Abstract
BackgroundHyperbilirubinaemia (bilirubin >51.3 μmol/L) alone is not indicative of severe malaria, and the immune response underlying hyperbilirubinaemia remains largely unexplored. Liver damage associated with hyperbilirubinaemia may alter the expression of hepcidin, which regulates systemic iron by degrading ferroportin. For this study, the association between hepcidin and the levels of cytokines and chemokines in the serum of individuals with mild and severe vivax malaria and subjects with malaria with isolated hyperbilirubinaemia was evaluated.MethodsCytokines/chemokines and hepcidin were measured in individuals with mild (n = 72) and severe (n = 17) vivax malaria, as well as in the serum of subjects with vivax malaria with isolated hyperbilirubinaemia (n = 14) from the Brazilian Amazon between 2009 and 2013 by multiplex assay and ELISA, respectively. The polymorphism 744 G > T in the ferroportin gene was identified by restriction fragment-length polymorphism analysis and the restriction enzyme PvuII.ResultsThe polymorphism at position 744 G > T in the ferroportin gene was typed and no differences in the distributions of genotypes or alleles were observed between the study groups. Subjects with severe malaria had higher levels of interleukin (IL)-2 and IL-13 than subjects with hyperbilirubinaemia. No differences in the expression of immune markers were observed between subjects with mild malaria and those with hyperbilirubinaemia. However, hepcidin levels were higher in individuals with severe malaria and hyperbilirubinaemia than those with mild malaria (p = 0.0002 and p = 0.0004, respectively) and cut-off values of hepcidin differentiated these groups from subjects with mild malaria. Hepcidin was positively associated with IL-6 and IL-10 levels and with parasitaemia in subjects with mild malaria and with IFN-γ in subjects with severe malaria.ConclusionsMalaria in the presence of hyperbilirubinaemia produces a less robust inflammatory response compared to severe cases of malaria. Hepcidin levels are positively associated with immune markers in vivax malaria outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0930-x) contains supplementary material, which is available to authorized users.
Highlights
Hyperbilirubinaemia alone is not indicative of severe malaria, and the immune response underlying hyperbilirubinaemia remains largely unexplored
Severe vivax malaria was defined according to the criteria for severe malaria established by the World Health Organization (WHO); malaria with hyperbilirubinaemia was defined by a serum total bilirubin level >51.3 μmol/L with no other criteria for severe malaria [6]
Individuals with hyperbilirubinaemia had the lowest PTL values (p = 0.0003) and the highest alanine transaminase (ALT) values (p = 0.0039); aspartate transaminase (AST) levels did not differ among the groups (p = 0.0686; Table 1)
Summary
Hyperbilirubinaemia (bilirubin >51.3 μmol/L) alone is not indicative of severe malaria, and the immune response underlying hyperbilirubinaemia remains largely unexplored. The association between hepcidin and the levels of cytokines and chemokines in the serum of individuals with mild and severe vivax malaria and subjects with malaria with isolated hyperbilirubinaemia was evaluated. Hyperbilirubinaemia, which is known as jaundice, is often associated with malaria infection. It occurs as a consequence of the intravascular haemolysis, disseminated intravascular coagulation and hepatocellular dysfunction [5]. Jaundice (serum total bilirubin >3 mg/dL) is no longer considered a single marker of malaria severity and the presence of hyperbilirubinaemia alone is not associated with a worse prognosis or a higher fatality rate in malaria [5,6,7,8]. Hyperbilirubinaemia is a common complication associated with severe malaria syndromes and concomitant jaundice can indicate more severe illness [9,10,11,12]
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