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.

Macrocytic anemia
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)  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.