HEMOGLOBINOPATHIES : HAEMOGLOBIN DISORDERS

INTRODUCTION Hemoglobin is produced by genes that control the expression of the hemoglobin protein. Defects in these genes can produce abnormal hemoglobins and anemia, which are conditions termed "hemoglobinopathies". Hemoglobin Structure Hemoglobin transports oxygen to the tissues. Each RBC contains hemoglobin. A normal hemoglobin molecule consists of: o o o Four globin chains (2 alpha, 2 beta). Each globin chain has an iron containing heme molecule. The iron in the heme molecule binds to oxygen.

FIGURE 1 Structure of Hemoglobin Molecule Genetics In the first 8 weeks of embryonic life the predominant forms of hemoglobin are: o Hb Gower 1 (22). o Hb Gower 2 (22). o Hb Portland 1 (22). By the 12th week embryonic hemoglobin is replaced by Hb F (22) which represents 70 100% of hemoglobin in fetal life. Adult hemoglobin Hb A (22) detectable from 16/40, replaces Hb F as predominant hemoglobin by 6/12 after birth, up to 30% of Hb in fetal life. Hemoglobin HbA2 (22) is present in utero but only very minor in normal adults. In normal adults 96 98% of hemoglobin is HbA, Hb A2 (2 3%) and HbF (<1%) constitute a minor component of the total hemoglobin.

FIGURE 2: The cross-linked between Chromosome 16 and Chromosome 11

FIGURE 3: Types of haemoglobin and globin chain present in normal adult blood and haemoglobinopathies

Abnormalities of Haemoglobin o Abnormal haemoglobins appear in one of three basic circumstances:

1. Structural defects in the hemoglobin molecule. Alterations in the gene for one of the two hemoglobin subunit chains, alpha (a) or beta (b), are called mutations. Often, mutations change a single amino acid building block in the subunit. Occasionally, alteration of a single amino acid dramatically disturbs the behavior of the hemoglobin molecule and produces a disease state. Sickle hemoglobin exemplifies this phenomenon.

2. Diminished production of one of the two subunits of the hemoglobin molecule. Mutations that produce this condition are termed "thalassemias." Equal numbers of hemoglobin alpha and beta chains are necessary for normal function. Hemoglobin chain imbalance damages and destroys red cells thereby producing anemia. 3. Abnormal associations of otherwise normal subunits. A single subunit of the alpha chain (from the a-globin locus) and a single subunit from the b-globin locus combine to produce a normal hemoglobin dimer. Types of hemoglobins There are hundreds of hemoglobin variants that involve involve genes both from the alpha and beta gene clusters. The list below touches on some of the more common and important hemoglobin variants. Normal Hemoglobins

Hemoglobin A. This is the designation for the normal hemoglobin that exists after birth. Hemoglobin A is a tetramer with two alpha chains and two beta chains (a2b2). Hemoglobin A2. This is a minor component of the hemoglobin found in red cells after birth and consists of two alpha chains and two delta chains (a2d2). Hemoglobin A2 generally comprises less than 3% of the total red cell hemoglobin. Hemoglobin F. Hemoglobin F is the predominant hemoglobin during fetal development. The molecule is a tetramer of two alpha chains and two gamma chains (a2g2).

PATHOPHYSIOLOGY
Hb S

Hb S is formed by the substitution of glutamic acid with valine at position 6 of the globin chain. Red cells which contain increased amounts of Hb S form sickle cell when deoxygenation takes place. This is caused by the polymerasation and gelation of the Hb molecule. Sickle cell have a shortened lifespan. They are removed by the spleen and liver. Hb C Hemoglobin C comprises 2 normal alpha chains and 2 variant beta chains in which lysine has replaced glutamic acid at position 6. This unstable hemoglobin precipitates in red blood cells to form crystals. These intracellular crystals lead to a decrease in red blood cell deformability and an increase in the viscosity of the blood. The spleen effectively removes these crystal-containing cells. Much like the mechanism in sickle cell hemoglobin, the amino acid change in the hemoglobin C molecule impairs malaria growth and development. It reduces parasitemia and confers protection against mild malaria attack. Therefore, persons who are heterozygous for hemoglobin C have a survival advantage in endemic areas. The risk of malaria is lower still in persons who are homozygous for hemoglobin C. Hb E This variant results from a mutation in the hemoglobin beta chain. People with hemoglobin E disease have a mild hemolytic anemia and mild splenomegaly. Hemoglobin E trait is benign. Hemoglobin E is extremely common in S.E. Asia and in some areas equals hemoglobin A in frequency. Unstable Haemoglobin The unstable Hb denature and form Heinz bodies. The cells are removed by the spleen causing a hemolytic anaemia. Patients have an enlarged spleen. Hb M Methaemoglobin. Extremely stable form of Hb. Formed when ferrous (++) iron has been oxidized to ferric (+++) iron. Met-Hb cannot carry oxygen. Babies with G6PD deficiency are unable to reduce ferric to ferrous (Fe) : resulting in Met-Hb formation

REFERENCES BOOKS 1. ESSENTIAL HAEMATOLOGY BOOK (4th Edition) By Hoffbrand, Pettit and Moss Blackwell Publisher (2005) 2. Medical Laboratory Technology Methods and Interpretation (5th Edition) By Ramnik Sood Jaypee Publisher (2003) 3. Oxford Medical Concise Color Dictionary (3rd Edition) By Elizabeth A Martin Oxford University Press (2002) INTERNET WEB SOURCES

1. http://emedicine.medscape.com/article/200853-overview 2. http://journals.lww.com/clinicalobgyn/Citation/1969/03000/Pathophysiology_of_the_Hemoglo binopathies.2.aspx 3. http://emedicine.medscape.com/article/204178-overview ( All sources retrieved on : 12th April 2010)