Pathogenesis of Thalassemias.docx

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Biochem. and Medical Genetics
BGEN 3020
Jason Leboe- Mcgowan

Pathogenesis of Thalassemias Alpha thalassemias – who do we see alpha thalassemias in? Asians (Far eastern) and blacks (all genetic hematologic dz’s are seen in the black pop’n – alpha/beta thal, G6PD def, SCDz). 1. Hb electrophoresis – separates things based on size and charge, therefore you can clearly separate HbA, HbF, and HbA2 clearly on cellulose acetate b/c they have different migrations. So, they fluoresce it, and HbA, HbF and HbA2 all settle down. Then they stain the cellulose acetate to see how much is there. Then, it produces density, and the density correlates with the concentration of each of the Hb’s. How will they know the percent? With a densitometer – it converts the density of the stain to the percentage. It turns out that HbA (2 2 ) is the predominant Hb in an adult (95-95%). HbA2 is 1-2%; HbF = 1%. These are the normal, which are expressed as a percentage. 2. Alpha thalassemias, auto rec, has a problem in making alpha globin chains. Do HbA2 and HbF require HbA to be made? Yes. Therefore, all will be equally decreased. This will NOT show up on an electrophoresis, b/c all are equally decreased, therefore, it shows to be totally normal. There are four genes that control alpha globin synthesis. Deletion of one of these four will not cause anemia. Deletion of 2 genes = problem b/c minimally decreased, and therefore a mild anemia. It is microcytic b/c the globin part is decreased, meaning you will get a microcytic anemia (decrease in Hb conc’n, which will be the stimulus). This called alpha thalassemia minor, seen in the far eastern pop’n and black pop’n. With a three gene deletion, that’s not good, and pt is really decreased (there is also a hemolytic component to it). The beta chains get irritated that there is no alpha chains around, so they from their own beta globin chains. So, four beta chains get together and form HbH. If you do an electrophoresis, there will be a different result. HbH is a diff Hb, and therefore will not migrate to the same place as other Hb’s. So, you can dx this alpha thalassemia with Hb electrophoresis (why its called HbH dz). Four gene deletions – spontaneous abortions (usually, therefore not usually born alive – aka hydrops fetalis). Gamma chains form together (like the beta chains did earlier) and form a Hb with 4 gammas, which is called Hb Barts. This will show up on electrophoresis, but won’t matter b/c baby is dead already. What is the spontaneous abortion rate in far east? High b/c this is where alpha thalassemia is most commonly located. Therefore, if the incidence of spontaneous abortions is increased, what cancer risk is increased? Choriocarcinoma (increased hydatidiform moles, which leads to choriocarcinoma). So, there is a high incidence of choriocarcinoma in the far east b/c of alpha thalassemia. Rx – DO NOT give Fe (will Fe overload them). So, just leave them alone. (2 MCC jaundice = Gilbert’s dz – esp with lack of food). Beta thalassemia – blacks, Greeks, Italians. B (by itself) = making normal beta chains; B (with a “+”) = making beta chains, but not enough; B (with a “0”) = not making beta chains at all. Beta thal is auto rec, and has to do with splicing defects, stop codons. The most severe form is due to stop codon (therefore terminate synthesis of beta chains, and don’t even make them). Mild thalassemia: slightly decreased beta chains, prob due to a splicing defect; beta chains are slightly decreased, alpha chains are okay, delta chains are okay, gamma chains fine (confined to fetus). So, HbA will decrease, and delta will get together (hence increase in HbA2) and gamma chains get together (hence increase in HbF). Therefore, see a decrease in HbA and an increase in HbA2 and HbF; this WILL show up on electrophoresis. This happened b/c beta chain is decreased, and it showed a decreased HbA. It is just a mild thalassemia and is very common. So, only way to dx Beta thal is with Hb electrophoresis. Cannot do anything about it. Hopefully it is not the severe type, where not making any beta chains – aka Cooley’s anemia and will not live past 30 y/o. Will have a constant transfusion requirement; many of these pts die from Fe overload, or Hep C or multiple transfusions or HIV. MC in black pop’n – beta-delta thalassemia (decreased beta chains and decreased delta chains, so what’s left are alpha and gamma chains). What will the electrophoresis show? HbF. This called hereditary persistence of HbF. No anemia, just dominant HbF. For thalassemias, know they are genetic, what groups of people they are in, and that you DON’T do anything to them, esp giving Fe b/c all their Fe studies are normal. Iron Deficiency Anemia (IDA): 1. Causes of Fe def anemia – look at age brackets: a) Prematurity – everyday a baby is not in utero, it is losing Fe (all their Fe stores are decreased, so baby must be given Fe supplements). b) Newborn – check stool for their blood; need to know it’s not mom’s blood, which can be swallowed. This is done with the apt test. Most of blood that comes out of baby’s meconium is blood the baby swallowed from mom, and it has HbA in it. However, if it was HbF blood that came out, the MCC is bleeding meckel’s diverticulum. Therefore, bleeding meckel’s diverticulum = MCC Fe def in a newborn and child. Meckel’s diverticulum is NOT the cause of Fe def in an adult, b/c most have bled by four years of age, and already would have known pt has it. c) Woman under 50 – MCC Fe def = menorrhagia, therefore need to get a good menstrual
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