The Significance of Enterohepatic Circulation in the Causation Neonatal Hyperbilirubinemia

Abstract

Sir, This is in reference to the study by Rana et al.[1] A robust triple-blind design, appropriate sample-size, and statistical methods–sensitivity analysis and effect-size estimation– employed by the authors could well make the investigation a landmark study evaluating the role of zinc in the prevention of hyperbilirubinemia in neonates. However, the study simultaneously conjures-up an important question about the role of enterohepatic circulation (EHC) in the causation of neonatal jaundice which may also have implications on the physiological doctrine for the intervention tested. Overproduction of bilirubin from heme is considered the most prevalent mechanism of neonatal hyperbilirubinemia apart from impaired uptake, conjugation, and EHC. We have limited instances where EHC is considered the prime mechanism for jaundice, e.g., pyloric stenosis, lower intestinal atresia, paralytic ileus, and meconium-plug-syndrome (virtually no removal of bilirubin due to distal obstruction). There is limited data to suggest that the resorption of bilirubin from the intestine can be a major cause of neonatal physiologic jaundice [2]. It has been stated that neonatal hyperbilirubinemia is exacerbated–if not caused–by enhanced bilirubin resorption through EHC [3]. In fact, more obvious than EHC, a markedly reduced UDP-glucuronyl transferase activity is noted in pyloric stenosis [3]. Enhanced EHC induced by human milk has a putative role in prolonging ‘breastmilk jaundice’ [4]. In the past, various strategies have been employed to counteract EHC with inconsistent results, in terms of the incidence and severity of jaundice [5]. Consequently, it is advised that such interventions are at the best used as an adjuvant, along with more established modalities like phototherapy [6]. The results of the present study by Rana et al., showing no significant reduction in the incidence of hyperbilirubinemia, requirement of phototherapy and mean STB (serum total bilirubin) at 72 h, are in line with the outcomes of previous studies employing other agents. Therefore, although past studies have suggested that EHC may play a significant role in the bilirubin metabolism, it appears less likely that EHC is a major cause of neonatal hyperbilirubinemia, though it may play some contributory role in prolonging physiological jaundice. Therefore, negative results of these studies probably have a bearing on the underlying doctrine of ‘prevention of hyperbilirubinemia by clogging-up EHC’, irrespective of the agent (agar, charcoal, cholestyramine or zinc) employed. Other limitations of the study were the use of nonstandardized oral zinc dose, lack of serum zinc level monitoring, inadequate reporting of the adequacy of breastfeeding and vomited and/or skipped doses, and delayed initiation of the intervention.