AssessmentsGlucose-6-phosphate dehydrogenase (G6PD) deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
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A 30-year-old male presents to the emergency room with severe, intractable abdominal pain localized to the right upper quadrant area of his abdomen. He reports that he had been having intermittent pain over the past few weeks, but this episode has been unrelenting. An ultrasound reveals numerous gallstones. The patient is taken to the operating room for a laparoscopic cholecystectomy. After the removal of the gallbladder, its contents were exposed, revealing numerous small, black gallstones. Which of the following is most likely finding on this patient's medical history?
Content Reviewers:Yifan Xiao, MD
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.
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.
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.
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.