the defective gene is inherited from one parent only, the anemia is very variable, but is usually mild; the individual has heterozygous beta-thalassemia (thalassemia minor). The diagnosis is suspected from microcytic, hypochromic red cells without iron deficiency, and with a greater than normal proportion of hemoglobin F or hemoglobin A2.

The inheritance of two defective alpha genes (homozygous alpha-thalassemia) is inconsistent with survival, but heterozygous alpha-thalassemia presents with only a mild anemia. It is much less common than beta-thalassemia.

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Copyright: Palmer and Reeder