A deficiency in screening for G6PD deficiency – just one more example of systemic racial injustice in our medical system? It’s hard not to see the lack of attention paid to favism as another sign of racism. Because, although G6PD deficiency, which can cause problems in red blood cells upon certain triggers, is the most common human enzyme defect, affecting over 400 million people, including over 1 in 10 Black American males, newborn screening for it is, as far as I could find out, only mandated in one US state and Washington D.C. 

Most people with G6PD deficiency go their whole lives without knowing they have it. So not knowing isn’t that big of a deal. But, for some with the condition, all it takes is one triggering incident – such as getting a bad infection, eating raw fava beans, or taking certain pharmaceutical drugs like hydroxychloroquine – and their blood cells can “explode” or get degraded in a phenomenon called hemolytic anemia which leaves them without enough red blood cells to carry out their role of transporting oxygen throughout the body. Although these events are temporary, going away once the trigger does, they can occasionally be severe and even life-threatening, and if they happen frequently the damage can build up leading to chronic anemia, liver, heart, & kidney problems. 

G6PD stands for Glucose-6-Phosphate Dehydrogenase, and it’s a metabolic enzyme protein. Enzyme proteins are proteins that help make biochemical reactions happen faster (such as by holding reactants together in the optimal positions, etc.) And metabolism refers to the making and breaking of biochemicals. G6PD is responsible for helping break down a molecule called – you guessed it! – Glucose-6-Phosphate (G6P) – as part of a metabolic pathway called the Pentose Phosphate Pathway (PPP). This pathway is important for several things including making the sugar parts of DNA & RNA and producing the reducing agent NADPH. And this NADPH is important for regenerating glutathione, which is a tripeptide antioxidant that our bodies use to protect against highly energetic “Reactive Oxygen Species” (ROS) that, if left unchecked, can attack our proteins, lipids, etc. and cause damage. 

Most cells in our body also make another protein that can do the same thing as G6PD. But our red blood cells (RBCs) don’t make that second protein – so they’re reliant on G6PD. If someone doesn’t make enough of it, or if what they do make doesn’t work that well, they’re unable to sufficiently regenerate that antioxidant in their RBCs, so events that trigger a lot of ROS (such as getting severe infections, eating raw fava beans, or taking certain drugs) can cause so much oxidative stress and damage to the cells’ lipid membranes that those RBCs “explode” and/or get degraded, leading to a phenomenon called hemolytic anemia. 

Before you get too scared, know that, this is pretty rare – in the vast majority of cases, people with G6PD deficiency go their whole life without even knowing they have it. People with extreme cases might find out as infants because it can cause neonatal jaundice (a buildup of blood waste products that make you turn yellow) and in rare cases, a condition called kernicterus that causes brain damage if untreated. But many people who find out do so later in life the hard way, such as by eating raw fava beans and having a “favism attack.” But this doesn’t have to be the case.

One consequence of pharma’s direct marketing of pharmaceutical drugs to consumers in the US is that you hear commercials with warnings like “Do not take if you have a G6PD deficiency” – as if you, the consumer, are supposed to know what “G6PD deficiency” is, let alone whether or not whether you have it. Your doctor hopefully knows what it is, but they might not know if you have it.  Because, although are easy tests for G6PD deficiency that can be included in newborn screenings, for the most part, they aren’t.

Meanwhile, we screen for super rare diseases, many of which are also enzymatic deficiencies. Of course, it’s not fair to just directly compare these. Many of the diseases we screen for in newborns are diseases that, although they are super rare, can be super serious, but if caught really early, you can take interventions to prevent irreversible developmental damage.

For some enzymatic disorders, patients lack a key enzyme needed to make some molecule, so they’ll have serious developmental problems which can be avoided just by giving them that molecule – or that enzyme. 

Other enzymatic disorders involve problems with enzymes that break down other molecules. So those bigger molecules build up & cause problems. But if you put them on a strict diet that avoids those molecules they can’t break down, they’ll be fine. This is the case with PKU (PhenylKetoneUrea) where those affected lack an enzyme needed to break down the amino acid (protein letter) phenylalanine (Phe, F). http://bit.ly/pkustoryandscience 

G6PD is in this latter category – it involves a breaker-down. But its impact is usually a lot less serious – until it is…

G6PD deficiency *has* been tested for more frequently recently – though in adults – because one of those drugs that can trigger a favism attack is hydroxychloroquine(HCQ)/chloroquine(CQ), which was over-hyped as a potential coronavirus treatment. HCQ is just a modified, stabler, version of CQ, so I’m just going to use CQ to refer to them both. 

CQ has been used for a long time as a treatment for malaria, which is caused by a parasite called Plasmodium. This parasite gets inside of red blood cells & degrades hemoglobin (the protein responsible for carrying oxygen in the blood) for food – it chews up the protein part (globin) to use the amino acids. But this leaves the non-protein part, the heme. Heme waste products can be toxic and ROS-y but normally they just crystalize into harmless form called hemozoin. But CQ prevents this recrystallization and this causes a large buildup in ROS in the parasite.

But people with G6PD deficiency already have ROS buildup “problems.” In fact, this might be beneficial for preventing serious malaria (which is believed to be a reason for G6PD deficiency’s high prevalence in areas where malaria is common). So, basically they’re cells are kinda already doing what CQ would do, so if you give those people CQ it can super overload them with ROS and cause that hemolytic anemia we want to avoid.

Therefore, doctors should screen patients for G6PD deficiency before prescribing CQ. These same precautions need to be taken with similar anti-malarial including primaquine & tafenoquine. For this reason, the Department of Defense (DoD) mandated screening of soldiers because they often go to areas where malaria is common. They shared what they found & this is one of the only sources of prevalence data in the US as I will get into https://bit.ly/2Ct24NL 

As for the fava beans (Vicia faba, aka broad beans)? It involves a similar phenomenon, but with different triggering chemicals, including a couple of “alkaloid glycosides” named vicine & covicine which. Glyco-refers to the sugar attached and when those sugars get chopped off in your body, you get divicine & isouramil. These are really reactive & lead to the production of hydrogen peroxide (H₂O₂) which is one of those ROS that glutathione is needed to neutralize. 

In addition to those few examples, triggers include a variety of other drugs & even some pesticides & cosmetics. 

So, why don’t we screen for it? 

One reason might be the distribution pattern. It’s common in the Middle East, South Asia, the southern Mediterranean region, and Africa. It’s less common among caucasians and, since white people basically have historically had all the power in our medical systems… I’ll leave you to connect the dots.

G6PD deficiency is not included on U.S. Department of Health and Human Services (HHS)’s Recommended Uniform Screening Panel (RUSP) https://bit.ly/2Zk6mjE but it has been considered by them. In 2004, the U.S. Department of Health and Human Services (HHS) put together a committee to look into “Heritable Disorders in Newborns and Children” – what did they find on G6PD deficiency screening? Well, not much! As one panel member said “We just don’t have any data in this population, in the U.S., to say anything about G6PD.” 

In a 2006 report “Newborn Screening: Toward a Uniform Screening Panel and System” where an expert group from the American College of Medical Genetics evaluated different conditions to recommend, “G6PD was moved to the category of conditions not recommended newborn screening because of a limited knowledge of the natural history of the mutations in the G6PD gene found in the United States. There is also limited knowledge of the implications of these mutations with regard to development of severe hemolytic disease in the United States population.“ https://bit.ly/302bFTY 

Hmm…. Maybe that should serve as a hint that we need to look into this?! Yet, “cost-effectiveness” won the day

Mostly, the emphasis on screening for G6PD has been pitched as doing it in order to prevent severe neonatal hyperbilirubinemia and kernicterus (a type of brain damage that can result from high levels of bilirubin in a baby’s blood. Bilirubin is a breakdown product of heme, that non-protein part of hemoglobin). Newborn babies with G6PD deficiency are more likely to experience these problems and are more likely to have worse outcomes if they do. Neonatal testing can prevent complications because a lot of the complications occur in the few days after they leave the hospital & if babies are identified before they get sent home some of those can be prevented or at least caught sooner. And this has been found to be really effective in places that have implemented them. 

But, since these complications are rare and noticeable (and thus findable – e.g. test them if they have elevated bilirubin) people have argued that there’s not a big need for universal testing and that targeted testing could suffice, only testing people from high risk populations and those with elevated bilirubin. The feasibility and usefulness of targeted testing has been demonstrated in the US https://bit.ly/2DxqPZO 

But targeted testing is the bare minimum that should be done but, especially as our country diversifies, you’re likely to miss a lot of cases if you only target people you think have ancestry with high prevalence of the mutation. 

The little research that has been done on G6PD screening focuses on those neonatal problems. https://www.nature.com/articles/jp201314 

But I feel the focus on these problems as the main reason for considering screening is narrow-sited & seems to be hindering it from advancing. What about those patients after they’re newborns? What’s their future risk for problems? How many problems could be prevented if they knew they had the deficiency and could avoid triggers? 

At the minimum we could get a better idea of the prevalence. As I mentioned above, we do have some prevalence data from the DoD, who reported the results of screening of their soldiers. They looked at the medical records of over 2.3 million active duty service records and found that, while the overall prevalence was low, 2.2%, the data were heavily racially skewed. The highest prevalence was in non-Hispanic Black males (11.2%) and the lowest was non-Hispanic white females (0.3%). The full breakdown (male; female):

  • American Indian/Alaska Native: (0.9%; 0.6%)
  • Asian/Pacific Islander: (3.3%; 1.5%)
  • Non-Hispanic black: (11.2%; 4.7%)
  • Hispanic: (1.7%; 0.7%)
  • Non-Hispanic white: (0.4%; 0.3%)
  • Other/Unknown: (2.3%; 1.5%)

Males are more frequently affected than females because the genetic instructions for G6PD are found in a gene on the X-chromosome, which is sex-linked. G6PD deficiency is considered recessive, meaning that one good copy of the gene for it is typically enough. So, most biological females (XX) have 2 copies of it, but most biological males (XY) only have a single copy, since they inherit a Y chromosome from their biological dad instead of an X. (note that people can have still be biologically male or female if they have sex chromosome abnormalities (such as having a 3rd X or 2X’s & a Y, or having a mutation in sex-determining regions). That’s beyond the scope of this post but I don’t want to leave anyone out. Also, sex is different from gender and if you want to learn more about all this: https://bit.ly/lgbtqstem 

But I’m just going to talk about XX females and XY males in this discussion. So the G6PD gene is on the X-chromosome, which XX females have copies 2 of and XY males only have 1 copy of. If that copy’s messed up, the male has G6PD deficiency. But it’s less common in females since they have a second copy that might be okay. If a female has 2 bad copies we say they’re “homozygous” for the trait and if they have 1 good 1 bad we say they’re “heterozygous.” “Homozygous” females *definitely* have the deficiency (though, again, this doesn’t mean they’ll definitely have problems because of it). 

Heterozygous females can also sometimes have symptoms because of something called X chromosome inactivation (XCI). It’s the same phenomenon which gives you calico cats, except here it involves different genes. Basically, since biological females have 2 copies of the X chromosome but they only really need 1 copy’s worth per cell, one X chromosome per cell will get silenced – its DNA gets coiled up super tight so it’s not accessible to be used. This silencing happens really early in development and gets carried on in that cell line. But different X chromosomes can be silenced in different cells during that early silencing part, so you can get “genetic mosaicity.” If you silence pigment genes on one chromosome in a cat cell, those cells will go on to make one color fur. And if you silence the opposite chromosome in a different cat cell you’ll get a different color fur. In the G6PD case, if you silence cells where the good copy is silenced those cells are therefore still at risk. So heterozygous females often have lower overall levels of G6PD activity.

It’s important to talk in terms of activity because that’s what really matters – how much can the protein you make do. How much NADPH generating power do you have? (and thus how much ROS-neutralizing power). That’ll determine the severity of the condition, and it depends on the severity of the mutation. Instead of just a single mutation that all people with G6PD deficiency have, there are lots of lots of different ones. And these different mutations can lead to different amounts of functioning, depending on how they impact the protein itself and/or its expression. 

There are a few different ways to test for G6PD deficiency. The simplest, cheapest, screening test is a fluorescence spot test, which uses a spot of blood from a heel prick, similarly to a lot of the other newborn screening tests babies get. They add G6P & NADP+ and if there’s working enzyme it’ll make NADPH which absorbs a wavelength of light (340nm) that NADP+ doesn’t. So if you stick it under far UV light and you see strong glow the person’s good to go! This is simple, but it has low sensitivity and can fake to detect heterozygous females with intermediate levels. 

Positivity should ideally be confirmed by a quantitative test to measure G6PD activity that basically does the same thing but in a test tube in a fancy machine and compares it to a range of standards. https://bit.ly/2C1nTUP 

These quantitative tests can also identify heterozygous females better. But these females can have a huge range of activity and the only way to truly their genotype is to use molecular tests like PCR tests to check for the presence of mutations in the gene. Limitations of this option are that it’s limited to known mutations unless you want to sequence the whole gene. 

Some last notes: CQ misusage might not be the only way that G6PD deficiency might be affecting Covid-19 patients. There have been several papers drawing links, which are summarized nicely in this piece: https://bit.ly/325OURE  

Basically, covid-19 seems to be one of those infections that can induce hemolytic attacks in some – here’s a case study where someone with G6PD deficiency seems to have a covid-induced severe hemolytic crisis. And then, to make things worse, was given hydroxychloroquine which appeares to have worsened it: https://bit.ly/2Wa5CLV 

Additionally, the virus itself is known to cause oxidative damage similar to the damage already seen in G6PD deficient people in hemolytic crisis. So G6PD deficient people might be more at risk for severe adverse outcomes. Another potential thing to keep an eye on is that a study with a similar coronavirus found that G6PD deficient cells were more affected by infection – the infected cells made more viral proteins & viral particles – but we don’t know if the same is true with SARS-CoV-2. https://bit.ly/325OURE 

At this point, there isn’t enough research to really know about any of the links between G6PD deficiency and COVID-19. Which brings us back to the point that we need to be doing more research on conditions that affect more than just white people. And we need to include a more diverse field of participants in our medical studies. https://bit.ly/diversitybumpus 

But even if we were to include sufficient proportions of G6PD deficient patients in studies, if doctors – and patients – don’t know their G6PD status, we don’t know if that correlates with their outcomes. There are so many ways in which G6PD deficiency *could* affect all sorts of things – from predisposition to certain diseases to the clinical outcomes when people with the condition *get* certain diseases, whether or not they had a disposition for it. But we don’t know. Because we don’t study it. And we don’t even know when people do or don’t have it. And this makes me really upset, because we easily could. end rant… for now…

more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0 

One Thought on “G6PD deficiency”

  • Thank you so much for all the work you are doing trying to raise awareness of G6PD deficiency. I really appreciate it & have been also trying to push for more research & to include g6pd deficiency in studies on COVID19- both correlational & drug trials.

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