G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications

Abstract

That primaquine and other drugs can trigger acute haemolytic anaemia in subjects who have an inherited mutation of the glucose 6-phosphate dehydrogenase (G6PD) gene has been known for over half a century: however, these events still occur, because when giving the drug either the G6PD status of a person is not known, or the risk of this potentially life-threatening complication is under-estimated. Here we review briefly the genetic basis of G6PD deficiency, and then the pathophysiology and the clinical features of drug-induced haemolysis; we also update the list of potentially haemolytic drugs (which includes rasburicase). It is now clear that it is not good practice to give one of these drugs before testing a person for his/her G6PD status, especially in populations in whom G6PD deficiency is common. We discuss therefore how G6PD testing can be done reconciling safety with cost; this is once again becoming of public health importance, as more countries are moving along the pathway of malaria elimination, that might require mass administration of primaquine. Finally, we sketch the triangular relationship between malaria, antimalarials such as primaquine, and G6PD deficiency: which is to some extent protective against malaria, but also a genetically determined hazard when taking primaquine.

Keywords: Clinical Implications; G6PD; pharmacogenetics.

Fig. 1

Clinical course of acute haemolytic anaemia in an adult volunteer receiving primaquine. Reproduced from Tarlov et al (1962)Primaquine sensitivity. Glucose-6-phosphate dehydrogenase deficiency: An inborn error of metabolism of medical and biological significance. With permission from the JAMA Network.

Fig. 2

Blood film from a 3-year-old G6PD-deficient boy with acute uncomplicated Plasmodium falciparum malaria. (A) On day 3 after treatment with a chlorproguanil-dapsone combination (see Pamba et al, 2012), numerous spherocytes, contracted red cells and haemighosts (arrow) are seen. (B) On day 1, at higher magnification, one sees a P. falciparum ring-parasitized red cell and a severely contracted red cell. Blood films courtesy of Dr A B Tiono, Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.

Fig. 3

Clinical course of acute haemolytic anaemia in children with malaria receiving an antimalarial containing dapsone (2·5 mg/kg/day for 3 d). There were 95 G6PD-deficient hemizygous boys, 24 G6PD-deficient hemizygous girls and 200 girls heterozygous for G6PD deficiency. The extent of the drop in haematocrit value in the first two groups indicates that, on average, about 25% of red cells have undergone haemolysis. Thirteen children required blood transfusion. Note that by the end of 6 weeks the blood counts are back to normal, with Hb values higher than before treatment, presumably as a result of the successful treatment of malaria. The shaded area shows the range of Hb over time observed in a group of children with malaria treated with an antimalarial not containing dapsone. Modified from research originally published in Pamba et al (2012). © the American Society of Hematology.

Fig. 4

Diagram showing red cell response to oxidative damage from drugs. (A). In glucose 6-phosphate dehydrogenase (G6PD) normal red cells, hydrogen peroxide (H₂O₂) and other reactive oxygen species (ROS) are detoxified by glutathione (GSH) peroxidase, which ultimately depends on G6PD activity for the continued regeneration of GSH (for simplicity, the role of catalase is not shown). Also, there is no significant accumulation of methaemoglobin (MetHb) because NADPH-dependent methaemoglobin reductase comes into play, backing up the NADH-dependent methaemoglobin reductase (not shown) that operates in red cells all the time. (B). When G6PD-deficient red cells are exposed to an oxidative challenge GSH will be rapidly exhausted. As a result, H₂O₂ and other ROS are not detoxified: methaemoglobin is allowed to build up and, more seriously, sulphydryl groups in haemoglobin are attacked, resulting in the formation of Heinz bodies, damage to the membrane and, eventually, the destruction of red cells through both intravascular and extravascular mechanisms. It is not clear why with some drugs there is more methaemoglobinaemia than with others: the case of rasburicase (see text) suggests that this may have to do specifically with H₂O₂. GSSG, glutathione disulfide; NADP(H), nicotinamide adenine dinucleotide phosphate (reduced form); 6PGI, glucose 6-phosphate isomerase; G6P, glucose 6-phosphate.

Fig. 5

The triangular relationship between primaquine, G6PD and Plasmodium falciparum. It is intriguing that P. falciparum has been a major selective force in increasing the frequency of glucose 6-phosphate dehydrogenase (G6PD) deficiency (Luzzatto, 1979), that primaquine is a powerful agent against P. falciparum gametocytes, but when thus used it causes AHA in G6PD-deficient persons. The simplest explanation is that the same oxidative stress is damaging for both the parasites and the G6PD-deficient red cells. Methylene blue, like primaquine, is also gametocytocidal and haemolytic in G6PD-deficient persons (see text). Fortunately, this is not so for other antimalarials that have different mechanisms of action, but, unfortunately, these are not gametocytocidal.