Hereditary Elliptocytosis
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In April of 1663, Galileo was condemned and trialed because of his opinion that turned out to be true, that the sun lies motionless at the center of the universe, that the earth is not at the center and moves around it in an elliptical fashion.

Turns out he was right, but that misunderstanding between the two parties led to his death. But he was 100% correct. It turns out that the Earth's orbit or revolution is an ellipse with the Earth and the Sun being at the focus. It has an eccentricity of about 0.0167,

which is so close to zero that the center of the orbit of the Earth is actually relatively close to the center of the Sun. And we know that because of the Earth's and Sun's relationship, because of the Sun's extreme amount of gravity. And that elliptical orbit is what kind of gives us our topic today. It turns out in medicine we have our own ellipses, but they have to do with red blood cells.

And that brings us to our topic of hereditary elliptocytosis. I'm Dr. Niket Sonpal, your friendly neighborhood internist and gastroenterologist, and let's kick off this week's podcast with our next topic on hereditary elliptocytosis. So what is hereditary elliptocytosis? Well, we know it's a red blood cell disorder that's inherited, and basically the red blood cells are elongated, elliptical shaped, and have some problems with hemolysis.

Now you might be thinking this sounds similar to spherocytosis and it kind of is very similar in the sense that the genetic alterations affect the alpha or beta spectrum proteins or some other proteins that are a little less common. But the difference is with hereditary spherocytosis, the shape of the cell was permanently changed because of that scaffolding internally.

Whereas in hereditary elliptocytosis, the red blood cells actually have a change in the structure of the proteins, but it's more so affecting its function. The cells struggle to regain their normal biconcave shape due to the loss of the elastic recoil. So when it goes through arteries and veins, and then it gets to really tight, itty-bitty little capillaries, they get squeezed into these little shapes, kind of like a cartoon character, and then they stay as elliptocytes.

Then later on they get entrapped and they get eliminated by the spleen and this can lead to a lot of destruction and intravascular hemolysis. So think of it this way. The genetic mutations in spherocytosis affect the way the structure and the shape of the cells are going to be permanently.

You know, Rhealyptocytosis, it's the same proteins, but its ability to recoil back after getting squeezed is affected. And once they get squeezed, they don't bounce back. So how common is this problem? Well, true prevalence data is uncertain, but we have some studies that tell us that the prevalence ranges from about 1 to 2,000 and 1 in 4,000 globally.

And we know it's very, very common in people from African heritage, Southeast Asia, and of course, Mediterranean descent. And the theory there is that it's an evolutionary advantage to prevent malaria. Now, one study looked at the prevalence of this data in people from Southeast Asia, especially from Malaysia, New Guinea, Indonesia, and even the Philippines, with a prevalence of about 5 to 25%. Now,

Now, as I mentioned earlier, most commonly the way people get diagnosed with hereditary lipocytosis is usually during a workup for anemia. So you'll have gotten a CBC, a reticulocyte count and a blood smear, and this will then trigger the workup.

More often than not on history and examination, you may not see any signs and symptoms that are very specific to this. They may have some jaundice. They may have some hemolysis findings. They may be also somewhat fatigued from symptomatic anemia, but there's no pathognomonic finding. You can see splenomegaly in those patients who have significant hemolysis, but again, there's no pathognomonic finding. So as you continue the workup and you get that CBC reticulocyte count, the

the blood smear is going to really tell you a lot of information. The elliptocytes are going to be seen and they're going to be oval, elongated, thin, rod or even cigar shaped. And the percentage can range anywhere from 15 to 100%. Remember, this is a genetic disorder. And so depending on the type of inheritance the patient experiences, just like with hereditary spherocytosis, depending on the type of inheritance they have, they could be completely asymptomatic or they can have significant hemolysis.

Now taking a moment to discuss hemolysis. If you notice that on your smear you see more than 15% elliptocytes and that characteristic morphology for hereditary elliptocytosis, the next step in management is going to be, if you haven't already got one, a reticulocyte count. Then you want to check your LDH

indirect bilirubin, and of course your AST and ALT. And in this case, you'll notice the predominance of AST over ALT. You also want to get a haptoglobin. Remember, haptoglobin is made by your protein, and its whole job is to be the recycling team that's going to get rid of hemoglobin that's left outside of your red blood cells, and so it's going to bring it back to become reincorporated.

And so remember, if you check the haptoglobin level and it's low, that actually means that more of it's being used because you can only measure free haptoglobin. Therefore, if it's low, that means it's out there doing its job, which in turn means there's more hemolysis. Now an interesting fact about the blood smear, remember,

The predominance of elliptocytes actually has no correlation with the severity of hemolysis. It has to do with the underlying genetic changes. Once you've confirmed all these tests and you see that the person is or not hemolyzing and the blood smear shows more than 15% red blood cells as elliptocytes, you've made the diagnosis. Now you might be wondering, well, it is a genetic disorder. Do we not need to do testing? It turns out that genetic testing is not necessary when the diagnosis is pretty straightforward, seeing more than 15% elliptocytes.

You can if the patient wants to go ahead if there's a diagnostic uncertainty or if they want to do testing for relatives or genetic counseling or reproductive counseling by referring to your genetics colleagues in the hospital to go through and consider doing gene testing. But for the patient themselves, all you need is that blood smear, rule out all the other causes, and check the hemolyzing labs.

Now, at this point, you might be thinking, well, we've got our diagnosis. What do we do next? Well, it turns out management depends on how they present. If the patient is asymptomatic, because remember, only about 5% to 25% actually have symptoms. The rest are usually asymptomatic. They do not require any specific therapy or even follow-up. And it turns out their routine monitoring is not necessarily recommended.

In addition, a very common question is, well, if they're asymptomatic and they're not hemolyzing, do I still need to supplement folic acid? The answer is they do not require supplemental folic acid unless there is going to be an episodic hemolysis. But remember, those people who are going to be asymptomatic, they can still develop symptoms after certain kinds of infections like hepatitis, mononucleosis, malaria and other bacterial infections.

Now other patients may have what we call chronic hemolysis, hereditary elliptocytosis, where it's low-grade, well-compensated, and they're not going to necessarily have spikes, but they'll have sort of a smoldering hemolysis all the time. And they can develop anemia, B12 deficiency, or folate deficiency, and so therefore they have to be supplemented in those cases.

In addition, these patients want to be managed with your colleagues in hematology as they may require periodic or regular transfusions, and you want to make sure that their iron stores aren't developing hemo-siderosis and complications of iron overload from those transfusions. Now, what's the next step? Well, you might be thinking splenectomy. In hereditary spherocytosis, that was the endpoint. But in patients with hereditary elliptocytosis, it's only appropriate for those with significant chronic hemolytic anemia.

You see, there aren't any observational trials, randomized control trials to say, "Hey, what's the right time to do it and who should we do it in?" It's a case-by-case basis in each patient. So what we basically say is if the hemolysis is severe, the anemia is life-threatening, then splenectomy may lessen the anemia and eliminate the need for regular red blood cell transfusions.

Remember, the spleen is going to pick out all those abnormal red blood cells. That's its job. So if the patient needs to have that spleen removed, remember they're going to have an increased risk of infections. So you may have to do vaccinations. So you have to discuss it case by case and then go through it with a risk benefit analysis.

Lastly, you want to go ahead and educate patients and families because remember, you want to talk about the autosomal dominant recessive inheritance patterns so that they can get regular screening for family members, especially with those with family history of anemia, so that therefore you can get early detection and get ahead of the issue. And with that, ladies and gentlemen, brings us to the end of this issue on It's All in the Blood. I'm Dr. Niket Slonpon, your friendly neighborhood internist and gastroenterologist. This has been hereditary elliptocytosis. I'll see you next week.