Next in our little series on hereditary hemolytic anemias is glucose 6 phosphate dehydrogenase (or G6PD) deficiency.
Before we get into G6PD deficiency, we need to discuss just what this G6PD enzyme does. If you can close your eyes and try to think back to biochemistry, see if you can recall something called glutathione (if you can’t, look on Wikipedia). It’s a tripeptide that protects cells from free-radical injury. It exists in two states: a reduced state (GSH) and an oxidized state (GSSG). In the reduced state, GSH is able to donate a hydrogen ion to dangerous toxic substances (like reactive oxygen species), making them much less nasty. You need to have this stuff in your cells, or else you won’t be able to detoxify the nasty stuff that the cell makes during metabolism – and the cell will die a mature death.
In doing its important detoxification work, glutathione moves from the reduced state (GSH) to the oxidized state (GSSG). Obviously, you need to change the GSSG back into GSH in order for this pathway to continue to work. That’s where G6PD comes in. G6PD reduces NADP to NADPH, a substance which in turn converts GSSG into GSH. Whew. That’s a lot of biochem. See the little “Pentose phosphate pathway and glutathione production” box here. So: if you don’t have G6PD, you can’t reduce your NADP, which means that you can’t reduce your GSSG. And the cell will suffer an untimely demise.
That’s what happens in patients with G6PD deficiency. Usually, patients are fine, with no perceptible anemia, until they encounter an oxidant of some sort (the list is long, and includes a wide variety of substances, from fava beans to aspirin to mothballs). The oxidant creates more free radicals in the red cell, which means that glutathione is particularly active. Without G6PD, the glutathione remains in its oxidized state, unable to act further, and the free radicals attach sulfhydryl groups and disulfide bonds, liberating heme from globin. The globin becomes denatured and forms into a little ball called a Heinz body, which sticks to the red cell membrane. Macrophages in the spleen see these Heinz bodies and bite them out of the red cells, making unusually shaped “bite cells.”
The gene for G6PD is on the X chromosome, so males are much more likely to have full expression of the disease. The disease is more common in African Americans (10% of African American males have the gene). It also has a particularly high incidence in areas in which malaria was endemic, and it is thought to confer a selective advantage against malaria infection.
If you look at a blood smear of a patient who is in an acute hemolytic episode, you’ll see cell fragments, including bite cells (yes, they’re really called that), which are caused by recent pitting of Heinz bodies. To see the actual Heinz bodies, you need to do a supravital stain (see the image above – the Heinz bodies appear as green dots).
Therapy is pretty straightforward. Obviously, the patient needs to avoid taking offending drugs or drinking hydrogen peroxide. The hemolysis in G6PD deficiency is self-limiting, usually resolving within a week. This is because it’s the older red cells (which are already pretty G6PD depleted) get killed off first; and as new ones come out into the circulation, they have a full amount of functioning G6PD, so they can handle the oxidant better. For severe or prolonged crises, red cell transfusions may be necessary.
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