Glucose-6-phosphate dehydrogenase (G6PD) deficiency

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Introduction0:00–0:19

Glucose-6-phosphate dehydrogenase deficiency, or G6PD deficiency, is a genetic disorder characterized by decreased levels of glucose-6-phosphate dehydrogenase, which leads to the destruction of red blood cells.

Physiology0:19–1:43

Normally, as a part of the metabolic process, our body produces free radicals like hydrogen peroxide, or H2O2. Free radicals can damage the cells in many ways including destroying the DNA, proteins, and the cell membrane.
Now, we have a molecule in our body called glutathione which acts as an antioxidant and goes around and neutralizes these free radicals.
In order to function, these molecules need to be in the reduced state where they can donate an electron to the H2O2 and convert them into harmless water and oxygen.
However this causes the glutathione to become oxidized, so before it can get back to work, an enzyme called glutathione reductase will use an NADPH as an electron donor and and reduce the oxidized glutathione back into its working state.
After giving up its electron, the NADPH will become NADP+. So to replenish the supply of NADPH, we have the glucose-6-phosphate dehydrogenase enzyme, or G6PD, which reduces NADP+ back to NADPH by oxidizing a glucose-6-phosphate.
Glucose-6-phosphate is a metabolite of glucose so we usually have a ready supply of this molecule as long as we are not starving.

Causes1:43–3:26

Now G6PD deficiency is caused by mutations on the G6PD gene which is found on the X chromosome and thus it’s an X-linked recessive genetic condition and it almost exclusively manifests as a disease in men, since they have one X and one Y chromosome, so if the one and only chromosome has the mutation, then they have the disorder.
Women on the other hand have two X chromosomes, so those with an X chromosome that has the mutation, still have another X chromosome with a normal copy of the gene and thus females are usually carriers and only transmit the disease to their sons.
The G6PD mutations cause defective G6PD enzymes to be produced and these have a shorter half-life, meaning they don’t last as long as the normal enzymes.
There are two common types of G6PD deficiency: a Mediterranean and an African variant. The Mediterranean variant is characterized by a more markedly reduced half-life of G6PD.
Now, sometimes this can actually be an advantage since it provides protection against falciparum malaria. G6PD deficiency makes the parasite-infected erythrocyte more susceptible to dying from oxidants, which will also kill the malaria parasites.
So despite the obvious downside to having any of these diseases, they do offer an upside when it comes to warding off a malaria infection.
In fact, because malaria has historically circulated in Africa, the genes underlying these diseases are thought to have conferred a natural selection advantage and therefore became more common in the genetic pool.

Pathophysiology3:26–5:58

Okay, so low levels of G6PD causes low levels of NADPH, leading to low levels of reduced glutathione. Now G6PD is the only way for red blood cells to get NADPH so they are especially susceptible to damage caused by free radicals.
When these build up, it causes the cell membrane to become unstable, causing their lysis, or hemolysis. Free radicals can also directly damage hemoglobin molecules which are the oxygen carrying protein in red blood cells.
These damaged proteins precipitates inside the cells and are called Heinz bodies. The spleen macrophages, that are responsible for eating up old or abnormal red blood cells, notice these Heinz bodies and try to remove them by taking a bite out of the cells, leaving these red blood cells partially devoured, so we call them bite cells.
Now, the good news is that only older red blood cells are at risk for lysis and the hemolytic episode is self-limited as hemolysis stops when only younger red blood cells remain.
Now, when a red blood cell dies, its hemoglobin breaks up into globin and heme. Heme is converted into bilirubin which is then taken up by the liver cells and eventually secreted out with bile.
If all of a sudden your body starts breaking down more red blood cells than the liver cells can handle, the excess bilirubin stays in the blood and cause jaundice where the bilirubin deposits in the skin and the eyes, causing them to turn yellow.
Some of the bilirubin is converted to urobilin which is what gives urine that yellow color. If there’s too much of it, the urine becomes a much darker, tea-like color.
This could also overwhelm the kidneys resulting in kidney damage. Okay, so there’s a long list of things that could increase free radical production and when there’s too much free radicals for the body to handle, it’s called oxidative stress, which leads to hemolytic episodes.
These include infections like viral hepatitis or pneumonia, metabolic acidosis, and foods and drinks like fava beans, soy products, red wine, and others.
Also certain medications can act as oxidant stressors like primaquine and chloroquine, which are ironically used to treat malaria.
Other common drugs include painkillers like aspirin and ibuprofen, quinidine that is used to treat arrhythmias, and other drugs that contain sulfonamide like the antibiotics trimethoprim.
OK. Now most of the patients with G6PD deficiency are completely asymptomatic until exposed to an oxidative stressor.

Symptoms5:58–6:21

Symptoms of acute hemolysis include jaundice, dark tea-colored urine, back pain due to kidney damage and anemic symptoms like fatigue, hypotension, tachycardia, confusion, and others.

Diagnosis6:21–7:46

The diagnosis can be suspected if there is a history of recent exposure to an oxidant like starting a new medication or eating a fava bean pita followed by a hemolytic episode.
Blood tests will show findings of hemolytic anemia like low levels of red blood cells and increased levels of reticulocytes, which are immature red blood cells made by the bone marrow in an attempt to keep up with the red blood cell loss.
Also, there will be high levels of lactate dehydrogenase, or LDH, which is an intracellular enzyme released in the blood.
Next, there is high bilirubin and low haptoglobin which is a molecule that binds free hemoglobin in the blood. Also, the Coombs test that is used to detect immune mediated anemias will be negative.
Now the blood smear will show bite cells, and Heinz bodies that are characteristic of G6PD deficiency and can be visualized with a special Heinz stain as dark intracellular inclusions within the red blood cells.
But the definitive test for G6PD diagnosis is an enzyme assay to detect the levels of G6PD. Given the high risk of hemolysis, it’s important to diagnose G6PD deficiency as early as possible and so newborns in many developed countries are tested a few days after birth.

Treatment7:46–8:03

Now because G6PD deficiency is a genetic condition there is no known cure other than avoiding known triggers. Treatment during an hemolytic episode include hydration and blood transfusion might be needed depending on the severity of the hemolysis.
All right, as a quick recap. G6PD deficiency is an X-linked recessive disorder and it’s characterized by low levels of glucose-6-phosphate dehydrogenase.

Review8:03–8:54

In G6PD deficiency, red blood cells are susceptible to oxidative stress which results in hemolysis. This is usually in response to certain triggers like infections, foods like fava beans and medications like sulfa-drugs and antimalarials.
Symptoms include jaundice, dark urine, back pain and anemia. Typical findings on the blood smear are Heinz bodies and bite cells.
Diagnosis can be confirmed with an enzyme assay. The mainstay of treatment is to avoid oxidant factors, but a transfusion might be needed if the hemolysis is severe.