5.3 Macrocytic Anemia

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The next section that we want to discuss concerns macrocytic

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anemia.

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Now,

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in macrocytic anemia,

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the idea is that the patient develops an anemia,

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however,

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the red blood cells are relatively bigger than normal.

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Recall that the normal MCV is about 80 to 100,

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and in a macrocytic anemia,

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the MCV is greater than 100.

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we can ask ourselves,

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well, why would the MCV be big?

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Or in other words,

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what's driving the cells to be large?

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And the answer goes back to the paradigm that we've already established

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in our discussion of microcytic anemia.

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Remember that I told you that in microcytic anemia,

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the idea was that we started with a red blood cell

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precursor in the bone marrow,

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and that that red blood cell precursor in the bone marrow divides

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divides and divides and divides several times until it eventually

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produces mature red blood cells.

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Recall that I said that the red blood cell precursor is a relatively large

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cell, and that each time it divides,

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it becomes slightly smaller.

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Now,

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in a microcytic anemia,

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it's as if an extra division occurs,

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making the cells just a little bit smaller than usual.

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Well, in a macrocytic anemia,

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it's as if one less division occurs,

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and when one less division occurs,

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the cells are going to be larger than normal,

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and hence the MCV will be greater than 100.

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We can then ask the question,

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why would one less division occur?

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And the answer here is that in a macrocytic anemia,

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there is usually an upset in the production of DNA precursors.

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Now remember that every time a cell divides,

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it requires DNA precursors because each division requires a copying

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of the nucleus.

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And so if there's a disruption in DNA precursors,

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the cell won't be able to divide because it doesn't have the necessary

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precursors to copy the nucleus.

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One less division will occur,

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resulting in a macrocytic anemia.

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Now this then raises the question of what are the major causes of

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macrocytic anemia?

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And of course,

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the major causes of macrocytic anemia will be those that are related to the

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production of DNA precursors.

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And so the two most common causes are folate deficiency,

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and vitamin B12 deficiency.

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Remember from biochemistry that both folate and vitamin B12 are

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necessary for the synthesis of DNA precursor molecules,

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and if folate or vitamin B12 is deficient,

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we won't be able to generate appropriate DNA precursor molecules.

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Decrease in DNA precursor molecules is going to lead to an inability

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of the cell to divide one extra time,

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which is then going to lead to a large red blood cell,

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or a macrocytic.

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red blood cell.

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Here we can take a step back and remind ourselves of a little bit of biochemistry.

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Remember that folate,

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when it comes into the body,

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comes into the body as tetrahydrofolate,

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and it is quickly methylated,

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and I'll just abbreviate this with an M here.

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Again,

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when folate comes into the body as tetrahydrofolate,

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it's quickly methylated.

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Now,

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in order for tetrahydrofolate to go and participate

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in the synthesis of DNA precursors,

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it

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needs to lose this methyl group.

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And so very quickly,

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folate will basically convince vitamin B12 to

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take the methyl group.

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And so vitamin B12 will actually take this methyl group.

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Tetrahydrofolate will lose the methyl group,

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allowing tetrahydrofolate to participate in DNA precursor

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synthesis.

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Now,

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once vitamin B12 takes the methyl group,

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it's as if vitamin B12 recognizes,

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hey,

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this methyl group is not cool,

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I need to get rid of it,

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and it very quickly passes it on to another molecule,

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and that molecule that it passes it on to is homocysteine.

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Now,

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homocysteine...

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Homocysteine accepts the methyl group,

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and when homocysteine accepts the methyl group,

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it becomes methionine.

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And of course,

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you're well aware from biochemistry that methionine is important in

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the transfer of methyl groups to various other important molecules,

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but we don't have time to discuss that here.

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That's more of a biochemistry notion.

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So again,

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general principle,

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tetrahydrofolate needs to lose the methyl group to...

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participate in DNA precursor synthesis.

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It hands the methyl group to vitamin B12.

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Vitamin B12 then hands it to homocysteine.

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Now,

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imagine if there is a folate deficiency.

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If folate is knocked out,

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then obviously DNA precursors won't be made.

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And also,

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if vitamin B12 is missing,

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tetrahydrofolate won't be able to pass.

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this methyl group to vitamin B12,

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and hence it will also not be able to participate in DNA precursor

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synthesis.

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And once you understand that,

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it's now easy to understand why I said that anemia,

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a macrocytic anemia

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is most commonly due to folate or vitamin b12 deficiency now

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it's worth taking a moment here

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to just understand a little bit of terminology.

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And that is when we have a folate or B12 deficiency,

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then the term that we apply to that anemia is called a megaloblastic

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anemia.

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And it's called a megaloblastic anemia because folate and vitamin B12 are

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obviously important for DNA,

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for synthesis of DNA precursors.

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And if we can't produce DNA precursors appropriately,

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not only will the red blood cells be affected,

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but other cells in the body that are rapidly dividing will also be affected.

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And so those cells can become big,

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i .e.

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the cells that are rapidly dividing can become big,

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and so it's called a megaloblastic anemia.

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So that's an important distinction in terminology.

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There are some macrocytic anemias that are not due to folate or

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vitamin B12 deficiency,

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and we'll briefly touch on those a little bit later.

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So now I think with that background,

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we can walk through the slides.

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So here I've told you in your text that folate and vitamin B12 are necessary

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for synthesis of DNA precursors.

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Recall that folate,

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when it comes into the body as tetrahydrofolate,

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it gets methylated.

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The methyl group must be given to vitamin B12 before tetrahydrofolate can

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participate in the synthesis of DNA precursors.

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So therefore,

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both folate and vitamin B12 are necessary for this

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synthesis of DNA precursors.

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A lack of folate or a lack of vitamin B12 is obviously going

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to impair the synthesis of DNA precursors,

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and then that will result in certain changes.

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We'll get a megaloblastic anemia with macrocytic

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red blood cells with an MCV greater than 100.

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Also characteristic of vitamin B12 or folate deficiency will

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be hypersegmented neutrophils.

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Hypersegmented neutrophils refer to neutrophils that have greater than

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five lobes.

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Now, normally the nucleus of the neutrophil has anywhere

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from three to five lobes,

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and greater than five lobes indicates that we're dealing with a hypersegmented

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neutrophil.

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Another change that we're going to see if folate or B12 is

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deficient is megaloblastic change in all rapidly dividing cells.

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So,

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for example,

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if we were to look at the gut,

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we would see enlargement of the epithelial cells within the gut.

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Here's a picture of a hypersegmented neutrophil,

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and basically the notion here is that this neutrophil

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has one,

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two,

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three,

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four,

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five,

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six,

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seven lobes,

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and again,

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anything greater than five is abnormal.

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In addition,

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you'll notice that most of these red blood cells are relatively normal in size,

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but you can see that there's a large red blood cell here,

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and this would be an example.

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of a macro ovale site,

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which is, again,

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a large red blood cell that would have an MCV greater than 100,

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but tends to have a little bit of an oval shape to it.

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These changes,

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both of these,

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the macrocytic cell along with the hypersegmented neutrophil

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are classic findings in a megaloblastic anemia.

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which would be due to folate or vitamin B12 deficiency.

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If you have a macrocytic anemia due to other than folate

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or B12 deficiency,

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then we would just simply call that a macrocytic anemia.

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We would not call that a megaloblastic anemia.

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And so a few other causes of macrocytic anemia to be familiar with include

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alcoholism.

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This gives you a macrocytic anemia.

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Liver disease can cause a macrocytic anemia.

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And there are certain drugs,

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for example, 5 -FU,

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that can cause a macrocytic anemia.

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In the case of macrocytic anemia,

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we would see large red blood cells with an MCV greater than 100.

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However,

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we would not see hypersegmented neutrophils,

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and we would not see megaloblastic change in the other rapidly dividing

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cells.

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That's the distinction between megaloblastic anemia and a macrocytic

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anemia.

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We're going to focus,

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obviously, on the two major causes of megaloblastic anemia,

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and the first is folate.

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Folate is the most common cause of a macrocytic or megaloblastic

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anemia, and so we want to understand a little bit about folate,

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in particular its biochemistry.

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Recall that folate is obtained from green vegetables and fruits,

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i .e.

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it's obtained from the diet,

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and it's absorbed in the jejunum.

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It is important for the purposes of examinations to know where folate

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is absorbed.

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Folate deficiency usually develops within months,

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and that's because the body stores are minimal.

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There is not much folate that is stored within the body.

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What are some causes of folate deficiency?

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Poor diet.

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Again, we have limited stores,

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and folate is obtained from the diet,

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so individuals with a poor diet will have an increased risk of developing folate

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deficiency.

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And the classic examples are alcoholics,

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who tend to have a poor diet,

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and the elderly.

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Another way by which folate deficiency can arise is by

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increasing...

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For example,

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if a woman is pregnant,

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she's making a baby,

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and each cell of the baby is going to have nuclear material,

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so folate would be necessary.

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If a patient has cancer,

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and cancer is generating cells that have nuclear material,

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folate would be necessary.

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And hemolytic anemia,

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where patients are rapidly turning over their bone marrow cells,

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would require an increased amount of folate.

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So increased demand can also cause a folate deficiency.

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And the final way,

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or a third way,

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I should say, by which folate deficiency can arise is via folate

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antagonists.

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Now, recall that methotrexate from pharmacology inhibits

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dihydrofolate reductase.

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That's important to know.

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Methotrexate inhibits dihydrofolate reductase,

10:44

S… Speaker 1 (5.3 Macrocytic Anemia)

which can then result in a folate deficiency.

10:48

S… Speaker 1 (5.3 Macrocytic Anemia)

And so these are some important causes of folate deficiency.

10:53

S… Speaker 1 (5.3 Macrocytic Anemia)

When a patient becomes folate deficient,

10:55

S… Speaker 1 (5.3 Macrocytic Anemia)

there are certain clinical and laboratory findings that would arise.

10:58

S… Speaker 1 (5.3 Macrocytic Anemia)

Obviously,

10:59

S… Speaker 1 (5.3 Macrocytic Anemia)

the patients would have a macrocytic anemia,

11:02

S… Speaker 1 (5.3 Macrocytic Anemia)

i .e.

11:03

S… Speaker 1 (5.3 Macrocytic Anemia)

the cells would have an MCV greater than 100,

11:05

S… Speaker 1 (5.3 Macrocytic Anemia)

and we would see hypersegmented neutrophils on blood smear.

11:10

S… Speaker 1 (5.3 Macrocytic Anemia)

In addition,

11:10

S… Speaker 1 (5.3 Macrocytic Anemia)

the patients classically have glossitis,

11:13

S… Speaker 1 (5.3 Macrocytic Anemia)

which is inflammation of the tongue,

11:15

S… Speaker 1 (5.3 Macrocytic Anemia)

and that partially has to do with the fact that the cells of the tongue

11:19

S… Speaker 1 (5.3 Macrocytic Anemia)

are not going to be turning over as well,

11:21

S… Speaker 1 (5.3 Macrocytic Anemia)

and so there will be discomfort in the tongue.

11:24

S… Speaker 1 (5.3 Macrocytic Anemia)

There will be a decreased serum folate.

11:28

S… Speaker 1 (5.3 Macrocytic Anemia)

I don't think that's hard to understand.

11:30

S… Speaker 1 (5.3 Macrocytic Anemia)

We're dealing with folate deficiency,

11:31

S… Speaker 1 (5.3 Macrocytic Anemia)

and so in folate deficiency,

11:33

S… Speaker 1 (5.3 Macrocytic Anemia)

the serum folate will be low.

11:34

S… Speaker 1 (5.3 Macrocytic Anemia)

There will be an increased serum homocysteine,

11:37

S… Speaker 1 (5.3 Macrocytic Anemia)

and this is very important.

11:40

S… Speaker 1 (5.3 Macrocytic Anemia)

Recall that I told you that tetrahydrofolate

11:44

S… Speaker 1 (5.3 Macrocytic Anemia)

gains a methyl group when it gets absorbed

11:48

S… Speaker 1 (5.3 Macrocytic Anemia)

into the human body.

11:49

S… Speaker 1 (5.3 Macrocytic Anemia)

It then passes that methyl group onto vitamin B12,

11:53

S… Speaker 1 (5.3 Macrocytic Anemia)

and then vitamin B12 then passes

11:57

S… Speaker 1 (5.3 Macrocytic Anemia)

that methyl group onto homocysteine.

12:02

S… Speaker 1 (5.3 Macrocytic Anemia)

And so imagine that if there is no folate,

12:06

S… Speaker 1 (5.3 Macrocytic Anemia)

then there is no passing of methyl to vitamin B12,

12:09

S… Speaker 1 (5.3 Macrocytic Anemia)

then vitamin B12 cannot pass the methyl group to homocysteine

12:13

S… Speaker 1 (5.3 Macrocytic Anemia)

to produce methionine.

12:15

S… Speaker 1 (5.3 Macrocytic Anemia)

And so if homocysteine cannot become transferred,

12:19

S… Speaker 1 (5.3 Macrocytic Anemia)

cannot be converted to methionine,

12:21

S… Speaker 1 (5.3 Macrocytic Anemia)

then homocysteine is going to pile up or build up.

12:25

S… Speaker 1 (5.3 Macrocytic Anemia)

And so there will be an increase in the serum homocysteine.

12:28

S… Speaker 1 (5.3 Macrocytic Anemia)

And because this ties into biochemistry and because it's useful clinically,

12:32

S… Speaker 1 (5.3 Macrocytic Anemia)

it is important to know.

12:33

S… Speaker 1 (5.3 Macrocytic Anemia)

The final clinical laboratory finding is actually a negative finding,

12:37

S… Speaker 1 (5.3 Macrocytic Anemia)

but it's a helpful finding,

12:38

S… Speaker 1 (5.3 Macrocytic Anemia)

and that is that the methylmalonic acid levels will be normal.

12:43

S… Speaker 1 (5.3 Macrocytic Anemia)

Now, methylmalonic acid gets converted to succinyl -CoA,

12:46

S… Speaker 1 (5.3 Macrocytic Anemia)

and the mechanism by which that conversion occurs is via

12:51

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12.

12:52

S… Speaker 1 (5.3 Macrocytic Anemia)

Otherwise stated,

12:53

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12 is necessary to convert methylmalonic acid to

12:58

S… Speaker 1 (5.3 Macrocytic Anemia)

succinyl -CoA.

13:00

S… Speaker 1 (5.3 Macrocytic Anemia)

Methylmalonic acid will be normal in these patients because this is not a vitamin

13:04

S… Speaker 1 (5.3 Macrocytic Anemia)

B12 deficiency.

13:05

S… Speaker 1 (5.3 Macrocytic Anemia)

We're discussing folate deficiency.

13:07

S… Speaker 1 (5.3 Macrocytic Anemia)

But again,

13:08

S… Speaker 1 (5.3 Macrocytic Anemia)

it's an important negative finding because when you have a megaloblastic anemia,

13:11

S… Speaker 1 (5.3 Macrocytic Anemia)

the differential diagnosis would be folate or vitamin B12.

13:15

S… Speaker 1 (5.3 Macrocytic Anemia)

And by seeing a normal methylmalonic acid,

13:17

S… Speaker 1 (5.3 Macrocytic Anemia)

we would gain an understanding that the vitamin B12 levels are

13:22

S… Speaker 1 (5.3 Macrocytic Anemia)

normal.

13:22

S… Speaker 1 (5.3 Macrocytic Anemia)

Of course,

13:23

S… Speaker 1 (5.3 Macrocytic Anemia)

we could also measure the vitamin B12 levels directly as well.

13:27

S… Speaker 1 (5.3 Macrocytic Anemia)

That then brings us into a discussion of the second cause of megaloblastic

13:33

S… Speaker 1 (5.3 Macrocytic Anemia)

anemia, and that is vitamin B12 deficiency.

13:36

S… Speaker 1 (5.3 Macrocytic Anemia)

So let's discuss a little bit of the biochemistry of

13:40

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12 in order to gain a better understanding of how a patient can become

13:44

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12 deficient and hence develop a megaloblastic

13:48

S… Speaker 1 (5.3 Macrocytic Anemia)

anemia.

13:49

S… Speaker 1 (5.3 Macrocytic Anemia)

Vitamin B12 is complex to animal -derived proteins,

13:53

S… Speaker 1 (5.3 Macrocytic Anemia)

for example,

13:54

S… Speaker 5 (5.3 Macrocytic Anemia)

meat or eggs,

13:55

S… Speaker 1 (5.3 Macrocytic Anemia)

and it comes into the body attached to those animal -derived

14:00

S… Speaker 1 (5.3 Macrocytic Anemia)

proteins.

14:00

S… Speaker 1 (5.3 Macrocytic Anemia)

Once it comes into the body,

14:02

S… Speaker 1 (5.3 Macrocytic Anemia)

however, vitamin B12 will be

14:06

S… Speaker 1 (5.3 Macrocytic Anemia)

cleaved from those animal proteins and will be bound by a

14:11

S… Speaker 1 (5.3 Macrocytic Anemia)

protein called R -binder.

14:15

S… Speaker 1 (5.3 Macrocytic Anemia)

Now, our binder is actually produced by the salivary gland,

14:19

S… Speaker 1 (5.3 Macrocytic Anemia)

and so the salivary gland has the job of producing this protein

14:23

S… Speaker 1 (5.3 Macrocytic Anemia)

that will then be complex to vitamin B12.

14:25

S… Speaker 1 (5.3 Macrocytic Anemia)

Our binder and vitamin B12 will then travel through the

14:30

S… Speaker 1 (5.3 Macrocytic Anemia)

esophagus and travel through the stomach until eventually they

14:34

S… Speaker 1 (5.3 Macrocytic Anemia)

reach the small bowel.

14:35

S… Speaker 1 (5.3 Macrocytic Anemia)

When they reach the small bowel,

14:37

S… Speaker 1 (5.3 Macrocytic Anemia)

our binder will be cleaved away from vitamin B12,

14:40

S… Speaker 1 (5.3 Macrocytic Anemia)

and how is that going to occur?

14:42

S… Speaker 1 (5.3 Macrocytic Anemia)

via the proteases that are produced by the pancreas.

14:45

S… Speaker 1 (5.3 Macrocytic Anemia)

Once vitamin B12 is cleared away from our binder,

14:48

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12 will then,

14:51

S… Speaker 1 (5.3 Macrocytic Anemia)

in the intestine,

14:52

S… Speaker 1 (5.3 Macrocytic Anemia)

bind intrinsic factor.

14:54

S… Speaker 1 (5.3 Macrocytic Anemia)

An intrinsic factor is a protein that's produced by the parietal cells

14:58

S… Speaker 1 (5.3 Macrocytic Anemia)

in the body of the stomach.

15:00

S… Speaker 1 (5.3 Macrocytic Anemia)

Again, intrinsic factor is a protein that's produced by the parietal

15:04

S… Speaker 1 (5.3 Macrocytic Anemia)

cells in the body of the stomach.

15:06

S… Speaker 1 (5.3 Macrocytic Anemia)

Once intrinsic factor binds vitamin B12,

15:08

S… Speaker 1 (5.3 Macrocytic Anemia)

this complex will then go to the ileum,

15:10

S… Speaker 1 (5.3 Macrocytic Anemia)

and it will be absorbed in the ileum.

15:14

S… Speaker 1 (5.3 Macrocytic Anemia)

This is the basic understanding of how vitamin B12

15:18

S… Speaker 1 (5.3 Macrocytic Anemia)

comes into the body.

15:20

S… Speaker 1 (5.3 Macrocytic Anemia)

Vitamin B12 deficiency is less common than folate deficiency.

15:24

S… Speaker 1 (5.3 Macrocytic Anemia)

And in addition,

15:26

S… Speaker 1 (5.3 Macrocytic Anemia)

it takes years to develop a vitamin B12 deficiency.

15:29

S… Speaker 1 (5.3 Macrocytic Anemia)

Why does it take years?

15:30

S… Speaker 1 (5.3 Macrocytic Anemia)

Because there are large hepatic stores.

15:33

S… Speaker 1 (5.3 Macrocytic Anemia)

The liver is loaded with vitamin B12.

15:36

S… Speaker 1 (5.3 Macrocytic Anemia)

And so if a patient were to absolutely not see any animal

15:40

S… Speaker 1 (5.3 Macrocytic Anemia)

protein, for example,

15:41

S… Speaker 1 (5.3 Macrocytic Anemia)

a vegan,

15:42

S… Speaker 1 (5.3 Macrocytic Anemia)

a very strict vegan who doesn't take milk,

15:44

S… Speaker 1 (5.3 Macrocytic Anemia)

doesn't take eggs,

15:45

S… Speaker 1 (5.3 Macrocytic Anemia)

et cetera,

15:47

S… Speaker 1 (5.3 Macrocytic Anemia)

That individual could become vitamin B12 deficient.

15:50

S… Speaker 1 (5.3 Macrocytic Anemia)

However, it would take years to develop due to large hepatic stores of vitamin B12.

15:54

S… Speaker 1 (5.3 Macrocytic Anemia)

The most common cause of vitamin B12 deficiency is

15:58

S… Speaker 1 (5.3 Macrocytic Anemia)

pernicious anemia.

15:59

S… Speaker 1 (5.3 Macrocytic Anemia)

Pernicious anemia is a disease that arises when there

16:03

S… Speaker 1 (5.3 Macrocytic Anemia)

is autoimmune destruction of the parietal cells.

16:06

S… Speaker 1 (5.3 Macrocytic Anemia)

Remind ourselves that the parietal cells are present in the body of the stomach

16:10

S… Speaker 1 (5.3 Macrocytic Anemia)

and they produce intrinsic factor.

16:13

S… Speaker 1 (5.3 Macrocytic Anemia)

Recall that intrinsic factor is necessary to bind vitamin B12 because

16:17

S… Speaker 1 (5.3 Macrocytic Anemia)

the ileum recognizes the vitamin B12 intrinsic factor

16:21

S… Speaker 1 (5.3 Macrocytic Anemia)

complex and that is what is absorbed by the ileum.

16:25

S… Speaker 1 (5.3 Macrocytic Anemia)

So if there is a loss of the parietal cells,

16:27

S… Speaker 1 (5.3 Macrocytic Anemia)

there will be a loss of intrinsic factor.

16:29

S… Speaker 1 (5.3 Macrocytic Anemia)

And if there is a loss of intrinsic factor,

16:31

S… Speaker 1 (5.3 Macrocytic Anemia)

there will be an inability to take up vitamin B12,

16:35

S… Speaker 1 (5.3 Macrocytic Anemia)

and so the patients will become vitamin B12 deficient.

16:39

S… Speaker 1 (5.3 Macrocytic Anemia)

And this happens to be the most common cause of vitamin B12 deficiency.

16:43

S… Speaker 1 (5.3 Macrocytic Anemia)

I'd like to take a step back here and also remind ourselves a little bit

16:47

S… Speaker 1 (5.3 Macrocytic Anemia)

about the parietal cells of the stomach.

16:49

S… Speaker 1 (5.3 Macrocytic Anemia)

The way I think about the parietal cells of the stomach,

16:52

S… Speaker 1 (5.3 Macrocytic Anemia)

is that it's associated with a bunch of P's.

16:54

S… Speaker 1 (5.3 Macrocytic Anemia)

So obviously,

16:55

S… Speaker 1 (5.3 Macrocytic Anemia)

parietal cell begins with the letter P,

16:57

S… Speaker 1 (5.3 Macrocytic Anemia)

but in addition,

16:58

S… Speaker 1 (5.3 Macrocytic Anemia)

the parietal cells are the ones that have the proton pumps.

17:01

S… Speaker 1 (5.3 Macrocytic Anemia)

They are the ones that make the acid in the body of the stomach.

17:05

S… Speaker 1 (5.3 Macrocytic Anemia)

In addition,

17:06

S… Speaker 1 (5.3 Macrocytic Anemia)

the parietal cells are pink,

17:07

S… Speaker 1 (5.3 Macrocytic Anemia)

so that's another P.

17:09

S… Speaker 1 (5.3 Macrocytic Anemia)

And what do I mean by pink?

17:10

S… Speaker 1 (5.3 Macrocytic Anemia)

When you look at the histology of the body of the stomach,

17:13

S… Speaker 1 (5.3 Macrocytic Anemia)

you'll see chief cells and parietal cells.

17:15

S… Speaker 1 (5.3 Macrocytic Anemia)

The chief cells look more blue,

17:17

S… Speaker 1 (5.3 Macrocytic Anemia)

and the parietal cells look more pink.

17:19

S… Speaker 1 (5.3 Macrocytic Anemia)

And then the third P is that the parietal cells are associated with

17:23

S… Speaker 1 (5.3 Macrocytic Anemia)

pernicious anemia.

17:24

S… Speaker 1 (5.3 Macrocytic Anemia)

When you knock out the parietal cells due to autoimmune destruction,

17:28

S… Speaker 1 (5.3 Macrocytic Anemia)

that results in pernicious anemia.

17:31

S… Speaker 1 (5.3 Macrocytic Anemia)

There are some other causes of vitamin B deficiency,

17:33

S… Speaker 1 (5.3 Macrocytic Anemia)

and examiners like to go after these because they allow the examiners to

17:37

S… Speaker 1 (5.3 Macrocytic Anemia)

test you on the biochemistry of vitamin B12 absorption.

17:41

S… Speaker 1 (5.3 Macrocytic Anemia)

So for example,

17:43

S… Speaker 1 (5.3 Macrocytic Anemia)

pancreatic insufficiency could result in a vitamin B12 deficiency.

17:47

S… Speaker 1 (5.3 Macrocytic Anemia)

Why would this happen?

17:49

S… Speaker 1 (5.3 Macrocytic Anemia)

Because remember that the pancreas produces the enzymes necessary

17:53

S… Speaker 1 (5.3 Macrocytic Anemia)

to cleave vitamin B12 away from our binder.

17:55

S… Speaker 1 (5.3 Macrocytic Anemia)

Go back and remind ourselves.

17:58

S… Speaker 1 (5.3 Macrocytic Anemia)

that vitamin B12 comes into the body,

18:00

S… Speaker 1 (5.3 Macrocytic Anemia)

is then bound by R binder,

18:03

S… Speaker 1 (5.3 Macrocytic Anemia)

which in the mouth,

18:03

S… Speaker 1 (5.3 Macrocytic Anemia)

which is produced by the salivary glands.

18:05

S… Speaker 1 (5.3 Macrocytic Anemia)

The R binder vitamin B12 complex then goes through the stomach and

18:10

S… Speaker 1 (5.3 Macrocytic Anemia)

then goes into the small bowel.

18:11

S… Speaker 1 (5.3 Macrocytic Anemia)

And it's in the small bowel that the pancreatic enzymes,

18:14

S… Speaker 1 (5.3 Macrocytic Anemia)

particularly the proteases,

18:16

S… Speaker 1 (5.3 Macrocytic Anemia)

will cleave away our binder,

18:17

S… Speaker 1 (5.3 Macrocytic Anemia)

which will then allow intrinsic factor to bind vitamin B12.

18:21

S… Speaker 1 (5.3 Macrocytic Anemia)

If there's pancreatic insufficiency and the enzymes are not produced properly,

18:26

S… Speaker 1 (5.3 Macrocytic Anemia)

this could result in a vitamin B12 deficiency.

18:28

S… Speaker 1 (5.3 Macrocytic Anemia)

So that would be one additional cause of vitamin B12

18:32

S… Speaker 1 (5.3 Macrocytic Anemia)

deficiency.

18:33

S… Speaker 1 (5.3 Macrocytic Anemia)

Another cause of vitamin B12 deficiency would be damage to the terminal

18:37

S… Speaker 1 (5.3 Macrocytic Anemia)

ileum.

18:38

S… Speaker 1 (5.3 Macrocytic Anemia)

Remember that vitamin B12 is absorbed in the ileum,

18:42

S… Speaker 1 (5.3 Macrocytic Anemia)

and so if there's damage,

18:44

S… Speaker 1 (5.3 Macrocytic Anemia)

for example, to the terminal ileum,

18:46

S… Speaker 1 (5.3 Macrocytic Anemia)

as would be seen in Crohn's disease,

18:48

S… Speaker 1 (5.3 Macrocytic Anemia)

or as would be seen with fish tapeworm,

18:51

S… Speaker 1 (5.3 Macrocytic Anemia)

then that would result in a vitamin B12 deficiency.

18:55

S… Speaker 1 (5.3 Macrocytic Anemia)

A third cause that I've listed here is dietary deficiency.

18:58

S… Speaker 1 (5.3 Macrocytic Anemia)

Recall,

19:00

S… Speaker 1 (5.3 Macrocytic Anemia)

and I would like to really hit home on this point because,

19:02

S… Speaker 1 (5.3 Macrocytic Anemia)

again, examiners like to go after it,

19:04

S… Speaker 1 (5.3 Macrocytic Anemia)

it's very rare to see dietary deficiency except in vegans.

19:08

S… Speaker 1 (5.3 Macrocytic Anemia)

And what are vegans?

19:09

S… Speaker 1 (5.3 Macrocytic Anemia)

These are strict vegetarians that do not eat anything that comes from

19:14

S… Speaker 1 (5.3 Macrocytic Anemia)

an animal.

19:15

S… Speaker 1 (5.3 Macrocytic Anemia)

So, for example,

19:16

S… Speaker 1 (5.3 Macrocytic Anemia)

they will not eat an egg.

19:18

S… Speaker 1 (5.3 Macrocytic Anemia)

That could then lead to a dietary deficiency.

19:22

S… Speaker 1 (5.3 Macrocytic Anemia)

The clinical and laboratory findings of vitamin B12 deficiency are

19:26

S… Speaker 1 (5.3 Macrocytic Anemia)

much of what we've already covered.

19:28

S… Speaker 1 (5.3 Macrocytic Anemia)

So for example,

19:29

S… Speaker 1 (5.3 Macrocytic Anemia)

there will be a macrocytic anemia with an MCV greater than 100 with

19:33

S… Speaker 1 (5.3 Macrocytic Anemia)

hypersegmented neutrophils.

19:35

S… Speaker 1 (5.3 Macrocytic Anemia)

There will also be glossitis due to poor turnover of the

19:39

S… Speaker 1 (5.3 Macrocytic Anemia)

cells of the surface of the tongue.

19:42

S… Speaker 1 (5.3 Macrocytic Anemia)

And third and...

19:44

S… Speaker 1 (5.3 Macrocytic Anemia)

Very important in the context of this discussion is that the patients can get

19:48

S… Speaker 1 (5.3 Macrocytic Anemia)

a subacute combined degeneration of the spinal cord.

19:51

S… Speaker 1 (5.3 Macrocytic Anemia)

Recall from biochemistry that there are only two chemical reactions that

19:56

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12 is involved in.

19:58

S… Speaker 1 (5.3 Macrocytic Anemia)

One is the reaction that involves a synthesis of DNA precursors.

20:02

S… Speaker 1 (5.3 Macrocytic Anemia)

Remember that folate transfers its methyl group to vitamin B12.

20:06

S… Speaker 1 (5.3 Macrocytic Anemia)

The second is the conversion of methylmalonic acid to succinyl

20:10

S… Speaker 1 (5.3 Macrocytic Anemia)

-CoA.

20:11

S… Speaker 1 (5.3 Macrocytic Anemia)

This reaction requires vitamin B12.

20:13

S… Speaker 1 (5.3 Macrocytic Anemia)

If vitamin B12 is lacking,

20:15

S… Speaker 1 (5.3 Macrocytic Anemia)

methylmalonic acid cannot be converted to succinyl -CoA,

20:19

S… Speaker 1 (5.3 Macrocytic Anemia)

and methylmalonic acid will then subsequently build up,

20:23

S… Speaker 1 (5.3 Macrocytic Anemia)

in particular,

20:24

S… Speaker 1 (5.3 Macrocytic Anemia)

within the myelin of the spinal cord.

20:28

S… Speaker 1 (5.3 Macrocytic Anemia)

And as it builds up within the myelin of the spinal cord,

20:31

S… Speaker 1 (5.3 Macrocytic Anemia)

it will cause degeneration of certain

20:35

S… Speaker 1 (5.3 Macrocytic Anemia)

regions of the spinal cord.

20:37

S… Speaker 1 (5.3 Macrocytic Anemia)

and that's called subacute combined degeneration of the spinal cord.

20:41

S… Speaker 1 (5.3 Macrocytic Anemia)

It's very important to remember that vitamin B12 is associated with

20:45

S… Speaker 1 (5.3 Macrocytic Anemia)

this neurologic finding,

20:46

S… Speaker 1 (5.3 Macrocytic Anemia)

and that this finding would not be seen in folate deficiency.

20:50

S… Speaker 1 (5.3 Macrocytic Anemia)

Laboratory findings would include a decrease in serum

20:54

S… Speaker 1 (5.3 Macrocytic Anemia)

vitamin B12,

20:55

S… Speaker 1 (5.3 Macrocytic Anemia)

In addition,

20:56

S… Speaker 1 (5.3 Macrocytic Anemia)

there would be an increase in serum homocysteine,

20:59

S… Speaker 1 (5.3 Macrocytic Anemia)

same concept.

21:00

S… Speaker 1 (5.3 Macrocytic Anemia)

If you have tetrahydrofolate,

21:03

S… Speaker 1 (5.3 Macrocytic Anemia)

which is folate that comes into the body,

21:05

S… Speaker 1 (5.3 Macrocytic Anemia)

it quickly gets methylated.

21:07

S… Speaker 1 (5.3 Macrocytic Anemia)

Remember that methyl group gets attached to vitamin B12,

21:11

S… Speaker 1 (5.3 Macrocytic Anemia)

and then vitamin B12 eventually takes that methyl group and passes it

21:15

S… Speaker 1 (5.3 Macrocytic Anemia)

on to homocysteine.

21:17

S… Speaker 1 (5.3 Macrocytic Anemia)

And homocysteine will then get converted to methionine.

21:21

S… Speaker 1 (5.3 Macrocytic Anemia)

So if vitamin B12 is not present,

21:24

S… Speaker 1 (5.3 Macrocytic Anemia)

it will not be able to pass this methyl group to homocysteine,

21:28

S… Speaker 1 (5.3 Macrocytic Anemia)

and so homocysteine levels will rise.

21:31

S… Speaker 1 (5.3 Macrocytic Anemia)

And so the serum homocysteine will be high.

21:34

S… Speaker 1 (5.3 Macrocytic Anemia)

The third lab finding would be an increase in methylmalonic

21:38

S… Speaker 1 (5.3 Macrocytic Anemia)

acid.

21:39

S… Speaker 1 (5.3 Macrocytic Anemia)

And I've already explained that vitamin B12 is necessary

21:44

S… Speaker 1 (5.3 Macrocytic Anemia)

to convert methylmalonic acid to succinyl -CoA.

21:48

S… Speaker 1 (5.3 Macrocytic Anemia)

And of course,

21:49

S… Speaker 1 (5.3 Macrocytic Anemia)

that methylmalonic acid,

21:50

S… Speaker 1 (5.3 Macrocytic Anemia)

as it builds up,

5.3 Macrocytic Anemia

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