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Chapter 31

The Hemoglobinopathies:

Sickle Cell Disease and Thalassemia

with JOHNNY U.V. MONU and STANLEY P. BOHRER

One million people die each generation from the hemoglobinopathies. Of all the genetic diseases that affect mankind, sickle cell disease and thalassemia wreak the greatest havoc. Sickle cell disease has its greatest frequency in Africa, where over 1 million persons are afflicted, but it occurs wherever the black races have migrated, particularly in the United States and Caribbean islands. It is less common in Asia and the European countries around the Mediterranean. Thalassemia, an even more universal disease, has its highest incidence in Caucasians from the Mediterranean littoral, but it is frequent throughout Asia and, to a lesser extent, Africa; it is seen in the Americas, but not commonly.

Unfortunately, statistics of incidence and mortality do not record the pain, disability, and recurrent illness which are part of the life of anyone who suffers from either sickle cell disease or thalassemia. Premature death is likely, and for some it may be a relief. Although the inheritance of the abnormal genes has been understood since 1949, there is no cure for either disease, and no method of prevention other than birth control. Hopefully, genetic engineering in the future will offer the promise of cure for the millions of sickle cell patients. The frequency and severity of sickle cell crises have been reduced in some West African countries by treatment with root and plant extractions whose active ingredients are urea-based compounds. Recently the FDA has approved the use of the compound hydroxyurea in the preventive management of sickle cell crises.

The genetic makeup of whole populations has been altered because of the sickle cell defect. Children who are carriers of this gene have some resistance to the severe effects, especially death, from Plasmodium falciparum malaria; they rarely have cerebral malaria. Because more such children survive long enough to become parents, the occurrence of the sickle cell trait in their population slowly but steadily increases in any part of the world where malaria is endemic. This is especially true in infants and children in sub-Saharan Africa, where it is thought this genetic mutation first occurred. Although this protection does not occur in all varieties of hemoglobinopathy, the trend is significant, until eventually equilibrium is reached. This is called balanced polymorphism. It is probable that hemoglobin C disease provides some advantage over P. malariae infections. There are many factors involved in this fascinating genetic mystery, which at present has been only partially unraveled.

Synonyms

Sickle Cell Disease
Hemoglobinopathy. Sickle cell disease. Sicklemia. Crescent cell anemia. Drepanocytic anemia. Dresbach's anemia. Herrick's anemia. Meniscocytosis. Abnormal hemoglobin disease. Hemoglobin molecular disease. (The individual gene combinations are designated accordingly, e.g., hemoglobin SS disease, hemoglobin SC disease).

Sp: Anemia a globulos falciformes. Anemia drepanocitica. Fr: Anemie drepanocytaire. Anemie á hématies falciformes. Syndrome de Dresbach. Ger: Anämie mit Erythrozytenformanomalie. Herrick Syndrom. Sichelzellen Anämie.

Thalassemia
Thalassemia. Thalassemia major. Thalassemia minor. Cooley's anemia. Mediterranean anemia. Erythroblastic anemia of childhood. Familial erythroblastic anemia. Rietti-Greppi-Micheli anemia.

The names and synonyms of the multiple gene variants are too numerous to list in full. A good description is provided in the chapter on "Abnormal Hemoglobin Diseases" in Pathology in the Tropics by G. M. Edington and H. M. Gilles (Edward Arnold, London) 1976, pp 415-469, and in other texts.

Definition
Sickle cell disease is caused by an inherited defect in the protein portion of hemoglobin. In thalassemia, there is a failure to produce enough normal globin. These are the two basic varieties of hemoglobinopathy. Both cause anemia, one by replacing the normal hemoglobin with an abnormal variant (sickle cell disease), and the other by failing to produce enough normal hemoglobin (thalassemia). In all varieties, the heme (porphyrin complex) is normal, and it is the genetic control of the globin or protein complex which is abnormal. There are however, many hemoglobin variants which do not produce clinical disease.

Geographic Distribution

Sickle Cell Disease

Hemoglobin S is widely distributed; it is found most frequently in tropical Africa, with a gene incidence of up to 40% in some tribes. It occurs among their descendants in the United States, Central and South America, and the West Indies, with a gene incidence of about 7%. It is also found in Sicily, Greece, southern Turkey, southern Arabia, and India. In Africa, it is limited in the north by the Sahara and the highlands of Ethiopia and spreads southward to the Zambezi and Kunene rivers.

Hemoglobin C disease is found mainly in West Africa, but also in the West Indies and America. It occurs rarely in North Africa and the Mediterranean.

Hemoglobin D occurs predominantly in the Punjab and elsewhere on the subcontinent of India.

Hemoglobin E is most frequent in Bengal in both India and Bangladesh, and in Myanmar (Burma), Thailand, and northern Malaysia, but occurs occasionally in other neighboring countries. It has been recorded in Indonesia, Vietnam, Sri Lanka, Turkey, Egypt, and the Netherlands.

Thalassemia

Thalassemia (literal translation: anemia of the sea) is seen most commonly in the countries bordering the Mediterranean Sea, especially in people of Italian and Greek parentage. However, the disease has been reported from scattered areas throughout the world, such as West Africa (Liberia), Mozambique, Syria, Turkey, Kuwait, India, Myanmar, Thailand, Indonesia, South China, the Philippines, and Hawaii. American Indians and African Americans have also been found to be affected.

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