Episode Transcript
Hi and Welcome to Clerkship Ready - Pediatrics - A podcast aimed at helping you excel during your clinical clerkship in Pediatrics. I am Dr. Ashlee Commeree and I am a Pediatric Resident at University of Virginia Pediatric Residency Program. Today, we will be reviewing what you need to know before you see an infant with jaundice. In this episode, we will be focusing specifically on the infant from newborn to about 2 months of age, as this is when jaundice most frequently occurs.
Jumping right in, jaundice is the yellow-ish discoloration of the skin, sclerae, and mucous membranes due to the deposition of bilirubin, which means that jaundice is caused by hyperbilirubinemia. If you break down the word, hyperbilirubinemia is “hyper-bili” or excessive bilirubin and “emia” suffix means “in the blood.” Thus, excessive bilirubin in the blood. You can quantify it as well - it is total serum bilirubin (commonly abbreviated as “TsB”) greater than 1.5 milligram/deciliter. Typically, you see jaundice in newborns with bilirubin over 5 milligrams/deciliter and in older children and adults when bilirubin is over 3 milligrams/deciliter. We can even go a step further and separate hyperbilirubinemia into conjugated or unconjugated forms. I’ll quickly point out that conjugated bilirubin is the same as direct and unconjugated is the same as indirect, so some articles and textbooks interchange those terms. How I remember it is that the shorter word is paired with the shorter word, while the longer word is paired with the longer word. To be even more confusing, another term for a jaundiced baby with conjugated hyperbilirubinemia is cholestasis.
To best understand the etiologies of jaundice, you will want to make sure you understand how bilirubin comes about. It all starts with heme. The majority of heme comes from the breakdown of hemoglobin, whereas the remainder comes from other hemeproteins. Heme is first converted to biliverdin then to unconjugated bilirubin. These steps are completed in the reticuloendothelial system of the liver, spleen, and bone marrow. The unconjugated bilirubin while attached to serum albumin then gets transported to the liver cells. Inside the hepatocytes, the unconjugated bilirubin is conjugated by an enzyme called bilirubin uridine diphosphate-glucuronosyltransferase, which I will refer to as “BUGT.” Once conjugated, bilirubin is able to be excreted into bile. It is then further broken down by intestinal flora and ultimately removed from the body via stool. The breakdown products of bilirubin are what causes the pigment in stool. Also, conjugated bilirubin can be converted back to unconjugated bilirubin by some of the gut bacteria, which allows it to be reabsorbed by the intestine. This process of being metabolized in the liver, transported into the bile and then reabsorbed in the small bowel is called enterohepatic circulation.
Now that we have briefly reviewed our normal or physiologic bilirubin breakdown pathway, let’s go through our differential diagnoses for both unconjugated and conjugated hyperbilirubinemia. However, I first wanted to point out that many infants develop jaundice in the first week after birth, and for most of them, this is physiologic. For infants and children who have persistent jaundice over 2 weeks of life or develop it after the neonatal period (>28 days of life), non-physiologic and pathologic causes should be higher on your differential. If your jaundiced patient has an elevated conjugated bilirubin (meaning the patient is cholestatic), it is crucial to refer to Gastroenterology as early as possible because you could save a child’s life or spare them a liver transplant.
For unconjugated hyperbilirubinemia, we can think of its etiology being caused by 1. Excessive or increased production of bilirubin, 2. Decreased hepatocellular uptake or decreased conjugation of bilirubin, thus leading to overall decreased clearance of bilirubin, or 3. Combination of both.
Firstly, we will cover causes of excessive or increased bilirubin production. Conditions that drive up a newborn’s bilirubin are conditions in which there is excessive breakdown of red blood cells and increased bilirubin, such as the presence of cephalohematomas because the blood reabsorption can lead to increased bilirubin or hemolysis from any cause. Hemolysis is most commonly caused by ABO incompatibility, as well as more rare maternal antibodies crossing the placenta, such as anti-E, anti-Kell, or anti-Duffy. Rh incompatibility can also cause significant hemolysis. However, this has largely been eliminated since we have started giving Rhogam to pregnant people who are Rh negative. Additionally, red blood cell membrane or enzyme defects can lead to hemolysis in the newborn period. Some examples are: hereditary spherocytosis, pyruvate kinase deficiency, G6PD deficiency. Also, sepsis, asphyxia, and acidosis can cause oxidative stress on red blood cells leading to hemolysis and increased bilirubin as well.
Secondly, we will cover the causes of decreased clearance of bilirubin, due to decreased conjugation of bilirubin or decreased hepatocellular uptake. One of the most common forms of jaundice in a newborn is breast milk jaundice, which is caused by decreased conjugation of bilirubin. This typically occurs after the first week of life and is thought to be due to inhibition of BUGT by a component in breast milk as well as increased enterohepatic circulation. Prematurity and congenital hypothyroidism are two conditions which are also thought to be associated with decreased or impaired BUGT activity. Gilbert and Crigler-Najjar syndromes are two genetic conditions that lead to unconjugated hyperbilirubinemia due to abnormalities in the BUGT protein. In Gilbert syndrome (the mild disease), there is a reduced expression of BUGT leading to elevated unconjugated bilirubin. Whereas in Crigler-Najjar syndrome (the potentially fatal disease), there is either none or very little BUGT present typically leading to severe hyperbilirubinemia.
A common cause of decreased clearance of bilirubin due to poor hepatocellular uptake is suboptimal intake jaundice, formerly known as breastfeeding jaundice. The mechanism of suboptimal intake jaundice is that the newborn isn’t clearing bilirubin due to inadequate intake of breast milk. Any difficulty with breastfeeding, from poor latch, poor milk transfer to the infant, or poor milk supply in the mother, can lead to poor breastmilk intake. This can lead to dehydration in the infant and poor hepatocellular uptake and clearance. You would expect a decrease in the number of urine and stool diapers if this was the case. Some drugs can impair bilirubin transport through altering bilirubin-albumin binding (such as aspirin and cephalosporins) or competitively inhibiting uptake (such as rifampin).
Lastly, we are going to cover the condition which is a combination of both excessive bilirubin production and decreased clearance. It is physiologic jaundice. It is the first and most common cause of jaundice in the infant and usually occurs within a few days of birth. There are several factors that play into this condition. Firstly, newborns’ overall red blood cell concentration or hematocrit tends to be higher, and the cells have a shorter life span and breakdown more quickly. This rapid breakdown of red blood cells results in increased bilirubin production. Newborns also have relatively low BUGT activity, and furthermore don’t yet have the bacterial flora which they need to convert bilirubin into the non-absorbable form, which leads to increased enterohepatic circulation. All of these factors can lead infants to appear jaundiced in the first few days after birth.
Now that we have covered the etiologies of unconjugated hyperbilirubinemia, let’s move to conjugated hyperbilirubinemia, which is ALWAYS pathologic. We can break it down into three generalized categories: 1. Obstruction of the biliary system, 2. Defect of bile acid synthesis or transport, and 3. Metabolic liver diseases and systemic conditions.
The first condition I think about in a jaundiced baby over 2 weeks old is biliary atresia which is the most common form of biliary obstruction in an infant. It is a “do not miss” condition and this is the problem I will focus most on for this episode. Biliary atresia is an inflammatory process that typically starts extra-hepatically and causes scarring and blockage of the biliary tree leading to blockage of bile flow which results in ongoing liver damage and ultimately cirrhosis. Because of the obstruction, the conjugated bilirubin in bile is reabsorbed into the bloodstream and makes the serum level elevated. Additionally, because there is no bile flow into the intestines, the stool color is pale or acholic. It is very important to identify these infants as early as possible because the earlier you relieve the blockage the less time there is for liver damage to occur. Once a cholestatic infant is identified as having biliary atresia, the bile flow can be reestablished with a surgical procedure called a Kasai portoenterostomy, which we will talk about in more detail later. Although biliary atresia is the most important cause of conjugated hyperbilirubinemia (or cholestasis), as I mentioned earlier, there are a ton of other conditions as well. These conditions can be from infectious, genetic, metabolic, and anatomic etiologies. If you determine a baby has cholestasis, it is very important to involve your Pediatric Gastroenterology colleagues early.
So, as you now know, the differential for jaundice in an infant is fairly extensive. Thus, the next steps – history and physical exam – are important to help sort through our differential.
As with any patient encounter, the two things you should always do well are: 1. gathering a detailed history and 2. performing a complete and thorough physical exam. For an infant with jaundice, the history you obtain should include the following:
Onset - when did they first notice the jaundice
Patient’s feeding pattern – what (breastmilk via breastfeeding vs expressed breastmilk vs formula, any fortification), how many ounces, how often, quality of feeds (such as good latch, suck, coordination, is mother’s milk in)
How many wet diapers are they producing and/or if the child is having any dark urine
Bowel movements (as physicians, especially in pediatrics you have to get really comfortable talking about poop) – you’ll need to ask about frequency, color (such as black, bloody, or acholic, which means pale colored stools). In newborns, it is important to find out if the stools have transitioned from meconium to yellow-seedy, because this is an important indication that the baby is excreting the bilirubin in their stools. I tend to point out the colors in the room or on the computer, so they have an idea of what colors I am talking about.
Any abdominal pain or distension that the caregivers have noticed
Current medications, such as Tylenol, antibiotics, etc.
Any recent infections
You should get details about prenatal history. A very important piece of prenatal history is mother’s blood type and antibody screening because we will want to assess for any ABO or antibody incompatibilities putting the infant at risk for hemolysis, as hemolysis leads to increased bilirubin. Additionally, you will want to ask about any prenatal infections or exposures (such as TORCH infections; TORCH stands for: Toxoplasmosis, “Other” for which Syphilis and Hepatitis B fall into, Rubella, Cytomegalovirus (also commonly referred to as CMV), and Herpes simplex virus (also commonly referred to as HSV), history of maternal diabetes, and delivery history. For the delivery history, you will want to know if it was a vaginal or c-section as well as if they had any cephalohematomas or a traumatic birth - asking about bruising is important, because collections of blood or bruising means more heme to break down increasing the risk of hyperbilirubinemia. Also, ask about if the child needed phototherapy prior to leaving the hospital after birth. Depending on when the patient is presenting, you can follow up on the newborn screen for any concerns of hemoglobinopathies or metabolic diseases. Family history is important to gather – focus on liver transplants, metabolic diseases, hemolysis, chronic liver diseases, and neonatal jaundice in siblings requiring phototherapy treatment, as these pieces of family history put them at higher risk for hyperbilirubinemia.
Very important components of any encounter with a child that spans history and physical examination are growth curves. Make sure you review the growth curves and determine if the child is appropriate for gestational age (AGA), small for gestational age (SGA), or large for gestational age (LGA), because this information can provide more clues to potential etiologies. For example, if a child is SGA, you would have TORCH infections higher on your differential.
After I gather my history and review their growth curves, I move onto my physical exam.
While it is really important to perform a thorough head to toe exam, for the sake of this podcast episode, I am going to highlight several key elements to not miss on exam. I start with an overall general impression “from across the room” so to speak– noting if the child is well-appearing vs lethargic vs ill-appearing or even notably jaundiced. Then I check fontanelles, as well as assess for any cephalohematoma. When assessing the patient’s eyes, note if there is any scleral icterus, which is yellowing of the whites of the eyes due to the depositing of bilirubin. Regarding the abdominal exam, I start with appearance (it is distended? rounded or flat?) and assess if the abdomen is soft or tender. While palpating, I will also assess for any organomegaly, ascites, or abdominal masses. When it comes to organomegaly, we should evaluate for an enlarged liver (known as hepatomegaly) as well as an enlarged spleen (known as splenomegaly). I was taught to determine the lower edge of the liver relative to the right costal margin using either percussion or the scratch test. While percussion is the accepted method for assessing liver size, the scratch test has been the most successful for me to determine the lower edge of the liver, especially in younger children. To perform the scratch test, you place your stethoscope superiorly to the umbilicus, then starting low in the right lower quadrant about where the midclavicular line would be, you quickly or briskly brush your finger over the skin in a parallel motion from the suspected liver’s edge. You will gradually move your parallel “brush strokes” superiorly up the abdomen, while listening carefully to the hollow sound until it turns duller, which is the signal that you have found the liver’s edge! On skin exam, you can note the level of jaundice (such as down to trunk, diffuse, etc.) as well as any rashes or bruising. Of note, jaundice tends to start at the head and spread downwards. It resolves in the reverse fashion, so toes up to head and face. A neuro exam is also very important – for infants, you will want to assess tone, activity level, and reflexes (such as suck, Moro, and plantar reflexes). If you have a patient who has neurological deficits such as poor tone or suck reflex with jaundice, you would get concerned for possible encephalopathy, which could be a sign of bilirubin building up in the brain, which is called kernicterus. It can be devastating if not promptly recognized and treated. In older infants with jaundice who you are concerned may have cholestasis, remember to look at the color of the stool to see if they are acholic.
Now that the history and physical exam are completed, we can move forward with any lab-work and imaging we would like to obtain to help us narrow down our differential further. Often, the nursing staff will obtain a transcutaneous bilirubin as an initial screen for hyperbilirubinemia. If this is elevated for the age of the infant, you will want to confirm this with a serum bilirubin. In the first few days of life, this may be as far as you need to go. However, if you’re worried that this is more than physiologic jaundice, you will need to do more. Typically, this might include complete blood cell count (CBC) to look for hemolysis, complete metabolic panel (CMP; which has total bilirubin, aspartate aminotransferase (AST), alanine aminotransaminase (ALT), alkaline phosphatase, albumin), conjugated or direct bilirubin, and/or coagulation studies (prothrombin time (PT), Partial thromboplastin time (PTT), international normalized ratio (INR)). Coagulation studies are vital to assessing liver function in that they assess the liver’s ability to make clotting factors. Other studies that you could consider based on history and exam findings would be reticulocyte count, Coombs test, gamma-glutamyl transferase (GGT), serum bile acids, blood and urine cultures, TORCH infection labs, toxins, drug levels, and genetic testing. As I briefly mentioned earlier, the newborn screen is very important to follow up on, because they can test for conditions such as common inborn errors of metabolism and G6PD deficiency (or Glucose-6-Phosphate Dehydrogenase deficiency). However, I will point out that not every state newborn screen has all the diseases we may be concerned about, so make sure to order separate lab-work for conditions that are high on your differential.
We usually think about imaging studies only for infants with conjugated hyperbilirubinemia. We start with a liver ultrasound, which is a simple and non-invasive way to assess both intra and extrahepatic biliary systems - specifically to evaluate for choledochal cysts. Additional imaging modalities that can be helpful are hepatobiliary iminodiacetic acid scan (HIDA scan), and magnetic resonance imaging cholangiopancreatography (MRCP). In those patients where biliary atresia is suspected, they typically undergo liver biopsy to help confirm the diagnosis.
Management is significantly determined by etiology and magnitude of the patient’s jaundice. For neonatal unconjugated hyperbilirubinemia, the treatment will be ensuring adequate feeding of the baby and possibly phototherapy. The decision to start phototherapy is based on the gestational age of the patient, the age of the patient (usually down to the hour), the total serum bilirubin (or TsB) (make sure you know the specific hour of life it was drawn), and the presence of any neurotoxicity risk factors. The presence of these neurotoxicity risk factors lowers the TsB threshold for when we would start phototherapy. These are:
Gestational age <38 weeks
Albumin <3 gram/deciliter
Hemolytic conditions (ABO incompatibility, isoimmune hemolytic disease, G6PD deficiency)
Sepsis
Concerns for significant clinical instability in the last 24 hours.
There are calculators and charts that allow us to calculate the threshold for each patient and guide our clinical practice. I’ve included a link to the one that we use at our institution in the show notes. Those tools also help guide us as to when we need to escalate treatment from phototherapy to exchange transfusion. Check with your resident or attending to see which tool is used at your institution. Of note, phototherapy works by converting unconjugated bilirubin into a water-soluble form that allows it to be more readily excreted in the urine and bile. Thus, this mechanism doesn’t work for conjugated bilirubin and therefore is not indicated in conjugated hyperbilirubinemia. In fact, it can lead to a discoloration of the baby’s skin making them seem “bronzed.” The 2022 practice guidelines from the American Academy of Pediatrics (AAP) provides further details on the detection, management, and follow up recommendations for patients with neonatal jaundice. I’ve provided this reference in the show notes.
For those children with conjugated or direct hyperbilirubinemia, the most important thing you can do is refer them to Pediatric Gastroenterology early. For all of the various conditions causing conjugated hyperbilirubinemia or cholestasis, the treatment is targeted at the specific etiology. For instance, if the infant has biliary atresia, they will need surgery. If caught early enough and the liver is not already cirrhotic, the infant will undergo a Kasai portoenterostomy. In this procedure, surgeons remove the non-functioning, scarred bile ducts, bring up a limb of bowel (called a Roux) and connect it directly to the liver to re-establish bile flow to the intestines. It is so important to diagnose children with biliary atresia early because the sooner a Kasai portoenterostomy is performed, the more likely an infant will keep his/her native liver and not progress to cirrhosis. If a child is already cirrhotic at the time of diagnosis, the Kasai is done too late, or just doesn’t drain well, then the only treatment left is a liver transplant. In fact, the most common reason for liver transplant in children is biliary atresia. Another important element of treatment for all of these patients includes nutritional supplementation, as they have impaired bile secretion which leads to malabsorption of fat and fat-soluble vitamins. These patients will need a diet that contains medium-chain triglycerides because these are water-soluble and can be absorbed without bile products. These patients will also need supplementation of vitamins A, D, E, and K, which are all fat-soluble. Remember, if you are concerned that an infant’s jaundice is due to conjugated hyperbilirubinemia, you will want to refer to your Pediatric Gastroenterologists as soon as possible. When it comes to the management of these infants, this early referral is imperative to achieve the needed care and to improve outcomes.
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