Hyperbilirubinemia of the Newborn

00:01 Welcome. With this talk, we're going to talk about elevated bilirubins that occur in the neonatal period.

00:07 This can be pathologic and way too much bile or heme coming into the system and not being excreted appropriately or this can also be physiologic.

00:19 And being able to assure the anxious parents that their little yellow baby is going to be fine, that this will resolve, is very important.

00:28 Or if more needs to be done, it's also important that you be cognizant of that and be able to do the appropriate workup.

00:36 So, hyperbilirubinemia of the newborn is basically just jaundice in the newborn period and it's again, elevated levels of bilirubin. The epidemiology of this overall, interestingly, greater than 50% of term infants and more than 4/5ths of preterm infants will have some visible jaundice after birth. And this is the so called physiologic jaundice.

01:00 It's associated with immaturity. It's associated with male sex because the liver is not yet making good levels of the conjugating enzymes necessary to metabolize bilirubin into a form that can be excreted.

01:15 And this will go away relatively quickly as the baby matures and the liver develops that enzymatic capacity.

01:22 But term infants, preterm infants are also subject to a substantialamount of trauma coming through the birth canal.

01:30 So, there will be significant bruising and the absorption of hematomas will also lead to increased heme burden that must be metabolized.

01:40 If there are greater causes or more important causes of hemolysis, that clearly will cause greater levels of hyperbilirubinemia.

01:51 And for example, maternal fetal blood group incompatibility due to erythroblastosis fetalis due to Rh incompatibility or ABO incompatibility, hemolytic disorders associated, say, with spherocytosis or glucose-6-phosphate dehydrogenase deficiency or infections that are causing hemolysis will all clearly impact the heme burden that must be metabolized.

02:17 The overall pathophysiology then, is reasonably straightforward once you understand how heme is metabolized.

02:24 And I would refer you to the hyperbilirubinemia talk elsewhere within the Lecturio lexicon.

02:31 Unconjugated or indirect hyperbilirubinemia is physiologic. Again, in the neonate, the erythrocytes have a shorter lifespan.

02:41 So, it's usually 120 days and it may be half of that in the neonate.

02:45 They also don't have sufficient hepatic bilirubin metabolism.

02:50 So, if it's a relatively immature UDP-glucuronosyltransferase.

02:56 And again, there are the other causes that we talked about, maternal fetal blood group incompatibility, hereditary causes of diminished glucuronidation and in Gilbert Syndrome and in the neonate, there's also increased enterohepatic circulation, so, normally, about 20% of the conjugated bilirubin that's put into the stool is recirculated, that actually goes up with breastfeeding. So, you may have a greater burden within the liver.

03:28 That was indirect unconjugated hyperbilirubinemia.

03:33 Conjugated or direct hyperbilirubinemia actually says the liver's working fine.

03:39 But now, we have some sort of obstruction and we're not getting that conjugated bilirubin out of the liver and that really requires intervention. This is not physiologic.

03:48 So, sepsis or bile duct obstruction, other disorders and/or really severe hemolysis with infections or major blood group incompatibility, etc.

04:00 So, how would your patients present? Neonatal jaundice is visible even in children of color because the neonate is not as pigmented as they will be later in life.

04:13 They're also very clearly be scleral icterus.

04:16 Interestingly, as you get higher and higher levels of hyperbilirubinemia, different parts of the body will start showing that cutaneous jaundice.

04:30 So, the face is because of the vasculature and the relative thinness of the epithelium will manifest jaundice at a much earlier stage at about 5 milligrams per deciliter.

04:42 Keep in mind normal, upper limits of normal, are one to 1.5.

04:47 When you start seeing jaundice in the mid-abdomen that tends to have more fat and not as well vascularized as the face is, when you see jaundice in the mid-abdomen, that's about 15 milligrams per deciliter. And then, on the soles of the feet which have very thick layers of keratin, that means you're up to about 20 milligrams per deciliter.

05:08 So, you can have a rough ballpark just by watching which part of the body becomes yellow.

05:14 Kernicterus is what we want to avoid at all costs. Bilirubin can cross the immature blood-brain barrier and then, cause a whole host of CNS complications. And that's the main thing.

05:25 Otherwise, the bilirubin is relatively benign but once it gets above 25 milligrams per deciliter, there may be permanent, irreversible damage to the baby's central nervous system.

05:38 In physiologic jaundice, and remember, this is the unconjugated jaundice because we have a relatively immature hepatocyte conjugation apparatus.

05:47 The jaundice usually appears within 24 hours and it peaks by days two to four and then, goes away by one week.

05:54 And by two weeks, 10 to 14 days, it's back to normal completely.

05:59 And this is the one being able to tell the very anxious parents, your baby's going to be okay.

06:03 He/she won't be yellow in about a week or so will do a lot to alleviate their anxieties.

06:10 So, that's the physiologic jaundice. Non-physiologic. So, it's either unconjugated or conjugated bilirubin.

06:16 There's then, again, different pathologies. With the unconjugated hyperbilirubinemia due to increased hemolysis and increased heme burden, the total serum bilirubin will get up to about 15 milligrams per deciliter, so, the abdomen will be yellow.

06:33 And this is due to things where we see hemolysis, hereditary spherocytosis, elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency.

06:45 There are a whole bunch of hemolytic disorders.

06:47 There is a heme talk somewhere in the Lecturio collection that you can refer to for hemolysis.

06:56 You can also have, because of breastfeeding and increased enterohepatic circulation, higher levels of bilirubin than you would expect and this falls in the non-physiologic category.

07:05 And then, there are genetic causes because of mutations or defects in the conjugating enzymes.

07:13 The conjugated hyperbilirubinemia in the non-physiologic category are going to be due to biliary tract disease.

07:21 So, obstruction due to primary atresia or cysts or an early cholangitis of a neonate can be infectious such as some of the torch pathogens, so, toxoplasmosis, rubella, cytomegalovirus and herpes can be required - other acquired perinatal infections can be genetic, apha1 antitrypsin deficiency or metabolic galactosemia and this is just a partial list.

07:48 So, all of these things are potentially causing outflow obstruction.

07:53 The hepatocytes are generally working okay. They're conjugating appropriately.

07:58 They're trying to release the bilirubin into the common bile duct and that's being frustrated by a variety of potential causes.

08:07 How are we going to make our diagnosis? It's going to be important to distinguish physiologic versus non-physiologic and then, whether it's conjugated or unconjugated, indirect or direct, etc.

08:18 The laboratory testing is very important. So, we want to assess whether it's indirect bilirubin in which case, we're probably not getting good metabolism or it's direct, in which case, you probably have obstruction.

08:28 We want to make sure that there's not a lot of hemolysis going on, raising the specter of potential infection.

08:33 In terms of hemolytic causes, autoimmune or antibody-driven hemolysis is a biggie.

08:41 So, we would do coombs testing looking for that.

08:44 We can get a sense or for whether there's biliary obstruction by whether the alkaline phosphatase is elevated and ultrasound is clearly going to be important for identifying dilated bile ducts.

08:55 Management. The key thing is to avoid the neurotoxicity associated with kernicterus.

09:01 That's what we want to do above all else.

09:04 And remember, kernicterus is going to occur when we have bilirubin in excess of about 25 milligrams per deciliter.

09:12 It turns out that we can administer just simple light at a particular wavelength shown there that converts the bilirubin into lumirubin which can be excreted directly in the urine, so, without any conjugation or anything else, we can get rid of that.

09:28 So, we can take what's in the skin and in the circulation and with this very passive light that doesn't hurt the infant or anything else, we can get rid of it by peeing it away.

09:39 For immune hemolysis, we clearly want to stop that process that's also going to cause severe anemia.

09:43 We'll have other developmental consequences. So, we can get intravenous immune globulin.

09:48 We can do plasmapheresis to remove the autoantibodies that are causing hemolysis or we can do a complete exchange transfusion.

09:57 With that, the hyperbilirubinemia of the neonate.