Tropical Medicine: A Clinical Text, 8th Edition, Revised and Expanded

Hereditary Anemias

Hereditary Anemias Anemia remains one of the most important medical problems of the tropics and subtropics. When relatively mild, it reduces the physical well being and work capacity of whole populations; when severe, it is an important cause of death. Common diseases already considered include malnutrition, with deficient intake of iron often compounded by hookworm infection; infections, especially malaria; hypersplenism; and nutritional deficiency of folate and vitamin B12, which may be compounded by intestinal malabsorption. Other major causes of anemia include the genetic disorders, which are prevalent wherever P. falciparum malaria is endemic. The hereditary anemias of the tropics and subtropics constitute the most numerous and important examples of human hereditary genetic defects. Hundreds of millions of people are born each year with these abnormal traits. Physiology Molecules of hemoglobin consist of four peptide chains, each chain being associated with a heme group. In extrauterine life, these are alpha, beta, gamma, and delta chains, and each hemoglobin molecule contains a pair of alpha chains and a pair of another type. The physiological hemoglobins so formed are: 1. HbF, or fetal hemoglobin, consists of two alpha chains and two gamma chains. This is the major hemoglobin synthesized from the eighth week of gestation; while synthesis normally ceases at birth, HbF is still found in decreasing amounts until the third month of extrauterine life. 2. HbA, or adult hemoglobin, which in extrauterine life, largely replaces HbF. It is composed of two alpha chains and two beta chains. PAGE 227 ................. 18086$ CH19 07-15-11 13:50:42 PS 228 hereditary anemias 3. HbA2 is composed of two alpha chains and two delta chains. It normally does not exceed 3.5% of normal hemoglobin. The synthesis of each of these chains is controlled by one or more genes. Thus, on chromosome 16, there are two alpha genes per haploid genome, while the other globin chains are controlled by single genes clustered on chromosome 11. There are two main groups of inherited disorders of hemoglobin production. 1. Deficient production of one of the globin chains: the thalassemias 2. Structural hemoglobin variants in which there is substitution of one amino acid for another in one of the globin chains: the hemoglobinopathies The Thalassemias The thalassemias are a heterogeneous group of disorders resulting from a reduced synthesis rate of one or more of the globin chains of the hemoglobin molecule. Most of the clinical features of the more common thalassemias are due to the unbalanced globin chain synthesis, the excess partner chains being precipitated in red cell precursors. These disorders occur worldwide, but the highest prevalence is in a broad band stretching from the Mediterranean to southern China. Beta Thalassemia Two allelomorphic genes on chromosome 11 normally code the beta globin chains. Beta thalassemia results from a variety of point mutations in these genes, leading to deficiencies in messenger RNA coding for the beta globin chain of adult hemoglobin. Some of these mutations result in no synthesis of the chains (Bo ) while others lead to reduced synthesis (B ). Beta Thalassemia Major represents the homozygous state when both genes on chromosome 11 are affected (Bo Bo ). Nonproduction of the beta globin chains results in precipitation of highly unstable alpha chains. This prevents normal maturation and release of red cell precursors from the bone marrow. The synthesis of gamma chains persists beyond PAGE 228 ................. 18086$ CH19 07-15-11 13:50:43 PS hereditary anemias 229 the neonatal period, with these chains binding to excess alpha chains. The pathological results of this are as follows: 1. A severe anemia with HbF accounting for 80% to 90% of the hemoglobin. HbF, which is heterogeneously distributed among the red cells, has a high oxygen affinity; this, together with the marked anemia, produces a severe degree of anoxia of the tissues. 2. The anoxia stimulates erythropoietin production and expansion of the bone marrow in an almost neoplastic fashion. The end result is erosion of bone with distortion and thinning of the cortex , the development of paravertebral tumors, and wasting. 3. Gross enlargement of the spleen associated with increased plasma volume and cardiomegaly. 4. Increased intestinal absorption of iron causing liver damage, multiple endocrine disorders, and cardiomyopathy. Patients require blood transfusion every 6 weeks, and this further accentuates the iron overload. Beta Thalassemia Intermedia is the homologous state causing disease of insufficient severity to require regular blood transfusion. The hemoglobin concentration remains between 7...