At what bilirubin level does brain damage occur? A parable

Before beginning, it may help refer to the Section in "KERNICTERUS" entitled WHEN DOES BILIRUBIN BECOME TOXIC TO THE BRAIN, I.E., WHEN DOES BILIRUBIN NEUROTOXICITY OCCUR to introduce the PARABLE. For convenience, I've reproduced the first three paragraphs of that section here.



The simple answer is that bilirubin becomes neurotoxic when it 1) exceeds the capacity of the blood to hold it inside the blood vessels and it escapes into the tissue, and 2) exceeds the capacity of the tissue (i.e., the brain) to get rid of it.


A more complex answer is that bilirubin (or UCB) is held in the blood bound to protein, especially albumin in the blood, and when it exceeds the capacity of albumin to bind it, it can escape into tissue. When this happens varies for different babies, depending on their maturity (gestational age), size, health (or sickness), amount of albumin in their blood, and amount of feeding and stooling which is how the bilirubin is eliminated from the body.


When UCB starts to leave the blood and go into brain tissue, it starts to cause neurological signs and symptoms. For more about this, please go to WHEN DOES BILIRUBIN BECOME TOXIC TO THE BRAIN, I.E., WHEN DOES BILIRUBIN NEUROTOXICITY OCCUR in the KERNICTERUS Section.

But now, let's go to the PARABLE:

How Bilirubin Moves Out of the Blood Into the Brain to Cause Acute Bilirubin Encephalopathy (ABE) and Kernicterus: A Parable


Let me make an analogy. Let’s say hyperbilirubinemia, or too much bilirubin in the blood, is like water in a river. A little water is good. It provides water for crops, for drinking, etc. But if the water gets too high, the river can overflow its banks or and/or its dikes. When the water gets too high and starts to spill over, that affects the town and its people, and they may begin to suffer some effects. Maybe a little water is okay – wet streets, damp sidewalks, no big deal, and nobody gets hurt. But too much water floods homes and other buildings and extreme floods can do great damage and be deadly.


The water spilling over the banks – this is like ABE. It can be fast or slow. It can be no problem or deadly.


And now let’s say your new baby is like a new town along the river. Let’s say it is a town named Darling, and we want to protect the town of Darling from a flood. So, we want to know how high is the river bank and dike (wall or barrier) around the town of Darling. Well, the problem is that we don’t know for sure for two reasons: 1) because the town of Darling is a new town (like a new baby) and nobody has measured the height that the river banks and dikes can hold, and 2) because precise measuring of the height of the dikes in a town is very difficult and the water engineers (bilirubin experts) haven’t yet figured out a good way, reproducible and inexpensive way to measure the flood stage in a particular town. So, we don’t know exactly what is the level that water will flow over the banks into the town of Darling.


But there is good news. We do know that the river banks in most towns are between about 35 and 40 feet high, and thus 35 to 40 feet height of the river is the flood stage in most towns. The flood stage is higher in some towns and lower in others. But we really want to know about our town, the town of Darling.


So here is what we do know. We know that in general, a big, well-developed town (by analogy, a large, full-term baby) has a flood stage of about 40 feet, that is their river banks can usually hold back about 40 feet of water. But a new, small, underdeveloped town, like a small, low-birth-weight, premature baby, might only have river banks that can hold only 30 or 20 feet of water, and we know there are some very small, very underdeveloped towns in the low lands (like an extremely low birth weight and extremely low gestational age, immature baby) that can flood at even very low levels of water. And there are some “sick” towns, that have leaky dykes where the water can seep through. So, how does this help us?


Well, let’s get back to the town of Darling or the baby of the same name? Nobody knows exactly how high the river banks and exactly what the flood stage is in the town of Darling. Similarly, we don’t know what is the bilirubin level in the baby Darling or any other specific baby, when bilirubin will it the brain and cause symptoms, ABE, and may cause permanent damage, kernicterus. (The good news: I believe research will be able to tell us this for each individual baby in the future).


But the other good news is that we can classify the town (and your baby) to better predict when flooding will occur.


Here’s what we know. We know that a big well-developed town starts to flood at about 35 to 40 feet, just a like a normal-birthweight, term-gestation baby is at high risk for developing ABE which can lead to kernicterus at a bilirubin level of 35 to 40 mg/dL. And we can measure the river upstream of the town and measure how fast the river is rising. If it is rising quickly upstream, we know that the town is going to be in trouble. If it’s raining hard, we know the town is going to be in more trouble. But if the river has stopped rising upstream, and it’s not raining, we know things are improving.


So, in the town, we can check the river level. We just don’t exactly know what is the flood stage. Similarly, with baby Darling, we check the baby’s bilirubin level, though we don’t know what is the “flood” stage for Darling. However, we can compare Darling to other babies that have a similar size, weight, development (i.e. gestation), and age after birth.


Wait a second! Why age after birth? The age (in hours) after birth is important because of an enzyme that changes bilirubin from something that is potentially harmful and hard to get rid of - unconjugated bilirubin, or UCB - to a form that is not harmful to the brain and can be easily eliminated - conjugated bilirubin (by the way, almost all older children and adults with jaundice have it from conjugated bilirubin, the form that is not toxic to brain). Think of this conversion of bilirubin from toxic UCB to non-toxic conjugated bilirubin as the town is building a water treatment plant with a canal for the bilirubin to runoff and not flood the town. Babies start building this enzyme (treatment plant) when they are born, and by a week or two of age this is functioning at full strength – it is the normal way all of us process and get rid of bilirubin, all the time, all throughout our lives. These babies and their parents usually never have to worry about flooding again because they built that canal or induce that enzyme just as the town builds the water treatment plant that gets rid of the water.


It takes a week or two to build that treatment plant (it's actually a liver enzyme called AGT1A1) and then then it all works fine for the rest of the life of the town (or the baby) and can handle much of the excess water that may come it's way. And that AGT1A1 enzyme is really good; it works well. In adults, more than 99% of jaundice is from the non-toxic form of bilirubin, conjugated bilirubin, even with mostly all adult causes of liver damage. So, if the flooding is too severe and fast and spills over the banks faster than the town can get rid of, it can destroy the town. But if the level does not rise past flood stage and then recedes, the town is safe. In fact, if there is only a small trickle of a flood that doesn’t last too long, then the town, or baby, can recover completely.


There are some conditions, such as hemolysis, where the water (bilirubin) rises very quickly and the flooding can be severe. This occurs because bilirubin is formed from the breakdown products of red blood cell hemoglobin. Autoimmune hemolytic anemia from Rh blood group mismatch – usually a sensitized Rh-negative mother with her 2nd or 3rd pregnancy with an Rh-positive baby – can cause flooding from a very rapid rise of bilirubin. Also, G6PD deficiency, an enzyme deficiency that is relatively common, can cause red blood cells to break down faster than normal and bilirubin to rise faster than normal. Knowing that there is a risk from these or similar conditions of hemolysis can very effectively lead to the prevention of ABE and kernicterus! For Rh disease, the mother should know her blood type because there is a preventive treatment call RhoGam that can be given in advance and during pregnancies (again there are Guidelines for Rh disease and RhoGam that are very well worked out)


So, to summarize, we think of a rising tide of bilirubin (unconjugated bilirubin or UCB) floodwaters held back by river banks (albumin) that can hold a lot of bilirubin until the new town (or baby) builds its treatment plant (the liver enzyme UGT1A1) that can process bilirubin and send it along the canal (bile duct into the gut) to get rid of it (out the baby’s stool).


If the river rises too fast, phototherapy can change the bilirubin to allow another path to temporarily get rid of it (the kidneys) until the liver enzyme pathway matures (gets built) and gets rid of the water.


So, we compare Darling to other babies that have a similar size, weight, development (i.e. gestation), and age after birth, and we develop Guidelines like the American Academy of Pediatrics Guidelines that if followed prevent almost all of the acute bilirubin encephalopathy (ABE) and kernicterus from occurring.


Finally, you might ask why don’t we treat all babies with phototherapy to prevent hyperbilirubinemia and not worry about it. Well, it turns out that a little bit of bilirubin is good for the baby, just like a little bit of water is good for the town. The unconjugated bilirubin (UCB) is a powerful natural antioxidant that can “clean up” any toxic substances that may occur during the birth process with mild low oxygen and blood flow. So a little bit of UCB is good for our human babies, good for humans as a species and for most other mammals, and that’s probably why this temporary rise and then fall in bilirubin in the first week or two of life is a normal part of human biology, and also a part of the biology of all mammals. There is a cost, ABE and kernicterus, that if we are eternally vigilant, we can control and avoid.


Here’s where we may need to start a new analogy. Because bilirubin, like anything else, it’s a double-edge sword. A little bit of UCB is good for you, both for babies and adults, but too much is bad. For more information on the benefits of bilirubin and why we humans and indeed all animals have it, see "Benefits of Bilirubin" (a coming section) with a link to a detailed scientific review article entitled, “A novel perspective on the biology of bilirubin in health and disease” with a summary in plain, non-technical language coming soon to this website by one of the co-authors (me!)

Steven M. Shapiro, MD

Kansas City, MO

April 2021