Unbound bilirubin – a predictor of kernicterus

Perspectives in jaundice management

With sixty percent of all infants experiencing jaundice, according to the Centers for Disease Control and Prevention (CDC),* researchers are investigating innovative ways to identify and treat hyperbilirubinemia – the number one cause of hospital readmissions for babies.

Dr. De Luca, MD, PhD, Medical Director of Pediatrics and Neonatal Critical Care and Associate Professor of Pediatrics at South Paris University, “A.Beclere” Medical Center, in Paris, France, has identified a novel relationship between skin bilirubin levels and free, unbound circulating bilirubin in the newborn baby, providing new insights into the development and prevention of kernicterus.

Results of Dr. De Luca's research were presented for the first time at The Pediatric Academic Societies (PAS) annual meeting in April, 2015.

A Resurgence of Jaundice
In 2000, Dr. De Luca, then a resident physician in Italy, noticed a reemergence of newborn jaundice and accompanying increases

in hospital readmissions with the initiation of early post-partum discharge protocols.

Prior to these new discharge practices, jaundice was diagnosed while newborns remained in the hospital setting, as hyperbilirubinemia formatively peaks at three to five days of age. As more families are returning to the hospital with their jaundiced babies, physicians and hospital administrators are attempting to curtail the health risks, while also decreasing hospital readmissions. With this smaller window of opportunity to diagnose and treat jaundice, bilirubin - which is a highly neurotoxic substance - may develop into a devastating neurologic condition
called kernicterus.

In my research, TcB was useful for reducing blood samples in upwards of fifty
percent of patients; it enables us to read skin bilirubin and use it as a clinical parameter.”

— Dr. De Luca, MD, PhD, Medical Director of Pediatrics and Neonatal Critical Care and Associate Professor of Pediatrics at South Paris University, “A.Beclere” Medical Center, Paris, France

Classifying Bilirubin
Newborn jaundice is caused by the normal destruction of red blood cells resulting in elevated bilirubin levels. Bilirubin is found in two distinct forms -“it's either bound to albumin, which prevents it from leaving the circulation and passing into the skin, or bilirubin is unbound or free” allowing it to pass into the skin and the brain, said Dr. De Luca.

In an effort to better understand the bilirubin that is circulating in the brain, which is potentially the most concerning, he examined the relationship between these bound and unbound forms in both transcutaneous (skin) and serum (blood) levels. His research methodology included simultaneous measurements of transcutaneous bilirubin (TcB) and unbound bilirubin (UB), obtaining samples from 194 jaundiced neonates. With other factors accounted for, a significant correlation was found between these two measurements, according to Dr. De Luca.

His research findings indicate that the free or unbound portion of bilirubin (UB) is responsible for the bilirubin that passes through the skin and this unbound portion is also known to cross into the brain. With no direct way to measure brain bilirubin levels, this correlation is important for clinicians to identify the high-risk newborns, Dr. De Luca said. Therefore, he postulates that bilirubin testing with a non-invasive TcB monitoring may best reflect the neurotoxic effects associated with unbound bilirubin levels.

Measuring Free or Unbound Bilirubin

In terms of medical research and methodology, “it is true that the only source of bilirubin circulating through the skin is free bilirubin, but this doesn't mean that all of the free bilirubin is passing into the skin.

There's a percentage of free bilirubin that's passing through the skin to be captured by transcutaneous bilirubinometer (TcB) measurements, but we cannot say that everything is passing homogeneously,” states Dr. De Luca, it is multi-factorial, involving variables such as: gestational age, skin temperature, and other medical comorbidities.

As far as diagnostics are concerned, Dr. De Luca states that TcB measurements with devices such as the BiliChek are practical tools for the prevention of trauma associated with bilirubin measurements, adding, “In my research, TcB was useful for reducing blood samples in upwards of fifty percent of patients; it enables us to read skin bilirubin and use it as a clinical parameter."

“From one side it allows us to avoid some blood samples, but from another side it has given us some new insight into jaundice physiopathology,” states Dr. De Luca; using 2nd generation TcB devices to measure the free or unbound skin bilirubin levels may best reflect a newborns risk of bilirubin neurotoxicity. Non-invasive TcB devices provide us with information that allows us to make a correlation, states Dr. De Luca, “which is very interesting because otherwise we have something that is not so easily measurable.”

Dr. De Luca urges that more work needs to be done by replicating his research and studying the findings in more detail. “If there's a rationale behind this history to let us suspect - at the very least - that brain bilirubin could be a little bit more predictable by skin bilirubin testing,” then that's a clinical win.

* “Jaundice and Kernicterus,” Centers for Disease Control and Prevention (CDC)
https://www.cdc.gov/ncbddd/jaundice/facts.html (accessed 1 May 2015).

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Unbound bilirubin – a predictor of kernicterus

Perspectives in jaundice management

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