Transcription
Okay, part two of sickle-cell disease. In the previous video, we discussed part one, which was an introduction. I highly recommend that you watch the previous video first.
Now, sickle-cell disease pathophysiology. Okay, so we have talked about Africa and the sub-Saharan Africa, like this region, and why is there sickle-cell disease there? The reason is malaria. Malaria infects the red blood cells. Through the process of evolution by natural selection, the red blood cells started to sickle to prevent malaria from attacking or infecting the red blood cells. What's really interesting is that the African American population, when they went to America, there is no malaria in the United States, so they tend to get hemoglobin S less than usual. Why? Because we no longer needed it, because there is no malaria, there is no need to protect us from malaria, so they tend to go back to the normal hemoglobin state. Isn't that fascinating? It is. When there was malaria, we developed the hemoglobin S and the sickle cell. When there is no malaria, no hemoglobin S and no sickling. So, in theory, if you'd like to reduce the number of people with sickle-cell disease, we should eradicate malaria first. This slide was from the previous video, so please watch that video first.
Oxygen: No cycling when there is no oxygen. Cycling occurs. Sickling is due to hemoglobin S polymerization. Hemoglobin is polymerized when there is no oxygen. So the defect is in unconservative mesons, point mutation, or single nucleotide polymorphism. The change is in a single nucleotide, which will yield another amino acid. And instead of the normal glutamic acid, now we have valine. Sorry, it is position number six, not five. So here's five, seven, here is position number six, valine instead of glutamic acid at position six. Where is the gene? HBB, the gene to remember it: hemoglobin beta chain gene, which chromosome? Chromosome 11. So what's the problem? Non-conservative missense point mutation, a single nucleotide polymorphism leading to valine amino acid instead of glutamic acid at position number six, the beta globin chain on the HBB gene on chromosome 11. When there is deoxygenation, the cells sickle. There is the oxygen dissociation curve. Anything that will shift the curve to the right, which means oxygen is being released, will lead to less oxygen and therefore sickling. So we start with no oxygen, then we cycle. Repeated cycling due to HBS polymerization will lead to membrane damage. Which membrane? The red blood cell membrane, which will lead to hemolysis. And hemolysis will lead to less oxygen because the red blood cells carry oxygen. When there are no red blood cells, there is no oxygen, and therefore it's a cycle. So please understand the defect is in the beta globin, not the alpha, the beta, where the glutamic acid is substituted with valine at position number six.
Okay, here is our deoxyhemoglobin, which hemoglobin? Hemoglobin S, fine in this form. When the hemoglobin is in the deoxy form, i.e., without oxygen, it tends to show its hydrophobic site. Okay, we used to have glutamic acid, so there was no problem because glutamic acid was hydrophilic. Now we have valine, and valine is hydrophobic. It will incorporate itself into this position, which is position number six, which will lead the hemoglobin to polymerize. A polymer is a molecule, like a very large molecule like this. When it polymerizes, what happened is fascinating: the calcium starts to go inside the cell, or calcium influx. Okay, to preserve the electronegativity of the cell, since we are having positive ion in, we should get positive ion out. This is the potassium. Potassium goes out, and the water will follow. This will lead to a dehydrated red blood cell. What's the problem here? Suppose that this is your red blood cell, and this is your hemoglobin S inside of it. If the cell gets dehydrated, the concentration of the hemoglobin is relatively increased because the cell is now dehydrated. When the hemoglobin S concentration increases, the cell wall cycles like that, and it has two different destinations. It can go to the spleen to be destroyed by the splenic macrophages because these cells are abnormal. This is called extravascular, which means spleen hemolytic anemia, or it can get stuck in the capillaries. Why get stuck? These cells are abnormal; they cannot maneuver themselves through the capillaries. They get stuck here in the capillary, especially at the venous end, and they will clog, causing vaso-occlusive crises, venous occlusion, which will lead to less oxygen going to the tissue, which will lead to pain and different symptoms as we will discuss later.
Now you know there are different types of hemoglobin. There is the normal adult hemoglobin A, for adult, which has two alpha subunits and two beta subunits. Okay, fine. And there is the fetal hemoglobin F, for fetal, which has alpha 2 and gamma 2, to also change into gamma chains. Okay, we have said that the sickle-cell disease is a defect wherein the beta chain, so this one can circle absolutely if there is a defect in the beta. This hemoglobin can be affected. The hemoglobin A will be replaced with hemoglobin S. However, hemoglobin F will never circle. Why is that? It has gamma 2. You cannot have a defect in the beta chain when you do not have any beta chains. So this hemoglobin will not get sickle-cell disease even if the hemoglobin S is there. Hemoglobin F contradicts it, so he will never get sickle-cell symptoms until the baby is six months of age postnatal. That's why, if you study obstetrics, the baby will never get sickle-cell disease inside the mother's womb. It doesn't exist. Why? Because he has hemoglobin F. Hemoglobin F is fascinating. Why? Hemoglobin F has a very high affinity for oxygen. What's the favorite word for the baby? It's the word mine, mine, mine, that's mine. This is mine. Babies are so greedy. So when there is an oxygen molecule in the placenta between the baby and the mother, where do you think the oxygen molecule will go? To the baby. Why? Because the baby has hemoglobin F, which has a high affinity for oxygen, will suck up this oxygen molecule cell towards its side. That's why the baby has hemoglobin F so that it can survive by taking the oxygen from mommy. So that's the story of hemoglobin F until the age of six months when hemoglobin F starts to be replaced by hemoglobin A, the adult hemoglobin. The baby is being protected from sickle-cell disease symptoms. There is a drug called hydroxyurea. It will increase our hemoglobin F and will protect us from sickle-cell disease symptoms, and we'll discuss this drug when we discuss the treatment or management of sickle-cell disease. Okay, hemoglobin F, you will not have sickle-cell symptoms. Hemoglobin A, absolutely, you can have sickle-cell symptoms if you have a defect in the beta globin chain on the HBB gene on chromosome number eleven, glutamic acid being replaced with valine at position number six.
Okay, Shakespeare time: To sickle or not to sickle, this is the question. What are the causes of sickling? Number one: increased hemoglobin S concentration. It has to be more than 60% hemoglobin S in order for you to sickle. That's why sickle-cell anemia, which has hemoglobin SS, will sickle because the hemoglobin S concentration is more than 60%. On the other hand, sickle-cell trait, now anemia trait, will have no sickling in most of the time. Why? Because hemoglobin S concentration is less than 50%. You have to have hemoglobin S concentration more than 60%. What are, what is the second cause of sickling? Increased the oxyhemoglobin concentration. Volume depletion will cause, why? I've told you, when the cell is dehydrated, the concentration of hemoglobin S is relatively increased, which will lead to deoxygenation, literally, to sickling when deoxygenated. Okay, so when there is an increase in global S concentration, it leads to sickling. When there is deoxygenation, ii acidosis, why? Increased hydrogen ion concentration will shift the oxygen dissociation curve to the right. Oxygen is being released, so there is less oxygen on the hemoglobin, which will lead to sickling. Hypoxemia. This is different than hypoxia. Hypoxemia is a subtype of hypoxia or a cause of hypoxia. Hypoxemia is decreased arterial PO2, which will lead to decreased oxygen percent saturation. When there's less oxygen, there is more deoxyhemoglobin concentration. To sickle or not to sickle, this is the question. To sickle or not to sickle, this is the hemoglobin constant S concentration. To sickle or not to sickle, this is that deoxyhemoglobin concentration. Here is the story: In the artery, you have oxygen. When you have oxygen, hemoglobin S is soluble, why? Because it's in oxyhemoglobin S form. In the vein, there is low oxygen. Hemoglobin S will precipitate and polymerize, why? Because it's in the deoxyhemoglobin S form. This deoxyhemoglobin S will polymerize, which will lead to membrane changes, calcium influx, potassium efflux, water gets out of the cell, vessel is dehydrated. This cell starts to sickle. It has two different destinations, either to go to that spleen, gets tried by the splenic macrophages, this is extravascular hemolysis and emia, or to get stuck in the capillaries, especially on the venous side, leading to vaso-occlusive crises, which are painful. And these clinical signs and symptoms will be discussed in the next video. I'll see you then. Keep safe, study hard. Bye.