Distinct mechanisms for rasburicase induced hemolytic anemia and methemoglobinemia in tumor lysis syndrome

To the Editor: I read with great interest the paper by Bauters et al. [1] titled ‘‘Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia.’’ in which the authors describe the third case in the literature of simultaneous occurrence of these two entities after the use of recombinant form of urate oxidase and also manifestations of acute pancreatitis. It is well recognized that production of hydrogen peroxide as a byproduct of the enzymatic oxidation of uric acid into the more water-soluble allantoin by rasburicase may trigger hemolytic anemia and methemoglobinemia in a genetically susceptible host with glucose-6-phosphate dehydrogenase enzyme deficiency and therefore this drug is contraindicated in this type of situation [2]. However there are several points that should be highlighted in relation to the pathogenesis of these two entities that are not explainable simply because of rasburicase induced hydrogen peroxide production. First of all, tumor lysis syndrome may itself elicit a systemic inflammatory response that leads to activation of endothelial cells and neutrophils which in turn release free radicals and reactive oxygen species (ROS). Besides, pro-inflammatory cytokines released by cell lysis induces nitric oxide production (which is one of the substances that can cause methemoglobinemia) and may combine synergistically with hydrogen peroxide to promote acute hemolysis too [3]. Secondly, serum uric acid plays an important role in protection from oxidative damage since it is a potent free-radical scavenger and increases in response to oxidative stress. So, rapid reduction in uric acid levels by rasburicase can compromise an important anti-oxidant mechanism and facilitates the emergence of acute hemolysis and methemoglobinemia [4]. Thirdly, under normal circumstances, cells are able to defend themselves against ROS damage with enzymes such as superoxide dismutases, catalases, lactoperoxidases, glutathione peroxidases and peroxiredoxins. Small molecules such as ascorbic acid, alpha-tocopherol, beta-carotene, methionine and glutathione also play important roles as cellular antioxidants. Decreased enzymatic activity and low antioxidant levels lead to an increased concentration of ROS which may facilitate rasburicase induced hemolysis and formation of methemoglobin [5]. Fourthly, urate oxidase is an endogenous enzyme found in most mammals but not in humans. Since humans do not express urate oxidase, rasburicase potentially can instigate an immune response that can include anaphylaxis or drug-mediated immune hemolytic anemia [6]. And last but not least, the symptoms of pancreatitis presented by the patient probably should be related to increased oxidative stress. It is known that pancreatic cells are highly susceptible to the effects of ROS. The use of rasburicase leads to a rapid reduction in uric acid and consequently there is an increase of enzymatic activity of xanthine oxidase to convert xanthine into uric acid. It is known that xanthine oxidase generates ROS and this coupled to the production of hydrogen peroxide by rasburicase may potentiate pancreatic inflammation [7, 8]. In summary, various host factors (impaired antioxidative mechanisms), disease characteristics (tumoral burden, cytokine release and ROS generation) and drug-related hydrogen peroxide production combined together create an environment of oxidative stress that ultimately triggers methemoglobinemia, hemolytic anemia and even pancreatic injury. R. Lopes da Silva (&) Hospital Santo Antonio dos Capuchos—CHLC, Alameda Santo Antonio dos Capuchos, 1169-050 Lisbon, Portugal e-mail: ronolosi@gmail.com