Transcription
Welcome to my channel. Médicos is perfection, Alice. Today's topic: hereditary spherocytosis. This is a video in a series on anemia, so you can go to my playlist on hematology oncology to get all of the videos. And please consider subscribing to get future videos.
Hereditary spherocytosis: what's the problem here? It's a hemolytic anemia. And of course, in hemolytic anemia, we can get what? Jaundice. Okay. Normally, your RBC membrane is this biconcave disc; it's flexible, it's nice, and it has an increased surface area. It's like the vagina has a lot of folds, so they can expand when birth of the baby comes. But in spherocytosis, your RBC is rounded. Is this a good thing or a bad thing? This is bad. This is not flexible. If it just swells a little bit, it can burst, and hemolysis can occur. There is jaundice because it's a hemolytic anemia. And since it's a hemolytic anemia, unconjugated bilirubin will rise. The liver will try to conjugate it and will send it to the gallbladder. It will bind to calcium and form pigmented stones. There are two types of stones: the yellow cholesterol stones and the dark pigmented hemolysis stones, which are these. Why did I draw a spleen here? Because it's an extravascular hemolysis, which occurred in the spleen. Oh, do you mean that I can have splenomegaly in hereditary spherocytosis? You bet. I repeat this slide every single video for a reason. See these nice red blood cells? Usually, they are biconcave, and when you see them like from above, there is a central pallor. That's the normal red blood cell. Not so in hereditary spherocytosis.
Normocytic anemia has an MCV from 80 to 100. Causes: blood loss, underproduction/destruction, or hemolysis. 3000-side index here is more than 2.5. Intrinsic defect or extrinsic defect? Whereas spherocytosis here, it's a membrane defect. Intrinsic? Yes, because it's intrinsically in the RBCs. It is not something from outside of the red blood cell; it's intrinsic. It's in the red blood cell membrane. As you know from the previous video, we have two types of hemolysis: intravascular, extravascular. Hereditary spherocytosis is an extravascular hemolysis, which means the hemolysis will occur in one of the reticuloendothelial organs, such as the spleen, mainly the spleen. And here is the slide that summarizes everything that occurs in extravascular hemolysis. I've explained this before in my video on extravascular hemolysis.
Now let's go to here. In hereditary spherocytosis, normally your red blood cell membrane is a membrane, really; yes, a lipid bilayer membrane, as any other membrane. So we have some proteins. You know, any lipid bilayer membrane has some proteins within it. Okay. These proteins will include band 3 protein and spectrin. Two proteins forming a helix; they are the alpha spectrin and the beta spectrin proteins. They are bound to actin-tropomyosin complex. So you know that any cell has a cytoskeleton. In the same manner that anybody has a skeleton, the cell, of course, has a skeleton called a cytoskeleton. It has actin, so it can contract. It can contract the membrane, giving it some flexibility. And the actin is joined to the lipid bilayer and to the spectrin helix. Okay. So in hereditary spherocytosis, where is the problem placed? The problem is a defect in band 3 protein in anchoring in spectrin. Wow. So you are saying that the lipid bilayer will have a problem? Yes. You're saying that the cytoskeleton will have a problem? Absolutely, yes.
So normally you have your red blood cell with a biconcave disc. It can expand. Yes, this biconcave disc can expand. Let's say that it is put in a hypotonic solution, and the osmosis will pull water from the hypotonic to the hypertonic. Inside the red blood cell is relatively hypertonic to this hypotonic fluid. So the red blood cell will pull fluid. So the hypertonic pulls from the hypotonic. Normally, the red blood cell is nice and can expand like this or even become circular like this. That's why we have a biconcave disc in the first place; it can expand. This is number one. Number two: it can maneuver through the spleen. The spleen has veins called sinusoids. Okay. These sinusoids have pores, okay, or openings. Normally, the red blood cell can squeeze itself through the sinusoids. That's the normal; that's why we have a biconcave disc, which is so nice. Not so much with hereditary spherocytosis. The defect in the spectrin anchoring and band 3 proteins, which will lead to formation of some microvesicles on the surface. Why is that? Because these proteins are missing; that membrane is weak, so it starts to blab like this, forming some microvesicles. Also, since the membrane is weak, some potassium and water will escape from the membrane to outside, so the blood cell will enlarge. You have blabs outside and dehydration inside; together will lead to forming a spherocyte. This is spherocytosis, which will lead to decreased surface-over-volume ratio. Why is that? This biconcave normal cell has a huge surface area; that's why we have a biconcave disc. The vagina has a huge surface area because it has a lot of folds inside, so they can expand when childbirth or parturition comes. This cell has not enough surface area; it's just a ball, a sphere. So there is decreased surface-volume ratio, and there is no central pallor. I've told you that normal RBC has central pallor here. Why are there no central pallor? Because the cell is condensed; it has lost a lot of microvesicles and blebs, and now it's just a small ball of condensed hemoglobin; small ball of condensed hemoglobin. That's hereditary spherocytosis. Please do not be fooled. Spherocytes can be present with any hemolytic anemia, but this is not the same as hereditary spherocytosis. In any hemolytic anemia, the bone marrow will respond by producing more and more of their red blood cells; many of them will become abnormal; many of them are spherocytes. In hereditary spherocytosis, there is a genetic problem; many genes are involved, which will lead to the same things. Spherocytes can be autosomal dominant, where the patient will be heterozygous. Why? 'Cuz when you have autosomal dominant, this is the dominant gene; you just need one copy or one allele to manifest the disease. So an autosomal dominant is just this heterozygous. So these are heterozygous. So autosomal dominant should be heterozygous. And in some other cases, it's autosomal recessive, and here the patient has to be homozygous. Sorry, I've mixed them up. So autosomal recessive: homozygous. Why? 'Cuz you know autosomal recessive diseases; to manifest the condition, not just a carrier, but to have the disease, you have to be homozygous, 'cuz it's a recessive; it needs another recessive gene to manifest the symptoms. So many genes are involved; it can be autosomal dominant where you are heterozygous or autosomal recessive where you are homozygous. Family history, of course, since it's autosomal dominant or recessive; you can have a family history, but not always. How about the population, which ethnicity or its geographical—which geographical location? Northern European. It's abundant in Northern European. Contrast that with thalassemia. Thalassemia is warm in the Mediterranean region, North Africa, Southern Europe, which means Greece, Italy, etc. Northern European with hereditary spherocytosis. Northern Europeans. You'll have a kid with a large spleen and some gallstones, and you don't know why he's so young to have some gallstones. Why is that? Because he has hereditary spherocytosis. You can blame his parents.
Now to the story: you have some microvesicles on this red blood cell due to a membrane defect in some proteins such as spectrin anchoring, band 3, and blebs will enlarge, and suddenly your cell is a spherocyte. This spleen will never let it happen. The cell—spherocytes—will get stuck under sinusoids, and then the macrophages will come and phagocytose them. Who needs to clean up the space? Nobody should be stuck here. I will eat them. And of course, and it's an extravascular hemolysis, so the macrophage eats the RBCs; you have an abnormal membrane and will eat it. The RBC has hemoglobin; hemoglobin has iron and protoporphyrin. Protoporphyrin will convert to unconjugated bilirubin; goes to the liver to become conjugated. The liver is working really hard; the spleen is working really hard to destroy the red blood cell; liver is working hard to conjugate the bilirubin. Conjugated bilirubin goes to the gallbladder. The gallbladder converts it back to unconjugated. Unconjugated bilirubin binds it to calcium, and now you have some calcium-bilirubin pigmented dark brown stones in your gallbladder. And of course, you have jaundice because you have a lot of unconjugated bilirubin. But for you to manifest jaundice, the bilirubin has to be more than 2.5. Keep this in mind. Okay. Add some parvo B19 virus, and you'll end up with aplastic crisis. And I've talked about that in my video on aplastic anemia. So this is the problem with hereditary spherocytosis. Can I get low haptoglobin? Yes, indeed. Can I get increased LDH? Of course, you can. Can I get some unconjugated hyperbilirubinemia? Of course. Can I get some urobilinogen in the urine? Yes, indeed.
Now to the diagnosis: clinically, a kid with anemia, jaundice, maybe gallstones, and huge spleen; maybe there is a family history. Now to that lab results: how about hemoglobin and hematocrit? Both are decreased. Why? It's anemia by definition. How about MCV? Usually normal; it's a normocytic anemia, or maybe decreased because I've told you that these spherocytes are small, rounded, condensed mass of hemoglobin. So it's normal or maybe decreased, but usually normal. Mean corpuscular hemoglobin concentration, which I've talked about in my video on erythrocyte indices, is increased. Big deal. Why? It's the only anemia with the high MCHC. Big-time. Take it to the bank. Normal MCHC is 33 grams per deciliter. Here and here, there is spherocytosis; it's increased; it's more than 33. How about the red cell distribution width? Maybe increased. Why? 'Cause the bone marrow is going crazy, producing a lot of RBCs; they are not equal in size; they're abnormal shapes; just keeps producing them. So maybe RDW can be high, but not always. Reticulocytes? Yes, that's hemolysis; any hemolysis will have reticulocytosis if your bone marrow is responding well. How about bilirubin? Increased. Which one? Unconjugated or conjugated? Both, but the unconjugated bilirubin is way higher than the conjugated bilirubin. And of course, you can have some urobilinogen in the urine. Coombs test negative. There is no antigen-antibody reaction here; it's just a membrane defect. The red blood cell gets stuck, and splenic macrophages eat them; no antigen-antibody reaction. How about liver ultrasound? Yes, you can see these ugly dark brown stones on ultrasound, but of course, ultrasound will not show you the stone is dark brown; it's just for you to know. On biopsy, okay. Have a peripheral smear? Yes, you will see these nasty spherocytes. They are small; they are numerous with no central pallor; they're just all red like this, and they are small, and they are numerous. How about an osmotic fragility test? I will talk about it in my next video, but for now, we put this red blood cell in a hypotonic solution. Normally, the red blood cell should take this water by osmosis because it's hypertonic inside relative to outside, and it should expand; that's normal. But inside the cell, it's already a sphere; it cannot expand more; it will burst. So that's a positive osmotic fragility test. You put the cells in a hypotonic saline solution, and then it expands and bursts, so you will have hemolysis, and that's a positive test. There is a test called eosin 5-maleimide binding test; looks for the band 3 protein on the cell membrane of the red blood cell. Maybe we can do some membrane studies to look for spectrin and ankyrin and band 3. Yep, we can do some molecular studies because there are a lot of genes identified to cause hereditary spherocytosis. Yes. Which of the following tests is the most accurate? Molecular studies; genes studies. Okay, but what if my exam doesn't have this as a choice? Then pick membrane studies. What if it's not there? Pick eosin 5-maleimide binding test. What if it's absent? Then pick osmotic fragility test. So accuracy of the test increases as we go down. Molecular studies is the most accurate.
How to treat hereditary spherocytosis? First, there is no cure. You have a genetic defect causing defective proteins in your membrane of your red blood cell. There is no cure for that till this moment, but you can manage by giving folate. Since it's anemia, normocytic, you can give folate to stimulate the bone marrow to try to produce more red blood cells because many of them are being destroyed. Give folate and iron. Why is that? Because in hemolysis, the bone marrow is going crazy; it needs a lot of food; it needs a lot of nutrients and a lot of supplies; they can build new red blood cells. And you know the DNA synthesis of the red blood cells required folate; hemoglobin synthesis of the red blood cell requires iron. And we can do splenectomy, but we should wait until puberty because the spleen is a lymph organ that is like necessary for kids, so we will wait until they become—they reach puberty. And before splenectomy, we give anti-pneumococcal vaccine because you know the spleen protects us against capsulated organisms, so when you remove the spleen, you can get infection with no more spleen. So you give the vaccine before removing the spleen. Then you go ahead and remove the spleen, and you can give penicillin prophylaxis after removal, but this is controversial; please be aware. Splenectomy will stop the hemolysis; yes, of course, but will never remove the spherocytes. She will always have these nasty spherocytes, but there is no way hemolysis will occur because I've removed the spleen with its nasty sinusoids and macrophages destroying every single thing that was hereditary spherocytosis. In a nutshell. And do not forget to remove the gallbladder if you have gallstones. I'll see you in the next video. I hope you have a wonderful time studying medicine. I know it's terrible; we are in it together.