Bilirubin and migraine: Critical review of the literature

The many and multifaceted metabolic functions of bilirubin, the final product of heme metabolism, are still not completely understood. Several lines of evidence now attest that this molecule may produce both toxic and protective effects depending on its blood concentration. More specifically, lower values of total bilirubin in serum or plasma have been linked with an increased risk of developing cardiovascular disease (5), pulmonary embolism (6) and many other severe and prevalent human diseases (1). Interestingly, total bilirubin serum levels are also related with clinical severity of sudden event, such as carbon monoxide poisoning (7). Although it remains unclear whether total serum bilirubin acts as an active player or a bystander in many of these conditions, its measurement may provide useful information for the clinical decision making. In accordance with these earlier findings in other clinical settings, the results of our analysis more convincingly suggest that low total bilirubin concentration would also be associated with enhanced risk of migraine (Table 1). This epidemiological evidence is supported by a biologically plausible link. Bilirubin is a well-known endogenous antioxidant compound (5), whilst oxidative stress is strongly involved in the pathogenesis of migraine (8). It is hence conceivable that a low concentration of total bilirubin would be ineffective to prevent (or limit) the burden of oxidative stress, thus ultimately predisposing the development (or worsening) of migraine.