Transcription
G6PD deficiency is the most common enzymatic deficiency worldwide. It has two variants: Mediterranean variants in North Africa, Italy, and Greece, as well as an African variant in sub-Saharan Africa. Which one is worse? The Mediterranean. And I'm a proud Egyptian. G6PD deficiency is very common in my home country, and now you will see how an Egyptian guy will explain a disease that's prevalent in his own country. Again, you will never understand anything if you have not already watched my previous video on G6PD, where I explained from biochemistry what's the purpose of G6PD in your life, as well as NADPH. So please go ahead and watch my previous video before this one. Let's get started. Okie-dokie.
G6PD deficiency, glucose-6-phosphate dehydrogenase deficiency, the most common enzyme apathy worldwide—400 million people, or about 10% of the world population, which is a lot of folks. 400 million is ah, maybe a little less than 10 percent of the world because 400 million times 10 is 4 billion people, and the world population currently is more than 7 billion, so it's close to 10 percent. Two variants again: African and Mediterranean. The Mediterranean variant is more severe. Okay, why Africa? Because it's protective against Plasmodium falciparum malaria. What else is protective against Plasmodium falciparum malaria? Thalassemia, cycle cell anemia or sickle-cell trait, HLA-B*53. All of these conditions are more common in Africa, which makes sense because malaria is more common in Africa. Why? A lot of reasons: because the climate is hot, and these infectious agents, the Plasmodium and the Anopheles mosquito, live in warm temperatures, and also because people there are poor. When people go from Africa, for example, to America, malaria is non-existent in America, so they tend to become better, and their hemoglobin is shifting toward the normal through evolution and the process of natural selection.
G6PD gene is X-linked. This disease is X-linked recessive, and of course, you know that anything that's X-linked recessive is almost exclusively affecting boys, so it affects males more. Many students just know that any X-linked recessive only affects boys; that's not correct. And you will have a medical professor in your school asking you, "Hey, son, are there any females with X-linked recessive diseases?" And you will say, "No," and then he will mock you and say, "Hahaha, you're stupid! Of course there are females!" But, doctor, you have never told us about this. Okay, yes, females can get it thanks to the process of X chromosome inactivation due to ionization. What's this gibberish? Okay, males are XY in general; females are XX. If the poor male has a defective X—there's a defect in this X—he is doomed. But for a female, if this X has a problem, she still has another X that's normal. The X will code for enough G6PD enzyme, and she will survive, and she'll be normal, and everything is fine. But if there is an inactivation of the normal X, okay, now she is left with the poor X. Whoo-hoo, bad luck, tough, huh? And she will get the disease. So males are either normal or G6PD deficient: either this X is normal and you are a happy dude, or this X is abnormal—null or G6PD deficient—poor guy. Females are different; they can be normal—most of them are—or G6PD deficient if both of the X chromosomes are affected, or they can be intermediate if only one of them is affected. Fine. So thanks to X chromosome inactivation, some females will get this disease because one of the X chromosomes will be affected by this mutation. I hope this is clear. Okay, let's go back to the general rule: males are affected; females are carriers. They carry it to their male offspring. Okay, only their male kids will be affected; their females will be normal, of course, unless there is an X chromosome inactivation, proving the point of your crazy professor. Okay, females can be affected in the neonatal period. Why? Because if you have a deficient X in your neonatal period, the other X is not mature yet to produce a sufficient volume of the enzyme G6PD, so in the neonatal period, there may be some problems. The second reason is X inactivation, as we have said before. And now you will enjoy this.
Okay, so this is a doctor in Egypt, and there's a mother, and she is terrified: "Doc, my kid is turning yellow, and his urine is dark." So the smart doctor asks, "What did you eat, my dear son?" "Nothing, just two pita and falafel sandwiches." This is a typical Egyptian dude. Okay, now we have something called favism. Favism is another name for G6PD deficiency. Favism related to falafel. Falafel and favism had the same Latin root. So in Egypt, we eat beans, which we call fool, and we eat falafel. So fool and falafel have—ism. Of course, we are doomed in Egypt. So the doctor will take this nice falafel sandwich from the kid and say, "Stop eating these beans and falafels, and you'll be fine, my little boy." And now the mother is happy, and everyone is fine. Okay, proud Egyptian, pay attention. This kid is yellow because of jaundice; they are in his dark because of jaundice and the bilirubin in the urine. So in the last video, I've explained this process. G6PD is a hero, why? Because it produces a very nice son called NADPH. NADPH has three purposes in your life: one, to protect you against free radical damage, so the red blood cells can be spared from this damage; number two, to protect you against methemoglobinemia by converting methemoglobinemia back, thus protecting you from oxidative agents or stressors—in this case, falafel; third, to convert oxygen into a superoxide in your neutrophils so that they can fight infections. So nice. If there is no G6PD, there is no NADPH, and the oxidative agents such as falafel can damage your red blood cells by free radicals, can damage your blood by converting your hemoglobin into methemoglobin, and now you have methemoglobinemia, and now you cannot fight infections. That's why infections are the most common stressor or the most common precipitating factor in G6PD deficiency. Okay, so infections, not falafels, are the most common cause of hemolysis in G6PD deficient patients.
Pathophysiology: so there is an oxidative agent, such as a drug and infection—maybe a falafel sandwich. Now you have free radicals. These free radicals will damage your red blood cells because you lack G6PD and NADPH, so you cannot protect your red blood cells. They get destroyed—intravascular hemolysis. Okay, also destroyed by macrophages in the blood. Hemoglobin is released from the red blood cell. There is a plasma protein called haptoglobin; it will get attached to the hemoglobin, and now all of this haptoglobin is consumed because it's binding all of this hemoglobin that's released from the destroyed red blood cells, so that plasma level of haptoglobin is reduced. Red blood cells have a lot of the enzyme LDH to convert lactate to pyruvate; it's a reversible reaction. Today, the red blood cell can get some ATP. Okay, the hemoglobin has heme and globin. Heme has iron and protoporphyrin. Protoporphyrin will become unconjugated bilirubin. Your liver will work hard to conjugate this bilirubin. The hemoglobin will go to the kidney. Hemoglobin has heme; heme has iron. Iron will be converted into hemosiderin. Hemosiderin will go into the urine—hemosiderinuria. Hemoglobin will go into the urine—hemoglobinuria. Intravascular hemolysis. There is a little bit of extravascular hemolysis, but mostly G6PD deficiency is an intravascular hemolysis process. Okay, clinical picture: either acute or chronic. Acute hemolytic anemia: the hemolytic episode after exposure to a stressor could be infection, could be a drug, could be a falafel sandwich, fava beans. Or chronic, which is mild, nonspherocytic hemolytic anemia. There is a difference between G6PD deficiency and favism. Favism is kind of the symptoms. So many of these patients are asymptomatic; those with symptoms, we call them—they have favism. So favism is a subset of G6PD deficiency. Favism is a part of G6PD deficiency. Most patients are asymptomatic; not all G6PD deficient patients have favism. Okay, symptoms related to anemia, related to jaundice, related to hemolysis. So first to appear are those related to hemolysis: malaise, weakness, abdominal or lumbar pain. Then maybe later you will have jaundice, yellow skin, yellow sclera, and dark urine, and some symptoms of anemia: fatigue, pallor, etc. You should expect full recovery after removal of the stressor. If this poor Egyptian kid stopped eating falafels, he'll be fine for the rest of his life, as long as he stops eating this falafel. So I'm always saying oxidative agents and stressors. So what are these stressors? They can be infections or fava beans, such as, mmm, falafel or broad beans, acidosis, and drugs: antimalarials such as primaquine, chloroquine. So let's review some pharmacology. These are drugs used to treat malaria, but they can damage your retina. So for drugs, as dapsone, which is a powerful antibiotic, usually against gram-negatives, and of course, prophylaxis for AIDS patients before getting PCP pneumonia. Dapsone can treat both leprosy and dermatitis herpetiformis. Side effects will include some skin lesions or a rash. Sulfasalazine, same thing; it can treat a lot of inflammatory bowel diseases. Antibiotics: cotrimoxazole, nitrofurantoin. This is high-yield; it treats urinary tract infections, especially in pregnant patients. And so I prefer ciprofloxacin. Analgesics, antipyretics such as naproxen and aspirin, but not just baby aspirin; the dose has to be greater than 3 grams per day. Others such as methylene blue and pegloticase. This is a very high-yield drug; why? It's a new medication to treat gout. So let's say that you have a patient coming from Egypt, and he would like to try pegloticase to treat his gout. Which of the following tests should you order before initiating treatment? The answer is G6PD level. Okay, this is a great board question. The most common stressor is infection, why? Because you cannot fight infections now; you don't have NADPH because you don't have G6PD, and you cannot form HOCl by neutrophils to kill bacteria.
Diagnosis: clinical picture—the story of the Egyptian doctor and the kid eating falafels. CBC: how about the hemoglobin level? It is decreased, and hematocrit is decreased as well. Reticulocytes are usually increased because the bone marrow responds to the hemolysis, and the serum LDH will be high. Haptoglobin will be low; unconjugated bilirubin will be high. The urine is dark in color because of jaundice, hemosiderinuria, or hemoglobinuria. Peripheral smear: you have bizarre poikilocytes; these are abnormally shaped red blood cells under the microscope. He will say uneven distribution of hemoglobin. What's that? This should be like evenly red or evenly pink. What's that? This is called a hemighost. Use a special stain such as methyl violet, and you'll see nice Heinz bodies. Heinz bodies are oxidized, denatured particles of hemoglobin; it's a signature that this red blood cell has been exposed to an oxidative stressor. Okay, so when you see Heinz bodies, this means oxidative stressors, damage to the red blood cells, which means that she cannot defend herself because she doesn't have G6PD. The splenic macrophages will remove this Heinz body and leave you with bite cells. Even doctors can be funny. Yes, sometimes the definitive diagnosis is by DNA testing. RBC enzyme level of G6PD. Pay attention, please. If you order G6PD level during the acute episode—you are one stupid doctor. Why? You will have a false negative result, so there's what will come back negative. He will say to mommy, "Your kid is fine; he does not have G6PD; he can continue eating five falafel sandwiches per hour." This is a foolish doctor. You never order this enzyme level during the acute episodes. Now, why is that? Because G6PD levels normally decline over the red blood cell lifespan, so the measured levels of the enzyme can be normal during an acute hemolytic episode. Why? Because the young cells, especially reticulocytes, will have a sufficient level of G6PD, and during hemolysis, there is reticulocytosis. These cells will enrich the test population because these reticulocytes have enough G6PD to fool the test, so you will see that we have normal levels of G6PD. No, you don't. The problem is that the old red blood cells with the least amount of G6PD are being removed, and they are being replaced with baby red blood cells called reticulocytes with high or sufficient levels of G6PD. So when you measure, you will measure these reticulocytes, and you'll say, "You're fine, kid." No, he's not. So you should wait two to three months after the hemolytic event, i.e., after the acute hemolytic episode, and then measure the RBC enzyme level of G6PD again. False negative test is possible during acute hemolysis with brisk reticulocytosis.
Management is pretty straightforward: prevention is better than cure. Avoid the oxidative stressors, avoid drugs, try to treat infections as early as possible, avoid fava beans, stop eating falafels, please. Screen for G6PD before prescribing drugs. So before prescribing dapsone or chloroquine, please order a G6PD level. It's normal; you can safely give the drug. By the way, there was a drug on the market containing both quinine and dapsone. Who imagines taking this drug together with a falafel sandwich? Good luck. Thankfully, this drug has been removed from the market. How to manage this condition? Blood transfusion, especially in cases of acute hemolytic episodes—the poor Egyptian guy eating falafels. Folic acid supplements, of course, because hemolysis consumes folate. If you are like some patients, require recurrent transfusions, of course you should do iron chelation, as recurrent transfusions contain a lot of iron, which can lead to secondary hemochromatosis. That's it for G6PD. Enjoy this lecture. Now you know everything about the disease because you are listening to an Egyptian medical student. Okay, it's just relevant and prevalent in our country; that's why it's important. Good luck with your studies. Be safe and study hard. To see you next section.