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New Treatments for  B-12 Deficiency, Folic Acid Deficiency and the Megaloblastic Anemias

The first step is just to recognize the megaloblastic anemia where basically for all practical purposes we are talking about either vitamin B-12 or folate deficiency. The second step, as important as the first, is to identify which vitamin is actually responsible. There’s a whole bunch of things that flow from that. The third step is to identify what the underlying disorder is that caused the vitamin B12 deficiency. This is a step that I find that people give short shrift to because the approach might be that it is all so easily treatable with vitamins these days that it’s not really that important to put the patient through a whole bunch of expensive evaluation.

Now you can have neurologic abnormalities, primarily in vitamin B-12 deficiency. These may coexist. More often they seem to exist in a somewhat inverse relationship with anemia. You can have oral symptoms. We don’t see that too much but some patients may present with rather troubling chilosis or tongue, things like that, or they may simply present with low vitamin levels. Or nowadays, as homocystine has become a real hot issue.

How do we then identify which vitamin is responsible? The classical way that has been in operation for 50 years now is the serum vitamin assay. You can imagine, number one, it’s fairly reliable because it has stood the test of time, although there may be some who argue that it has stood the test of time because it hasn’t been properly examined and reexamined with modern techniques. But it has stood the test of time, however, there is something inherently unsatisfying about serum vitamin levels because they don’t always reflect tissue levels. Because, for example especially with vitamin B-12, changes in the transport proteins, changes in clearance may affect the vitamin levels in the blood without actually affecting tissue status. For example, there are certain conditions where one sees low vitamin B-12 levels commonly.

The next step is tissue levels. You hear a lot about red cell folate levels. For a long time it was said that red cell folate levels are much preferable to serum levels. But in fact the big problem with red cell folate levels is a technical one.

What about homocystine? This whole circle is the folate cycle, and folate interacts with homocystine in a critical way. Homocystine is metabolized in two ways. It can be transulfurated - and this is vitamin B-6 dependent. That’s one pathway. But the pathway that will be more germane to today’s discussion is it’s remethylation to methionine because that requires both methyltetrahydrofolate and methyl B-12. So therefore if somebody is deficient in either folate or vitamin B-12 homocystine levels go up. This is a fairly striking tool.

The other metabolic test that I mentioned is methylmalonic acid. The only other reaction that B-12 takes part in, besides the remethylation of homocystine, is the isomerization of methylmalonyl- CoA succinyl in B-12 deficiency, but not in folate deficiency, methylmalonic acid levels go up. So methylmalonic acid is a much better differentiator between folate deficiency - which doesn’t affect methylmalonic acid levels - and B-12 deficiency where levels rise.

So, so much for making the diagnosis of the vitamin B-12 deficiency. We now have these powerful metabolic tools that I think should be resorted to in your problem patients.

The next step is; what about the cause or the disorder that caused the deficiency? So let’s talk about vitamin B-12 first. In order to do that I first want to run with you through the folate assimilation cycle. The reason we know about these steps is there have been patients identified with problems at every single step. There are probably many other steps in here that we don’t know about simply because the patients haven’t been identified yet. So B-12 is taken in in food, in the presence of acid and pepsin. B-12 is released from food.

To bring to your attention an interesting issue, omeprazole is now a big seller. Omeprazole actually, by suppressing acid secretion very potently, will cause food B-12 malabsorption. This study shows food B-12 absorption which is normal in these two individuals. Before omeprazole and after omeprazole, and lots of groups have reproduced these findings.

Okay, so much for the underlying disorders of B-12. What about folate deficiency? This is a study done in the 70’s by John Lindenbaum in New York and what he showed was that 90% of his folate deficient patients, the folate deficiency arose as a combination of alcoholism and poor diet. Only about 6% were due to malabsorption.

The daily requirement of folate, however, is about 100 -200 mcg, where as for B-12 it’s about 1% of that. So you can see that a person has to be B-12 deficient almost 100 times as long in order to become B-12 depleted as for folate. So you can get folate deficient with a poor diet in a matter of months. It will take years to become dietarily depleted of B-12. Not only that, but food folates are highly labile in all the ways we prepare food, whether it’s canning or cooking.