G6PD Deficiency: Interaction with Quinine, Viral Susceptibility

Quinine-based malaria drugs are being tested and used for preventing acute respiratory distress syndrome (ARDS) in people with COVID-19 infections. And yes, there are many stories floating around on the internet of people obtaining chloroquine, hydroxychloroquine, or quinine for personal use…

People who carry the genetic mutations that cause G6PD deficiency are at an increased risk for hemolytic anemia when taking quinine-based medications

This article is intended to be a ‘heads up’ for anyone who is considering using quinine or chloroquine  – without a doctor’s advice – for COVID-19.

If you are under a doctor’s care and they prescribe chloroquine, please talk with your doctor and go with their recommendations. There is not a one-size-fits-all answer here, and every one of us is unique.

(Members: Read the enhanced version of this article with your genetic data included.)

What is G6PD?

The G6PD gene codes for the glucose-6-phosphate dehydrogenase enzyme. The G6PD enzyme is part of the pentose phosphate pathway and supplies the energy needed to produce NADPH within cells.

NADPH is important in maintaining homeostasis in cells in several ways.  One way is that it is responsible for maintaining the supply of glutathione, one of the important antioxidants that your body produces to counteract oxidative stress.  [ref]

While the G6PD enzyme is expressed in all tissues, red blood cells are the only type of cells that rely entirely on this pathway completely. Thus G6PD deficiency can cause the destruction of red blood cells through a build-up of oxidants in certain situations.[ref]

G6PD Deficiency

Mutations in the G6PD gene can cause the glucose-6-phosphate dehydrogenase enzyme not to function properly. The G6PD gene is located on the X chromosome. Males only have one copy of the G6PD gene, and thus are more likely to be affected by G6PD deficiency than females (who have two X chromosomes). The amount of G6pD enzyme deficiency varies, depending on the mutation in the gene. Researchers have identified at least 187 different mutations in the gene.[ref]

About 400 million people worldwide carry the mutations that cause G6PD deficiency. The majority of people who carry the mutations are from the tropical and subtropical regions of Africa, India, SE Asia, the Middle East, and Mediterranean regions like Sardinia.[ref] [ref][ref]

One key that I want to emphasize is that the different mutations that cause G6PD deficiency cause different reductions in the enzyme function. Some mutations cause a milder loss of enzyme function, while others cause a more severe loss. Even within people who have the same mutation, there is a range of enzyme function.[ref]

Hemolytic Anemia: Triggers for People with G6PDD

Normal red blood cells (RBC) have a lifespan of around 120 days, after which they are destroyed and replaced with new RBC. This is happening all the time in the body, and a natural process that the body handles really well.

A decrease in the G6PD enzyme causes older red blood cells to become increasingly vulnerable to oxidative stress, due to a lack of glutathione, an intracellular antioxidant. Thus, when subjected to oxidative stress, red blood cells are destroyed more quickly than normal.[ref]

While most people have no day-to-day symptoms from this disorder, hemolytic anemia can occur more easily in people with G6PD deficiency. Hemolytic anemia is a serious condition that happens when red blood cells are destroyed faster than the body can replace them.[ref]

Symptoms of hemolytic anemia include:

  • paleness
  • jaundice (yellowing of the eyes and skin)
  • dark urine (or red urine)
  • fatigue
  • shortness of breath
  • rapid heart rate

The triggers for hemolytic anemia in G6PD deficiency include:

  • infections (including viral and bacterial infections)
  • Fava beans, and several other foods
  • medications (including quinone and methylene blue)

Where are people more likely to have G6PD deficiency?

The mutations in the G6PD gene are deleterious – bad – and thus should have been weeded out of the genome, according to the normal way that mutations work in a population.

But… the G6PD mutation has a big positive: it protects against severe malaria. Thus, the mutation has survived in the genome in areas where malaria is (or was) prevalent (Africa, Middle East, India, Southeast Asia).

Males who have a mutation in their single copy of the G6PD gene are protected from severe malaria infections, and it also turns out that females who only carry one copy of a G6PD mutation also have partial protection from severe malaria.[ref]

Here are a few examples of population frequencies of G6PD deficiency (includes mild and severe):

  • Guangxi, China – 7% [ref]
  • Sardinia – 12% [ref]
  • India – 8% (varies from 0 – 27% depending on ethnic group)[ref]
  • S.E. Iran – 30% [ref]
  • Burkina Faso – 15%[ref]
  • West Africa – generally 10-20%[ref]
  • Japan and Northern European populations – 0.1% [ref]

G6PD deficiency: viral and bacterial infections

One trigger of hemolysis in people with G6PD deficiency is bacterial or viral infections which cause increased oxidative stress in the cell.

But — there may be a lot more to this than just the increase in oxidative stress and possible hemolysis.

Recent research shows that G6PD deficient cells are ‘highly susceptible to viral infections’. Both bacterial and viral infections can be more severe in people with G6PD due to a reduced immune response. This has been shown to go beyond just the response in red blood cells. [ref][ref][ref]

  • G6PD deficiency has been shown in a lung cell study to increase susceptibility to one strain of human coronavirus (HCoV 229E – cold symptoms, different receptor than COVID-19).[ref] [ref][ref]
  • People with G6PD deficiency may be more at risk for complications with hepatitis. [ref][ref]
  • Pneumonia and typhoid can also cause hemolysis for people with G6PD deficiency.[ref][ref][ref]
  • G6PD deficiency causes increased susceptibility to the virus that causes dengue fever.[ref]

G6PD deficiency: interactions with medications

A number of medications have been shown in research to cause hemolytic anemia in G6PD deficiency. Please be sure to check with your doctor or pharmacist, though, for more complete information here. Some medications are only a problem at certain dosages or intervals. [ref]

Primaquine, an anti-malaria drug, is linked to a dose-dependent risk of hemolytic anemia in people with G6PD deficiency.[ref]

Other drugs that cause Predictable or Possible hemolysis include:[ref]

Drugs that cause Predictable hemolysis:

  • Dapsone
  • Primaquine
  • Methylene Blue
  • Cotrimoxazole
  • Sulfadiazine
  • Quinolones (ciprofloxacin, ofloxacin, nalidixic acid)
  • Nitrofurantoin
  • Rasburicase
  • Toluidine blue

Drugs causing possible hemolysis:

  • Chloroquine
  • Quinine
  • high dose aspirin, acetaminophen
  • Sulfasalazine
  • Chloramphenicol
  • Isoniazid
  • Ascorbic acid (very high doses[ref])
  • Glibenclamide
  • Vitamin K
  • Isosorbide
  • Dinitrate

What about hydroxychloroquine? One study found that hydroxychloroquine, which was prescribed for rheumatoid arthritis and lupus, did not cause hemolysis in 11 African American patients with G6PD deficiency. [ref] With Primaquine, which is dosed on a weekly schedule, there is a need for medical supervision and pre-treatment screening for G6PD.[ref][ref]

Quinine has been used for centuries to combat malaria. Found in the bark of the cinchona tree in Peru, it was exported from the New World by Spanish colonists in the 1500s.  Dr. Livingstone, the missionary explorer famous for his journeys through Africa, survived using quinine to combat malaria. [ref]

Quinine can be transferred by breastmilk. A case study showed three cases of hemolytic evens in babies with G6PD deficiency when the mothers had consumed tonic water (which contains quinine).[ref]

Naphthalene, in mothballs, can also trigger hemolysis in people with G6PD deficiency. [ref]

G6PD deficiency: interactions with foods

An ancient term for G6PD deficiency is Favism, due to Fava beans often triggering hemolytic anemia in people with the mutations. In fact, ancient Greeks knew about Favism, and Pythagoras warned against eating fava beans.

Fava beans are also known as broad beans in some areas of the world. They are not the same as lima beans, although they look similar.

Common triggers for hospitalization in Egypt for people with G6PD deficiency include fava (broad) beans, chickpeas (falafel), green pea, peanuts, lentils, and black-eyed peas. [ref]

 

 


Genetic variants that can cause G6PD deficiency:

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There are many other genetic mutations linked to G6PD deficiency that are not covered in 23andMe or AncestryDNA data, so you can’t rule out carrying a mutation by using these data sources. If you have reason to suspect G6PD deficiency, you would need to get a blood test done to confirm it.

Check your genetic data for rs1050828 v98M (23andMe v4, v5; AncestryDNA)

  • C/C: typical
  • C/T: G6PD deficiency carrier (A- variant, usually milder)
  • T/T or T: G6PD deficiency carrier (A- variant, often milder) [ref]

Members: Your genotype for rs1050828 is .

Check your genetic data for rs5030868 (23andMe v4, v5; AncestryDNA) :

  • A/A or A: G6PD deficiency (Mediterranean variant)[ref]
  • A/G:  G6PD deficiency carrier
  • G/G: typical

Members: Your genotype for rs5030868 is .

Check your genetic data for rs72554664 (23andMe v4, v5)

  • C/C: typical
  • C/T: G6PD deficiency carrier
  • T/T or T: G6PD deficiency carrier (Kaiping variant)[ref]

Members: Your genotype for rs72554664 is .

Check your genetic data for rs72554665 (23andMe v4, v5 i5012739)

  • C/C: typical
  • C/T: G6PD deficiency carrier
  • T/T or T: G6PD deficiency carrier (Canton variant)[ref]

Members: Your genotype for rs72554665 is .

Check your genetic data for rs5030869  (i3003411 in 23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: G6PD deficiency carrier
  • T/T or T: G6PD deficiency carrier (Chatham variant)[ref]

Members: Your genotype for rs5030869 is .

Check your genetic data for rs137852327 (i5008436 in 23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: G6PD deficiency carrier
  • T/T or T: G6PD deficiency carrier [ref]

Members: Your genotype for rs137852327 is .

Check your genetic data for rs137852330 (i5008440 in 23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: G6PD deficiency carrier
  • A/A or A: G6PD deficiency carrier  [ref]

Members: Your genotype for rs137852330 is .


Lifehacks:

If you carry the genetic mutations related to G6PD deficiency, talk with your doctor about and possibly consult a dietician. In addition to fava beans, there are quite a few foods that are recommended to be avoided.  As far as medications to be avoided, again, talk with your doctor or pharmacist.

Cell studies show that adding an antioxidant, such as alpha-lipoic acid, helped to mitigate the increased viral susceptibility to coronavirus in G6PD deficiency.[ref]

Several older studies suggest that N-acetylcysteine may be a good antioxidant support supplement for G6PD deficiency.  [ref][ref]

Again, read the research and talk with a doctor on all of this.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.