Skip to Main Content

++

For many years, unconjugated bilirubin (UCB) was thought to be a useless waste product of heme catabolism, with no physiological function, but with potential toxicity. Toxicity resulting from unconjugated hyperbilirubinemia has been known for more than a century, since the landmark study of Schmorl describing autopsy findings from 120 jaundiced infants, as cited by Hansen.1

++

Interestingly, evidence obtained in the last decade revealed a beneficial role of the molecule. Indeed, physiological or modestly elevated serum levels of UCB have been shown to have a protective effect in several disorders, ironically even including neurodegenerative diseases.2 Protective effects of UCB rely on its antioxidant properties.

++

Above a certain threshold, toxic effects of UCB become evident. In this circumstance, prolonged exposure and accumulation of UCB can lead to reversible or irreversible cell damage, or even cell death.3 In fact, severe neonatal hyperbilirubinemia can lead to acute bilirubin encephalopathy (ABE) and kernicterus,46 underscoring the need for models to enhance our understanding of how hyperbilirubinemia causes permanent brain damage in some infants.

++

UCB binding to human serum albumin (HSA) provides UCB solubility and thus facilitates its transport to the liver. Decreased levels of HSA and lower capacity for UCB binding, usually found in neonates, especially in preterm babies, may contribute to higher tissue UCB levels. Under such conditions, there is an increase in the unbound (free) UCB (Bf) fraction, increased cellular uptake, and greater likelihood of bilirubin-induced neurological dysfunction (BIND).79 Bf is able to enter the cells by passive or facilitated diffusion and usually represents less than 0.1% of serum UCB.10

++

In neonates, serum UCB is usually elevated for the first 2 weeks of postnatal life due to increased breakdown of fetal erythrocytes, deficient HSA transport to the liver, and decreased conjugation.11 The central nervous system (CNS) is the most vulnerable site to UCB toxicity in the neonatal period, resulting in a wide array of neurological deficits collectively known as BIND.12

++

Despite the number of studies performed in patients and animal models, as well as in tissues and in different cellular systems, the molecular mechanisms underlying or contributing to UCB cytotoxicity are not completely understood. The disruption of several cellular functions rather than a single death-signaling pathway suggests that UCB toxicity is mediated by multifaceted mechanisms. On the other hand, there is difficulty in the extrapolation of in vitro observations to infants, namely because many studies are of doubtful relevance due to the use of nonphysiological concentrations of UCB, binding proteins, or improper experimental conditions.3

++

Here, we will summarize the most recent and relevant information on the widespread effects of UCB toxicity.

++

Experimental in vitro and in vivo models have been developed to study UCB toxicity and valuable data have been obtained by both. Nevertheless, each approach has its advantages and disadvantages. While animal models are believed to ...

Want remote access to your institution's subscription?

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

About MyAccess

If your institution subscribes to this resource, and you don't have a MyAccess profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus.

Subscription Options

AccessPediatrics Full Site: One-Year Subscription

Connect to the full suite of AccessPediatrics content and resources including 20+ textbooks such as Rudolph’s Pediatrics and The Pediatric Practice series, high-quality procedural videos, images, and animations, interactive board review, an integrated pediatric drug database, and more.

$595 USD
Buy Now

Pay Per View: Timed Access to all of AccessPediatrics

24 Hour Subscription $34.95

Buy Now

48 Hour Subscription $54.95

Buy Now

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.