Hemoglobin and Beta Thalassemia Trait

 

Hemoglobin and Beta Thalassemia Trait

         PKGhatak,MD

Hemoglobin is a metalloprotein. Four molecules of Ferrous iron are attached to four individual porphyrin rings known as protoporphyrin in a tetrahedron configuration. This compound is called Heme. The porphyrin rings intern are attached to Polypeptide chains (protein) called Globins. Of the total four globins,  two identical globins are Alpha globins and the other also identical are Beta globins. The alpha and beta globins differ from each other by the numbers and sequence of amino acids composition.

In the developing human fetus, globin chains are different. Two alpha globins are the same but the beta globins are replaced by Gamma globulins and the hemoglobin is called fetal hemoglobin or hemoglobin F. In a newborn the fetal hemoglobin is rapidly replaced by adult hemoglobin (A).

The variations in globin amino acids sequence, substitution or deletion produce many abnormal hemoglobins, most of them are not important for humans but a significant one is hemoglobin S of Sickle cell disease and the other is the hemoglobin of Thalassemia.

The genes responsible for coding goblin chains are inherited by the recessive mode. When both parents are carriers of abnormal globin genes, the progeny will be homozygous and the resultant disease is called Thalassemia. If one parent is the carrier then out of four pregnancies, two children will be carriers and the condition is known as the Thalassemia trait.

The defective coding gene of Beta globin results in deficiency of beta chain synthesis, it is located on chromosome #11p 15.5 location. Due to the deficiency of the beta chain, the metalloporphyrin joins with two globin chains called the Delta chain. In normal circumstances delta chain is present in a minuscule amount. But in Beta Thalassemia trait the delta chain becomes significant. The resultant hemoglobin (designated alfa2 delta2) orA2. The A2 hemoglobin does not function like normal hemoglobin. The red cells (RBC) containing A2 hemoglobin have a shorter life span and are broken down by the spleen. The blood count of Beta Thalassemia trait patients shows a picture almost like iron deficiency anemia. The red cells are smaller, a bit paler in color and some of the RBC show bluish spots called basophilic stippling and the presence of target cells and occasional nucleated RBC. The total number of red cells is either normal or higher, the MCV is high normal or just above normal, the reticulocyte count is high. The serum iron, ferritin and ferritin saturation are high normal, or just above normal levels. The rest of the hemogram appears like iron deficiency anemia. Another major difference in beta thalassemia is the red cell mean width distribution called RWD. The RWD remains normal in beta thalassemia trait, whereas, in iron deficiency, the RWD is over 15 %.  The confirmation of the Beta Thalassemia Trait requires Hemoglobin electrophoresis.

Beta Thalassemia Trait:

Beta Thalassemia trait is prevalent in India, Mediterranean counties and the North African Arab population. Most of the patients remain symptoms free. Beta thalassemia trait patients are often mistakenly diagnosed with Iron deficiency anemia and are prescribed iron therapy. Iron is not only useless in beta thalassemia but iron overload in men and post-menopausal women may produce liver disease, heart disease and gastrointestinal diseases.

Blood picture of minor and moderate beta thalassemia.

Blood test	minor	moderate
Hb	Low	Lower
Hct	28 -40 %	15 -10 %
MCV	50 -75 fL	40 -60 %
MCH	Low	Lower
Reticulocytes +Target cells + poikilocytes	+	++
Basophil stippling	+	++
Nucleated RBC	0	+
Hb Electrophoresis. Hb A.-alfa2beta2 HbA2.-alfa2 delta2 Hb F.-alfa2gamma2	85 % + 4%+ 2%+	Less than 80% More than 5 % More than 5 %

Beta thalassemia clinically presents as mild or moderate. The degree of deficiency of Beta globin determines the clinical groups.

In mild disease, the patients are asymptomatic almost their entire lives. The hemoglobin level is slightly low. On electrophoresis, the pattern is listed above. These patients need only genetic counseling.

In the moderate beta Thalassemia trait, the anemia is moderate and patients in their adult life show signs of easy fatigue and low capacity of strenuous exercise. The spleen may be enlarged and bone marrow may be hypercellular. There is a much higher rate of RBC turnover as a result the bilirubin in serum may be above normal levels. In many cases, periodic blood transfusion is required for anemia. Some patients may require splenectomy.

Association of beta thalassemia and autoimmune disease:

Patients with beta Thalassemia have shown an increased incidence of autoimmune diseases like Diabetes mellitus, fibromyalgia, asthma and arthritis. It is postulated that the location of an abnormal gene in beta thalassemia (11p15.5) is in proximity to immune-regulating eight genes. This association may be a spillover effect.

Another alternative explanation is that when hemoglobin is broken down to hemoprophyrins and hematoporphyrin bind with opioid receptors and act as anti-inflammatory agents. In beta thalassemia the concentration of hemoporphyrins is low thereby increases the chance of autoimmune inflammation.

The increasing numbers of Vietnamese immigrant population found to have Thalassemia E disease. Thalassemia E is due to a different variation of amino acids in the beta globin. Patients are generally asymptomatic but mildly anemic. The hemogram shows a picture similar to the beta thalassemia trait. Genetic counseling is advocated to limit the thalassemia E in the population.

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