When a Geneticist Writes Glucose-6-phosphate dehydrogenase (G6PD) deficiency - the intricate realtionship between haematology, pharmacogenetics and malariology Written by: Prof. Dr. Narazah Mohd Yusoff, MBBS, PhD Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Penang, Malaysia.
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lucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most common enzymopathy worldwide. It affects approximately 400 million people, the majority of whom are at risk for malaria [1-4.] The G6PD enzyme helps red blood cells function normally. Without enough G6PD enzyme to protect the red blood cells, a sufficient amount of reduced glutathione cannot be produced. This will result in oxidative stress. The clinical expression of G6PD-deficient individuals are mostly asymptomatic, but they can have episodic acute haemolytic anaemia (AHA) or a few can have chronic haemolysis when they are exposed to certain infection or drugs. In neonates with G6PD deficiency, decreased bilirubin elimination may play a role in the development of jaundice [5-6]. As such the clinical expression of G6PD-deficient individuals encompasses a spectrum of syndromes. The gene for G6PD is located on the X chromosome (band X q28) [7] and has been cloned and sequenced [8-10]. The G6PD locus shows a considerable degree of genetic heterogeneity and at least 186 distinct alleles involving mutations leading to single amino acid substitutions or deletions, scattered throughout the entire coding and non-coding region have been identified [11, 12, 13]. Most of the variants occur sporadically, although some, such as the G6PD Mediterranean and the G6PD A-202A/376G variants, exist with an increased frequency in certain populations [14, 15]. Almost three billion people are at risk of contracting the Plasmodium vivax infection globally [16, 17] . Beyond Africa, it is the predominant cause of malaria [18]. Recent evidence suggests considerable morbidity and mortality associated with vivax malaria due to its association with recurrent episodic presentations [19- 21] since complete eradication of Plasmodium vivax is not be feasible without systematic treatment of the dormant liver forms (hypnozoites) of the parasite [22]. Currently, the only available treatment to kill hypnozoites is primaquine (PQ), which causes dose-dependent haemolysis in patients with G6PD deficiency [23]. G6PD deficiency is common in areas of endemic malaria [24] thus the WHO anti-malarial treatment guidelines recommend that wherever possible routine testing for G6PD deficiency should be undertaken prior to PQ-based radical cure. However, if testing is not available, an individual risk–benefit assessment should guide the decision whether to administer without testing or withhold PQ [25]. Thus, implementing routine testing for G6PD deficiency is challenging for countries which do not test
for G6PD deficiency on routine basis and often, PQ is not prescribed [26, 27]. Pharmacogenetics is described as genetically determined variations in how individuals respond to drugs, with regards to the therapeutic and adverse effects. Historically this concept arose when it was discovered that the ability to taste phenylthiocarbamide (PTC) was shown to be inherited [28]. But it was with the discovery of G6PD deficiency as the biochemical basis of PQ sensitivity that this became a prototype study case in pharmacogenetics [29]. Soon, it became clear that G6PD deficiency was also the biochemical defect underlying favism as a cause of AHA [30]. Subsequently, in the 1960s and 1970s, numerous drugs other than PQ were reported as possible triggers of AHA in G6PD-deficient individuals. The main features of drug-induced AHA are well known [31]. In the steady state, the blood of a G6PD-deficient individual is normal, drug-induced AHA is the paradigm of a pharmacogenetics event: haemolysis results from the action of an exogenous factor on latently but intrinsically abnormal red cells [32]. An increasing number of countries in Asia have set themselves the ambitious goal to eliminate Plasmodium vivax malaria: in order to do this, PQ is needed. .However, there is a consensus among malaria experts that eliminating Plasmodium vivax will prove more technically challenging than eliminating Plasmodium falciparum [33] as this involves critical decision-making on need for prescription of PQ in G6PD deficient individuals. This situation has escalated from a circumscribed pharmacogenetics problem to a major public health issue. In principle, there are two solutions i.e. either to give PQ regardless, and let the G6PD deficient individuals bear the consequences, with the hope that appropriate medical supervision and intervention will be available when necessary. Secondly the option is to test for G6PD, and then either exempt those who are G6PD-deficient from receiving PQ, or give them PQ under supervision [32]. Meanwhile, WHO recently recommended an important change for one of the two indications for PQ mentioned above where the stated dose of PQ has been decreased. Subsequently there is evidence that the gametocytocidal action may be sufficient, and the AHA caused in G6PD-deficient individuals will be certainly much milder [34]. AHA in G6PD-deficient individuals remains a unique case in pharmacogenetics, where a specific enzyme deficiency is the single determinant of a severe, potentially life-threatening side effect [32]. MyHVP Newsletter | Jan-July 2017| page 4