Alpha Thalassemia: Etiology

00:01 Microcytic anemia is here.

00:03 We’ll take a look at alpha and beta thalassemias.

00:05 Keep in mind now that we are dealing with the globin portion of hemoglobin.

00:10 What do I mean by that? Well, when you’re dealing with hemoglobin, what we looked at, microcytic anemia as dealing with the heme portion.

00:17 So therefore, we dealt with iron studies, right? And by that, the big prototype for microcytic, of course, is being your iron deficiency anemia.

00:27 And we also looked at anemia of chronic disease which deals with chronicity.

00:31 And we also looked sideroblastic anemia.

00:33 Remember, in all 3 of those microcytic anemias, we looked at iron studies and each one was a tad bit different.

00:40 Once you’ve completely mastered the iron studies for those 3 microcytic anemias, it is only then that you have permission to come into your thalassemias and dealing with the globin.

00:50 Is that clear? Okay.

00:52 So here, that’s difficult for us to control the genes, isn’t it? Especially when there is mutation of, and hopefully the type of genes that we have inherited from our parents and such, gave us the right genes so that we can transition from the normal fetal hemoglobin to our adult hemoglobin.

01:09 Now what’s really convenient about the name fetal and adult is the first letter of each one of those words.

01:16 F – fetal.

01:18 Therefore, we have hemoglobin F.

01:20 Now, what you will have to memorize then is the type of genes that are comprising your fetal hemoglobin.

01:29 If you want, you might want to use -- Well, you have alphas and you have “gugu gaga”.

01:34 What does that mean? That means your gamma if that helps you.

01:37 So alphas and gammas, maybe “go gugu gaga”.

01:40 And then as an adult, “A.” Use the A and that’s hemoglobin A And that will be A’s and B’s, meaning to say alphas and betas.

01:47 Okay, keep those mind.

01:48 We have a few more that we have to go through as we proceed.

01:51 Now, our topic here brings us to alpha thalassemia.

01:55 I don’t care what kind of hemoglobin that you have, hemoglobin A, hemoglobin A2, hemoglobin F, hemoglobin S, hemoglobin C, so on and so forth.

02:02 Every single one of those of hemoglobins have an alpha, alpha, alpha in them.

02:06 Keep that in mind, that becomes important for us later on when we do a type of electrophoresis called hemoglobin electrophoresis.

02:13 Next, well, we have four alleles of alphas on each gene.

02:20 What does that mean? I want you to take a look at the bottom portion of this picture here and you'll notice that there are four.

02:27 And by that, we mean that you get two from mama and two from papa.

02:31 So we have a total of 4.

02:33 What are going to do? We are going to do target practice.

02:36 Ready? Bring out your gun.

02:38 You knock out one alpha, that gives you one kind of alpha thalassemia.

02:42 It’s called silent.

02:45 Next, knocked out two, that’s alpha thalassemia trait.

02:51 Take the T in trait and then know that you knocked out two alpha alleles, T and T.

02:57 Let’s stop there for now and as you can imagine, you’re going to knock out each one of these alphas.

03:02 How many do you have total? Four, which means that technically you can have four very variants of alpha thalassemia.

03:09 Is that clear? Once again, what about these hemoglobins where every single hemoglobin, the once that are important for us, ladies and gentlemen, will be hemoglobin A, hemoglobin A2 and hemoglobin F.

03:21 That’s what we’re going to be dealing with here.

03:23 The reason we are not going to work with hemoglobin S, what category of anemia are we doing here? Good, Microcytic.

03:31 Where do you think hemoglobin S belongs to? Tell me about hemoglobin S? That’s sickle cell.

03:37 Isn’t that hemolysis? There is no hemolysis here in microcytic anemia, well, in general.

03:44 Okay, but when you think massive hemolytic anemias, such as sickle cell, that comes in our normocytic, okay? So that discussion of sickle cell is not going to even be had here in this section for microcytic.

03:57 Let’s continue.

03:58 There are two alpha globin genes, as I said, on chromosome 16 from each parent for a total of four alleles.

04:06 Let's continue.

04:07 So what are we going to do? Nice little table here for you to knock out each alpha, alpha, alpha.

04:12 And as we do so, I’m going to give you the important associations and symptoms and, really, epidemiology of your patient.

04:22 And if you have understood those three things about the alpha thalassemias, you’re in fantastic shape.

04:28 First, if you knock out one alpha, that is going to be silent.

04:33 And so therefore, clinical manifestation asymptomatic, let it go.

04:37 Clear? You’re not going to be tested on things that are asymptomatic.

04:41 If the patient is not going to suffer, then the patient is not going to come into the clinic.

04:46 Know about it, know that it exist and please don’t get confused with silent and trait.

04:52 That I beg of you.

04:53 Many students end up doing that.

04:55 I asked them about two and they’ll tell me silent and that’s not true.

04:59 So T means two, T means trait.

05:03 Do not confuse that with silent at all.

05:05 Now let’s move on to trait though.

05:08 Now with trait, let me show you how to interpret what I have given you.

05:11 Very important in the second row here for you to interpret the genotype because it actually tells you of what kind of ethnicity, believe it or not.

05:19 Okay.

05:20 So second row, the first genotype pattern that you see there, you see two dash lines together, a slash and then two Greek alpha symbols, okay? And what that represents is that you have two alleles that are missing from the same gene.

05:40 Same.

05:40 In biochemistry, when something is missing from the same, the pattern that you see there is called cis.

05:46 So if you want cis, same and by cis, it’s C-I-S.

05:52 Correct? So here, the cis pattern of alpha thalassemia trait, unbelievably, do you have any idea as to what population this would be? Good, This would be more about the Far East.

06:05 And more about Chinese, and that type of population when you have cis pattern.

06:09 Unbelievable, right? Next, by definition, what does trait mean? Two alleles that have gone awry or not missing, mutated.

06:18 In the second pattern that you see here for trait, you have one allele missing from each side of the slash.

06:25 So that means, one allele from the mother and one allele from the father is missing for a total of two.

06:31 This type of pattern in biochemistry is known as? Good.

06:35 Trans pattern.

06:36 So the trans pattern is another ethnicity.

06:39 And this is more likely to be found in African.

06:42 Is that clear? So that is how important it is for you to know the actual pattern of the alleles that are missing from that particular gene for alpha thalassemia trait.

06:51 Okay, now, at rest, the patient most likely will be asymptomatic.

06:55 However, upon exertion, then what happens? Well maybe at this point, the hemoglobin is a little compromised and is not able to properly provide the oxygen that is required for normal activity.

07:08 Is that clear? There might be mild anemia.

07:11 Once again, Asia and by Asia, you might be thinking about Malaysia.

07:15 You might be thinking Singapore, the Far East - cis pattern.

07:20 Trans – African.

07:22 Let’s go into another type here of alpha thalassemia.

07:24 Now things get a little bit more dangerous, it really does.

07:28 So I told you earlier that every single hemoglobin relevant to us right now has alpha allele 2 and an alpha globin, right? And the three major ones that you want to know here, hemoglobin A, hemoglobin A2 and then hemoglobin F (fetal).

07:44 Let’s go into now the genetic patterns.

07:46 I will say it, introduce them.

07:48 Hopefully, you know it and then we’ll keep reinforcing.

07:51 We said that as a fetus, what is it? Alpha and gamma.

07:53 All jokes aside, okay? Alpha and gamma.

07:56 Hemoglobin A will be A’s and B’s and that will be alphas and betas.

07:59 And then you have to know hemoglobin A2 which is alpha and delta.

08:02 Is that clear? You have to know that and I’ll tell you why later.

08:06 Now to begin, if you have HbH disease, this is a hemoglobin that is going to be produced in excess.

08:13 Because take a look at how many alpha alleles you're missing here.

08:17 You have three dash lines total.

08:19 You’re missing three alpha alleles.

08:21 That’s major.

08:22 By that, I mean that is devastating.

08:25 Meaning to say that you’re not going to produce too much hemoglobin A.

08:28 You can’t even produce too much hemoglobin F, nor can you produce too much hemoglobin A2 because each one of them had alpha, alpha, alpha.

08:35 And you’re missing three alleles from both of the genes in total.

08:40 This is not a good situation.

08:42 This is not a good situation. So what does the body do? Well, remember the body always find to compensate, compensate, compensate.

08:47 What are we talking about here? Alpha thalassemia, not beta.

08:51 Why am I bringing that up? Because if you start losing the alpha, guess what the body does? The body is very resourceful, at least trying to be.

08:58 And so what does it upregulate? You need that hemoglobin A.

09:02 What does that hemoglobin A mean? Alphas and beta.

09:05 Clear? So if you start losing your alpha, what do you think the body is going to do? Upregulate beta, beta, beta.

09:13 Unfortunately, once you start losing three alpha alleles, your body starts producing more betas.

09:19 And when four of these betas, which should never have a pattern of beta-beta, beta-beta, right? It should be alphas and betas.

09:25 But if you have 4 betas put together and aggregating or precipitating, this then forms a completely different pathologic hemoglobin called HbH.

09:35 You’ve heard of HbH disease, what you’ll have to do please is memorize four beta that you’re forming with three alphas missing, then forms hemoglobin H.

09:46 Now, what you’ll have to do later on is memorize another one called hemoglobin Bart’s.

09:49 We’ll do that later, step by step by step.

09:52 Here, you’re going to have either intermediate at best to severe chronic anemia.

09:59 Stop! What does that mean? If over a period of time you have chronic anemia and end up forming a weird or bizarre hemoglobin, where are you right now? What do you mean where are you? You’re in the RBC, right? And you formed a weird hemoglobin like an HbH, this is unrecognizable by the body.

10:18 The RBCs then rendered as being an alien or an invader.

10:23 So that’s interesting.

10:25 So where is this RBC going to go? Where is the grave site of an RBC? Good.

10:29 The spleen, right? But if you have a bizarre HbH in your RBC, you’re going to be transported to the spleen like that.

10:38 And over a long period of time, chronic, when you start destroying your RBCs, guess what that patient is going to have? You tell me.

10:44 This is the same stuff that you’ve been learning for years now.

10:47 This is extravascular hemolysis.

10:49 The spleen is destroying your RBC.

10:52 They are going to destroy your hemoglobin.

10:53 What are you going to release into circulation? Good.

10:56 Unconjugated bilirubin.

10:57 This unconjugated bilirubin will give you what color? Yellow jaundice or icterus around the eyes or mucosa.

11:04 And you end up having what kind of stones in the gallbladder? Good.

11:07 Pigment stones.

11:08 Is that clear? Interesting, isn’t it? Do you see as to how big, big, big time it is for you to know HbH disease and the fact that you’re missing three alleles? Look how much of a difference it makes you go from two to three missing alleles.

11:21 And then what about 4? My goodness.

11:23 If you’re missing four alleles, unfortunately the fetus is dead.

11:28 So you’re looking at an intrauterine death, that’s unfortunate.

11:31 And the reason for that is, well, you can’t even form hemoglobin F.

11:35 Can you? You can’t form any hemoglobin because all alphas are not present.

11:39 So this is more or less hydrops fetalis, anasarca.

11:42 There’s going to be massive, massive what’s known as high output cardiac failure.

11:46 No hemoglobin in the fetus.

11:49 Do you see how significant that is, okay? All four.

11:52 And for the most part, here you go, here's your presentation.

11:54 If you know this table well, you’ve understood alpha thalassemia.

11:58 Let us now fill in the gaps.