LAUSR

Dear Editor, We thank Joob and Wiwanitkit for their comments and questions on our paper. We hypothesized that an endogenous form of retinoid toxicity related to malaria infection may be the common factor linking frequent malaria, Epstein–Barr virus (EBV) and Burkitt’s lymphoma (BL). Based in part on the observation that Plasmodium falciparum selectively absorbs vitamin A from the liver, the main storage organ for the vitamin, it was proposed that the merozoitestage parasites emerging from the liver use the ingested vitamin A as a cell membrane destabilizer to enter and reproduce in the red blood cells (RBCs). It was further suggested that the subsequent release of vitamin A from the RBCs into the circulation triggers an endogenous form of hypervitaminosis A, recognized as the signs and symptoms of malaria. Repeated episodes of malaria would be expected to expose affected individuals to multiple toxic doses of vitamin A, particularly fatty tissues such as the brain and lymphatics. Latent EBV is also activated by the presence of excess retinoid, which in turn activates retinoid-responsive genes, thereby enhancing expression of the molecular mechanisms of BL. Joob and Wiwanitkit noted that “the aberration of vitamin A biological process” would have to be very long for it to contribute to the trigger of carcinogenesis, and although liver can be affected by malaria, chronic liver deterioration is unlikely. In response, the concept of liver damage associated with malaria is not critical to our hypothesis, and liver deterioration in malaria may indeed be uncommon. However, in patients with previously normal liver, complicated forms of falciparum malaria can present with bleeding in the presence of jaundice, mimicking acute liver failure due to acute viral hepatitis. Acute liver failure (ALF) is associated with rapid deterioration of liver function, resulting in hepatic encephalopathy and/or coagulopathy. Multiple bouts of malaria in early childhood would be expected to lower the serum concentration of vitamin A (retinol), which is the case. It is hypothesized, however, that the form of vitamin A ingested and used by the parasite to enter the RBCs would be mostly retinyl ester (RE), which is stored in the liver; it is also known that RE, when unbound to protein, can be highly damaging to cell membranes. REs have not been measured in patients with malaria. Joob and Wiwanitkit further comment that “in areas with a high prevalence of malaria and vitamin A deficiency disorder, there is still the high incidence of BL.” In response, we note that low serum retinol concentrations do not necessarily indicate vitamin A deficiency, nor do they rule out vitamin A toxicity. In fact, low serum retinol may be accompanied by a high ratio of RE to total vitamin A (retinol plus esters), and the latter defines a state of toxicity when >10%. Joob and Wiwanitkit comment that other tropical diseases such as chronic viral hepatitis, that may affect vitamin A metabolism, are not associated with BL. In fact, chronic infection with hepatitis B and C viruses andmany other viral, bacterial and parasitic infections are associated with BL, nasopharyngeal carcinoma and other types of cancer, all of which, we surmise, affect vitamin Ametabolism. The association between malaria and Burkitt’s lymphoma in particular may be due to the frequency and duration of malaria infection and the hypothesized prolonged state of retinoid toxicity which, coupled with EBV, triggers the mutational changes leading to BL, as compared to the presumably lower level and shorter duration of exposure to retinoid toxicity resulting from chronic viral hepatitis.