Q. I wanted to check a fact with you because my friend and I were confused by something in First Aid, and it wasn’t listed in one of the errata for the new edition. Under non-megaloblastic macrocytic anemias, it lists liver disease, alcoholism, reticulocytosis, and drugs such as 5FU and AZT and hydroxyurea as potential etiologies. Is this right?
A. I love First Aid – it’s a great review resource for boards and also as a supplement to your coursework. Occasionally, though, I run across errors, like this one. Let’s take a look.
First, let’s just review macrocytic anemias quickly. There are two kinds of macrocytic anemias: megaloblastic ones and non-megaloblastic ones.
The megaloblastic anemias have a problem with DNA synthesis. Something (usually B12 and/or folate deficiency) is inhibiting DNA synthesis, but RNA synthesis is proceeds as usual. So you get really big cells (the cell cycle, and hence cell division, takes longer due to the impaired DNA synthesis – so the cells grow big before dividing). There is also nuclear:cytoplasmic asynchrony, meaning that the nucleus is immature compared to the maturity of the cytoplasm (because the synthesis of DNA in the nucleus is impaired, whereas the RNA in the cytoplasm is just fine). These cells are called megaloblasts.
The non-megaloblastic anemias don’t have a problem with DNA synthesis. Uncomplicated anemia in liver disease (e.g., plain old macrocytic anemia without superimposed iron-deficiency anemia or anemia of blood loss) can be macrocytic, as can anemia in alcoholism. The mechanism in these types of anemias is different. In liver disease, it has to do with insertion of cholesterol into the red cell membrane, which expands the membrane and makes the cell bigger. Ok, so far so good.
Here are the corrections to the errors
1) Â Drugs that impair DNA synthesis (including the ones you mention: 5-FU, AZT and hydroxyurea) do, in fact, cause megaloblastic anemia. Their mechanism involves inhibition of DNA synthesis, so just as in B12/folate deficiency, you would definitely get a megaloblastosis!
2) You do NOT get a macrocytic anemia from reticulocytosis. Let’s just get that out in the open and cleared up right now. It’s a common misconception that if you have a patient with a lot of reticulocytes, that can make the MCV bump up above the normal range. But it’s not true! You just need to do the math to see that it can’t happen.
Normal red cells are between 80 and 100 fL. Reticulocytes are bigger than normal red cells, but not that much bigger. You can see them in the supravital stain above; they’re the ones with the blue dots/strings. They are somewhere between 103 and 120 fL. So let’s say you have a normal MCV (around 90), and let’s say retics are an average of 115 fL. To get the MCV up into the macrocytic range by just adding reticulocytes, you’d have to have at least 40% reticulocytes (60% at 90, and 40% at 115). The retic count never gets that high in humans! It can get as high as 15%, or even 20%, but it just doesn’t get up to 40% (here’s a reference from Blood if you need to prove this to your attending). It does in animals, but not in humans. So while it sounds good in theory (retics are bigger, add retics and the MCV will go up) it just doesn’t work out in practice.
That being said, I would bet $5 that the next time you see someone present on macrocytic anemias, they’ll list reticulocytosis as one of the potential causes. But now you know the truth.
I’ll keep repeating it until my fingers can’t type anymore: your webblog is amazing. In fact you have just blown my mind with this text. Well, despite the fact that First Aid is aimed to students willing to take USMLE, this post lead me to a reflection about the amount of information that we admit as right without thinking about it. Knowledge is something that arises from criticism and confrontation with reality.
Amazing post! THX!!
Thank you very much dr for clearly explaining key concepts! I’m a second year resident in pathology and had a heated discussion with my senior regarding this last week. Now I can b sure of what’s correct and what isn’t. Thanks a million again.. please do keep posting!
Nice work
thanks so much, I wish every med student and doctor would see this……………may God bless you.
1. Does reticulocytosis come under the heading of ”Causes of High MCV”?
2. For a normal range of MCV at 76-96 fL, can reticulocytosis raise MCV upto, say, 101?
1. Yes – in some books it does. It’s not a true cause of an elevated MCV, but there you go. It’s a common misconception.
2. No. To get the MCV over 100, you’d have to have a LOT of reticulocytes (like 40%). And in humans, the percentage of retics just never gets that high (the highest it goes is 20%).
amazing information…thanx a million for this awesome post
So where did the idea that reticulocytosis cause macrocytic anemia? And because the books still carry this information?
I believe the idea came about because reticulocytes are larger than mature red blood cells. So if you don’t think about it too much, it would seem logical that if you have bigger red cells, you should get a macrocytosis. It is true that if you have a lot of reticulocytes around, the MCV will rise. However, there are never enough reticulocytes to push the MCV into the macrocytic range (>100 femtoliters). Some books may still state this as fact because sometimes incorrect ideas are perpetuated because they have been around a long time and they sound like they should be true.
So in cases of reticulocytes with macrocytosis, which actually causes macrocytosis would be another disease?
Yes…it would have to be due to another cause.
I am perplexed with this too when doing manual differential. If your MCV is normal say 87 and see maybe see a 2+ polychromatic cells, I could not result out maybe a 1+ macrocytosis because of the presence of the big polychromatic cells?
If your MCV is 87, then you don’t have a macrocytosis (regardless of the polychromatophilic cells). It’s pretty hard to tell whether red cells are macrocytic just by looking at the smear, by the way. You really need to look at the MCV. If there are some smaller and some larger red cells, your eye can detect that. The overall MCV, though, is impossible to determine by microscopic examination.
Thank You for getting this concept cleared up!! I was spending the last hour struggling through this concept and had inferred that retics do have an increased MCV, for them to cause a macrocytic anemia! But I thought to look it up. And. Lo and behold! Came across your question!!!
So glad have it cleared up now. Alhamdolilah!
why does blood loss increase the MCV?
Blood loss, with a corresponding brisk reticulocytosis, can increase the MCV slightly because reticulocytes are larger than regular red cells (which are between 80 and 100 femtoliters). So if you have more retics around, the average size of the red cell (the MCV) will go up. It never gets into the macrocytic (>100 femtoliters) range, though, for reasons stated in this blog post.
In haemolysis, what causes the (sometimes grossly) elevated MCV if not reticulocytosis? Thank you in advance!
Hemolysis in and of itself does not give you a macrocytosis (MCV>100). There are relatively few causes of macrocytosis, some of the more common being megaloblastic anemia, myelodysplastic syndrome, and alcohol toxicity; hemolysis is not in the differential diagnosis for macrocytosis.
Thank you for such a wonderful explanation…..I have been always in search for this kind of explanation since my 2nd Prof year and finally found it…..I can’t thank you enough for this great explanation.
I feel like everyone is missing scientific backing and just relying on pure logic. Whoever thought that that cells are 2D circles is really stupid in saying that a little bigger does not equal a much bigger volume. I’m not saying you’re completely wrong or right, but you forgot to take into account that erthrocytes are 3D cell where most of their cell volume comes from the peripheral areas and not central….
I agree that red cells are 3D structures. However, with a few exceptions, it is difficult to distinguish the size of red cells with the naked eye. For example, in mild cases of thalassemia, the MCV may be well below the cutoff of 80 fL, but it is virtually impossible to identify the cells as microcytic simply by looking at them on a blood smear, because a red cell with an MCV of 70 does not look THAT different from a red cell with an MCV of 80 – particularly if you don’t have a red cell that you know is normocytic to use as comparison.
If there is a range of red cell sizes, however (for example, in cases of severe iron-deficiency anemia), that makes it easier to detect changes in red cell size. Also, red cells that fall at the extremes of microcytosis or macrocytosis are detectable by the naked eye.
hello I want to say that the 7º edition of the pocket medicine just says the opposite of what you wrote. Analyzing it what you say makes sense, just saying that a good site of information like de pocket medicine does not agree (page 222 hematology-oncology macrocytic anemias)
Yes – I agree! I’ve seen that error in several sources – it’s just one of those mistakes that doesn’t get corrected unless someone points it out specifically, because it seems like it should be true!
THANKYOU SO MUCH DR , JUST WITH THIS QUICK READING I CAN UNDERSTAND THE COMPLICATED MECHANISM ON HOW IT HAPPENS <3