Epiphany Hidden in Fava Beans

January 6 is Epiphany, not a week into the new year and its tradition causes many Louisianians to abandon any resolutions related to gustatory moderation. I’m referring, of course, to the King Cake. In modern tradition, a King Cake is a circular pastry made of Danish-type dough, filled with fruit spread, cream cheese, flavored sugar or some combination thereof topped with an additional layer of icing decorated with purple, yellow and green colored sugar. There is a plastic baby, representing Jesus, inside, and the eater finding the slice with Jesus is charged with purchasing the next King Cake. This continues throughout the Carnival season. It truly is the decadence of Mardi Gras captured in cuisine.

King Cake via Wikimedia

Traditionally, the King Cake has slightly more humble origins. It has always been associated with Epiphany, the church holiday marking the visitation of the Three Kings to see the baby Jesus, but the recipe was not always the refined sugar freight train it is today. Think more bread and dried fruit. Before the advent of plastic trinkets, the baby Jesus was symbolized by the fava bean.

Vicia faba via Wikimedia

The fava bean (Vicia faba) or broad bean is a hardy legume that has been in cultivation for thousands of years. This low maintenance crop has been a source of quality protein for the human diet for just as long. Its class connotations have waxed and waned throughout history, but for some people it can trigger a potentially deadly anemia. The condition is so tightly linked to fava beans, it is known as favism.

The king is dead?

Favism is really just one manifestation of a deficiency in the enzyme Glucose-6-Phosphate Dehydrogenase (G6PD). This is the rate-limiting enzyme within the pentose phosphate pathway, which the cell uses to generate reducing power in the form of NADPH and glutathione as well as 5-carbon sugar groups to use as building blocks of DNA or amino acids. People can display a range of G6PD deficiency levels. This depends on the type of mutation and the relative amounts of the mutant G6PD expressed. This mutation is X-linked, which means you inherit it from your mother. Because males inherit only one X chromosome copy, if they get a defective version, they will always display some level of favism. Female carriers of the G6PD mutation can also show some deficiency as well. Even though female carriers contain two X-chromosomes (of which has a normal G6PD and the other has the mutant version), cells only need to use one copy. Relatively early in development, one copy of the X chromosome in each cell is silenced. Thus, there is a random inactivation of one copy of the G6PD gene in each cell; in some cases the mutant version will be inactivated, in others the normal version. This creates the potential for a range of G6PD deficiency to be observed even when the woman has one copy of a normal G6PD.

So how can fava beans wreak such havoc on basic human metabolism? Fava beans synthesize the alkaloid glycoside, vicine. This substance is a particularly powerful trigger for oxidative damage to the cells. In the red blood cells of G6PD deficient individuals, there’s just not enough reducing power within the cell to protect them from the build-up of hydrogen peroxide and other damaging reactive oxygen species. Consequently, the red blood cells burst open resulting in acute anemia.

Vicine chemical structure via Wikimedia

Long live the king!

How have this metabolic mutation and food crop coexisted for so long? It seems like nature and/or agriculture would select for one or the other. There are other beans out there, ‘Am I right?’ And how could a mutation in such a critical enzyme in central metabolism accumulate in more than 400 million people worldwide? The answer lies within another disease- malaria. The incidence of G6PD deficient versions is higher in individuals of African and Mediterranean descent. There is a working hypothesis that some level of G6PD deficiency offers a fitness advantage over normal individuals when it comes to malaria infections. When the Plasmodium parasite infects red blood cells, some amount of oxidative stress occurs. Because G6PD deficient individuals have a sensitivity to this stress, their red blood cells burst eliminating the parasite’s home. When you consider a population of red blood cells within a G6PD deficient individual infected by the parasite, it’s advantageous to be able to sacrifice some red blood cells in order to give the immune system the chance to clear the parasite. In normal individuals, all red blood cells are easy targets for the parasite, which can enter them and hide more effectively from the host’s immune system. It should be noted though that some malarial treatments given to G6PD deficient patients can be toxic themselves as they also generate a fair amount of oxidative stress.

G6PD deficiency is a relatively benign condition when it is diagnosed and certain oxidative triggers are avoided. So in the same way that it’s good to uncover a plastic Jesus in your King Cake, it’s good to know your G6PD variety. If you’re G6PD deficient, it’s not so good to uncover a fava bean. However, the complicated hidden interrelatedness of each of these things will lead to new epiphanies in malarial infections and their treatment.


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