Cardiometabolic risk in childhood : could bilirubin act as a circadian clock-related mediator via autonomic dysfunction?

R e v i s t a C i e n t í fi c a d a O r d e m d o s Médicos www. a c t a m e d i c a p o r t u g u e s a . c o m 79 CARTAS AO EDITOR Cartas ao Editor, Acta Med Port 2020 Jan;33(1):76-80 Cardiometabolic Risk in Childhood: Could Bilirubin Act as a Circadian Clock-Related Mediator Via Autonomic Dysfunction? Risco Cardiometabólico na Infância: Pode a Bilirrubina Atuar como Mediador Associado ao Relógio Circadiano Via Disfunção Autonómica? Keywords: Autonomic Nervous System; Bilirubin; Child; Circadian Rhythm; Hypertension Palavras-chave: Bilirrubina; Criança; Hipertensão; Ritmo Circadiano; Sistema Nervoso Autónomo The interesting paper from Yu and colleagues on the association of neonatal serum bilirubin and childhood hypertension recently published in Plos One,1 flagged up a plausible role of bilirubin as a mediator of hypertension in later life. This is a highly important topic since hypertension, a main cause of cardiometabolic associated morbidity and mortality, may affect 2% to 4% of children. Bilirubin is a toxic endproduct of heme catabolism in the body, commonly seen in newborns and causing jaundice. It is detoxified mainly in the liver by means of several steps involving circadian regulated enzymatic processes.2 A balanced autonomic output to the liver is crucial for maintenance of the circadian rhythmicity that ensures the normal function of liver metabolic enzymes and glucose level.3 Bilirubin production is known to oscillate in a circadian fashion. Several studies showed that free bilirubin is negatively associated with hypertension and other cardiometabolic risk factors, although with controversial issues remaining to be clarified. A non-dipping hypertensive profile was also linked with nocturnal lower bilirubin levels compared to those having a dipper hypertensive profile, consolidating the circadian signature on hyperbilirubinemia associated hypertension. Furthermore, bilirubin seems to increase after light therapy not only as a result of activation of photoreceptors but also impacted by circadian clock regulatory mechanisms.4 Nonetheless, in their retrospective study, the authors of the aforementioned paper found that neonatal serum bilirubin levels were positively associated with childhood blood pressure/hypertension in preterm infants. This suggests that neurotoxicity of bilirubin and its plausible impact on autonomic pathways via sympathetic nerve fibers may be involved in the neonatal pathophysiological mechanisms leading to hypertension. Interestingly, in a prospective study in full-term newborn infants it was found that severe unconjugated hyperbilirubinemia may cause cardiac autonomic dysfunction, with parasympathetic predominance.5 These findings can also raise the important question of whether newborn babies with kernicterus are predisposed to developing hypertension or cardiovascular morbidity. Despite the contradictory observations, the relationship of hyperbilirubinemia and autonomic function and their circadian variations is particularly important in preterm babies due to the immature nature of the brain-blood barrier and consequent higher risk of toxicity and encephalopathy leading to autonomic related cardiovascular and metabolic signs. REFERENCES 1. Yu H, Zou L, He Y, Luo L, Dong W, Zhang Y, et al. Associations between neonatal serum bilirubin and childhood hypertension. PLoS One. 2019;14:e0219942. 2. Chen HL, Wu SH, Hsu SH, Liou BY, Chen HL, Chang MH. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J Biomed Sci. 2018;25:1-13. 3. Plano SA, Casiraghi LP, Moro PG, Paladino N, Golombek DA, Chiesa JJ. Circadian and metabolic effects of light: Implications in weight CONFLICTS OF INTEREST On behalf of all authors, the corresponding author states that there is no conflict of interest. FUNDING SOURCES None REFERENCES 1. United States National Library of Medicine - National Institutes of Health [accessed 2018 Jul 11]. Available from: https://www.ncbi.nlm.nih.gov/ pubmed. 2. Google. [accessed 2019 May 8]. Available from: https://www.google.pt. 3. Goodreads. Popular Psycho Books. [accessed 2018 Jul 11]. Available from: https://www.goodreads.com/shelf/show/psycho. 4. Marques JG, Adão F, Branco MJ. Madness at movies: psychopathology in 1968 Pasolini’s theorem. Australas Psychiatry. 2015;23:190-1. 5. Gama Marques J, Pantovic Stefanovic M, Mitkovic-Voncina M, Riese F, Guloksuz S, Holmes K, et al. Equal access for all? Access to medical information for European psychiatric trainees. Psychiatry Res. 2016;238:150-2. João GAMA MARQUES1,2, Elias BARRETO1, Francisco MONIZ PEREIRA1,3, Isabel FERNANDES1, Rui DURVAL1,3, António BENTO1,4 1. Hospital Júlio de Matos. Centro Hospitalar Psiquiátrico de Lisboa. Lisboa. Portugal. 2. Clínica Universitária de Psiquiatria e Psicologia Médica. Faculdade de Medicina. Universidade de Lisboa. Lisboa. Portugal. 3. Departamento de Psicologia. Universidade Autónoma de Lisboa. Lisboa. Portugal. 4. Universidade Lusófona de Humanidades e Tecnologias. Lisboa. Portugal. Autor correspondente: João Gama Marques. [email protected] Recebido: 28 de outubro de 2019 - Aceite: 29 de outubro de 2019 | Copyright © Ordem dos Médicos 2020 https://doi.org/10.20344/amp.13031 80 Re vis ta Ci en tí fic a da Or de m d os Méd ic os ww w.ac ta med ic ap or tu gu esa .c om CARTAS AO EDITOR Cartas ao Editor, Acta Med Port 2020 Jan;33(1):76-80 Miguel MEIRA E CRUZ1,2, Isabel ROCHA2, Oliviero BRUNI3 1. Sleep Unit. Centro Cardiovascular. Faculdade de Medicina. Universidade de Lisboa. Lisbon. Portugal. 2. Cardiovascular Autonomic Function Lab. Centro Cardiovascular. Faculdade de Medicina. Universidade de Lisboa. Lisbon. Portugal. 3. Department of Developmental and Social Psychology. Universitat Sapienza. Rome. Italy. Autor correspondente: Miguel Meira e Cruz. [email protected] Recebido: 04 de setembro de 2019 - Aceite: 18 de setembro de 2019 | Copyright © Ordem dos Médicos 2020 https://doi.org/10.20344/amp.12786 homeostasis and health. Front Neurol. 2017;8:1-21. 4. Larsson A, Hassan M, Ridefelt P, Axelsson J. Circadian variability of bilirubin in healthy men during normal sleep and after an acute shift of sleep. Chronobiol Int. 2009;26:1613-21. 5. Bhutani V, Wong R. Bilirubin neurotoxicity in preterm infants: risk and prevention. J Clin Neonatol. 2013;2:61.