Abstract
Restrictions on the cultivation and ingestion of fava beans were first reported as early as the fifth century BC. Not until the late 19th century were clinical descriptions of fava-induced disease reported and soon after characterised as “favism” in the early 20th century. It is now well known that favism as well as drug-induced haemolysis is caused by a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme, one of the most common enzyme deficiency in humans. Interest about the interaction between G6PD deficiency and therapeutics has increased recently because mass treatment with oxidative 8-aminoquinolines is necessary for malaria elimination. Historically, assessments of haemolytic risk have focused on the clinical outcomes (e.g., haemolysis) associated with either a simplified phenotypic G6PD characterisation (deficient or normal) or an ill-fitting classification of G6PD genetic variants. It is increasingly apparent that detailed knowledge of both aspects is required for a complete understanding of haemolytic risk. While more attention has been devoted recently to better phenotypic characterisation of G6PD activity (including the development of new point-of care tests), the classification of G6PD variants should be revised to be clinically useful in malaria eliminating countries and in populations with prevalent G6PD deficiency. The scope of this work is to summarize available literature on drug-induced haemolysis among individuals with different G6PD variants and to highlight knowledge gaps that could be filled with further clinical and laboratory research.
Highlights
The first clinical descriptions of what we know as drug-induced haemolysis were documented in the late 19th century (Mulè-Bertolo, 1886)
The biochemical cause of favism remained unknown until the mid-20th century when a similar clinical syndrome of acute haemolytic anaemia (AHA) was observed in ethnically African males who received primaquine for the treatment of Plasmodium vivax malaria (Hockwald et al, 1952)
Further assessments showed that these haemolytic syndromes shared the same biochemical defect; a deficiency in the glucose-6-phosphate dehydrogenase (G6PD) enzyme (Carson et al, 1956)
Summary
The first clinical descriptions of what we know as drug-induced haemolysis were documented in the late 19th century (Mulè-Bertolo, 1886). The biochemical cause of favism remained unknown until the mid-20th century when a similar clinical syndrome of acute haemolytic anaemia (AHA) was observed in ethnically African males who received primaquine for the treatment of Plasmodium vivax malaria (Hockwald et al, 1952). G6PD variants and haemolysis dosing with subsequent haematologic recovery beginning the following week (Beutler et al, 1954; Dern et al, 1954). These male individuals were given a clinical diagnosis of “primaquine sensitivity” or having “primaquine sensitive” erythrocytes. Further assessments showed that these haemolytic syndromes shared the same biochemical defect; a deficiency in the glucose-6-phosphate dehydrogenase (G6PD) enzyme (Carson et al, 1956). Limitations of current laboratory and clinical characterisation as well as possible future research approaches are discussed
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