The Cribsiders podcast

#65: Liver Lovers Unite! An Approach to Pediatric and Adolescent Hyperbilirubinemia

October 5, 2022 | By


Does the sight of a jaundiced patient send you into a spiral about what to do next? Indirect, unconjugated, direct, conjugated…what’s the difference?! Why do patients with Gilbert’s live longer?? Find out in this Kasai-ting discussion of hyperbilirubinemia in the pediatric and adolescent patient. In this second part of our hyperbilirubinemia series, Dr. Niviann Blondet breaks down a stepwise approach for diagnosis, work-up, and management of hyperbilirubinemia.



  • Producer, Writer, Infographic: Angela Y. Zhang MD
  • Executive Producer: Max Cruz MD
  • Showrunner: Sam Masur MD
  • Cover Art: Chris Chiu MD
  • Hosts: Justin Berk MD, Chris Chiu MD, Angela Y. Zhang MD
  • Editor:Justin Berk MD; Clair Morgan of
  • Guest(s): Niviann Blondet MD

Pediatric & Adolescent Hyperbilirubinemia Pearls

  1. A thorough personal and family history and skin and abdominal exam are key!
  2. Fractionate the bilirubin!! If conjugated hyperbilirubinemia, get liver function labs.
  3. Although indirect hyperbilirubinemia is not always pathophysiologic and can self-resolve, direct hyperbilirubinemia always requires further workup. 
  4. Some advice from our guest, Dr. Blondet: Build your community and have multiple mentors – not every mentor is right or can do everything for you.


We are excited to announce that the Cribsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out and create your FREE account!

Pediatric and Adolescent Hyperbilirubinemia

First, some pathophysiology foundation: Jaundice is the manifestation of excess bilirubin. Bilirubin is the byproduct of red blood cell metabolism as they go through the spleen and break down. The unconjugated bilirubin is transported to and conjugated in the liver, and excreted through the intestines. If there is a problem at any of these points, the total bilirubin can rise and lead to clinical consequences. 

Second, how does this episode differ from our neonatal approach? In general, use the neonatal approach until their livers, guts, and brain-blood barriers mature (around 3-4 weeks of age). At this age, the risk for kernicterus will significantly decrease, and we can use the approach highlighted below.

Approaching Jaundice in the Pediatric/Adolescent Patient

Overarching Framework: Determine Direct vs. Indirect Hyperbilirubinemia

Unconjugated hyperbilirubinemia (usually less serious, not always pathologic)

Root problem is in the blood/more systemic, and overloads the liver. Examples: hemolysis, infection (systemic inflammation leading to RBC  breakdown).

  • Unconjugated hyperbilirubinemia is like a traffic jam – if you give the liver a bit of time, it will conjugate and excrete the backed up bilirubin. The delay may irritate other organs or create a stone.
  • If your patient is no longer a neonate, the indirect hyperbilirubinemia is often just cosmetic and not clinically dangerous.
  • For younger children (e.g. 4-5 weeks of life), consider Criggler-Najar. Type 1 has less ability to conjugate than type 2, so is more severe. 
  • In older child, consider Gilbert’s disease, which is a clinical diagnosis (genetic screening is expensive and not beneficial)
    • Expert opinion: Patients with Gilbert’s disease actually live longer!

Conjugated Hyperbilirubinemia (more serious)

  • Root problem is something that’s preventing the liver from fully excreting the bilirubin it’s already conjugated. Examples:
    • Babies: obstructive diseases like biliary atresia, infection (gram negative bacteria may slow down bilirubin excretion), metabolic disease (most are on the newborn screen but not all).
    • Older children: hepatocellular diseases like hepatitis, Wilson’s, infection
  • One of the most important diseases to catch with conjugated HB is biliary atresia, where the outcome is tied to the time of diagnosis.
    • Biliary atresia occurs when the extrahepatic biliary ducts are completely absent, or underdeveloped. You would see hyper-proliferation of intrahepatic bile ducts. 
    • Early surgery (Kasai procedure) before 60 days of life is key, and outcomes are also tied to surgeon experience.
    • If surgery occurs too late, the liver may already be cirrhotic. Surgery is contra-indicated if there are signs of liver failure.
    • Expert opinion: Later in the disease, can consider liver transplant as a treatment strategy, not as a “failure” of treatment.
    • Expert opinion: COVID and other healthcare barriers can lead to delayed diagnosis of biliary atresia. Make sure to have good PCP follow-up in the first month of life, especially if the patient is jaundiced as a newborn.
  • Alagille Syndrome
    • Paucity of intrahepatic bile ducts (in contrast to biliary atresia).
    • Is usually a syndrome that includes: cardiovascular findings, butterfly vertebrae, vascular anomalies, atypical facies.
  • Hepatitis: autoimmune, viral, iatrogenic (e.g. acetaminophen overdose).
    • Hepatocellular injury → decreased ability of excretion of conjugated bilirubin.


  • Use a thorough history to determine your workup. Note any history of infection, history of travel, history of medications such as acetaminophen, failure to thrive and/or difficulty eating, prior labs such as the newborn screen.
  • Elucidate family history, even the non-hepatic diseases. A family history of autoimmune or unusual heart disease may suggest Wilson’s, for example. 
  • This wouldn’t be a GI topic if you didn’t ask about stool! Ask patients/parents to be specific – is the poop bright mustard-colored, or pale yellow? 
    • Pale colored stool may indicate obstruction. It can also sometimes self-resolve if the patient is young and the liver is just maturing. 
    • Expert practice: Have patients/parents download the PoopMD+ app so they can take a photo of the stool. There are also stool color cards available for parents to match colors on their own.
  • Abdominal pain: usually non-specific. If it localizes to the RUQ, then sometimes you could think of obstruction or hepatitis.

Physical Exam

  • General appearance is key! If your patient is a well-appearing, healthy, growing child with indirect hyperbilirubinemia (more on that in the labs section), then chances are the diagnosis is benign (e.g. dehydration, immature liver).  
  • Abdominal exam – assessing the liver AND spleen.
    • Expert practice: Start low (at the iliac crest) and work your way up to ensure you catch the edge of the spleen/liver if they’re enlarged. Sometimes the liver is shrunken from being cirrhotic, so you won’t be able to palpate it. Make sure your patient is calm so they’re not tensing their muscles.
  • Skin: Assess for jaundice by blanching the skin. Look at the conjunctivae and the mucous membranes inside the mouth. Don’t assume that a “yellow” undertone is physiologic.
    • While a cephalohematoma is a neonatal risk factor for hyperbilirubinemia, other sources of bruising are unlikely to be clinically significant enough to cause hyperbilirubinemia.

Labs & Imaging

  • A CBC can provide information on hemolysis or splenic sequestration.
  • In babies, send thyroid studies, A1AT, and hepatitis B/C if history of exposure.
  • In older kids, send AIH panel, ceruloplasmin for Wilson’s, hemochromatosis, hepatitis B/C if history of exposure.
  • Fractionate your bilirubin! 
    • Expert pearl: Conjugated and direct bilirubin are not the same, pick one or the other to trend, but you can’t compare them to each other! Direct bilirubin is bound to albumin, which has a long half-life (20-28 days), so resolution of this number will lag behind the clinical process. Conjugated bilirubin is the active metabolite and thus will clear faster. The “delta bilirubin”, or the measurement of the bilirubin bound to albumin, isn’t clinically significant because you will always be picking direct or conjugated. 
      • Delta bilirubin = total bilirubin – (unconjugated bilirubin + conjugated bilirubin) (This is similar to iCal and tCal – both measure calcium, but iCal is the active metabolite, whereas tCal can fluctuate depending on albumin concentration).
    • Expert pearl: There are 2 ways to determine if a hyperbilirubinemia is direct: if 20% of the total is direct, or if the direct component is 2 g/dL, indicating cholestatic jaundice.
  • If unconjugated, then there are ways to test for diseases like Criggler-Najjar or Gilbert’s, such as the Jaundice Chip. But, these are expensive and may not have much clinical utility. Rely on exam and other tests first.
  • If conjugated, then you need further workup (expert pearl: if nothing else, remember the ABCs of Liver Function: albumin, bilirubin, coags)
    • AST/ALT
    • GGT – bile duct specific
    • Albumin – may be falsely low in inflammation (negative inflammatory marker).
    • ALP – can’t just use this because it’s elevated in growing patients.
    • INR – crucial in deciding inpatient disposition (e.g. floor vs. ICU).
      • In cholestasis, INR may be falsely elevated secondary to vitamin K deficiency since it’s not being enterally absorbed. In this case, can add thrombin time and other coagulation studies, or can give IV/IM vitamin K and retest.
  • Imaging: Consider getting a full abdominal ultrasound instead of just RUQ, as it can provide information on the spleen, signs of chronic liver disease, abnormal vasculature, etc.

What Next?

  • If well-appearing, maintaining oral intake, and doesn’t have healthcare access barriers: Follow up in 48-72 hours and repeat labs
  • If at follow-up, bilirubin is rising: Consult hepatology (curbside and/or refer)
  • If ill-appearing, is dehydrated, has signs/labs of coagulopathy or hypoalbuminemia, or has altered mental status: send directly to the ED.


You can find out more about our guest’s recommendation, Picky Eating Help (, at their Instagram.


Listeners will differentiate between the causes, workup, and management of direct and indirect hyperbilirubinemia in an outpatient setting, and when to escalate care.

Learning objectives

After listening to this episode listeners will be able to…  

  1. Describe the basic pathophysiology of indirect and direct hyperbilirubinemia.
  2. Distinguish direct versus indirect hyperbilirubinemia.
  3. Recognize the importance of early intervention in biliary atresia.
  4. Discuss the utility of liver function tests for triage of care and management.


Dr Blondet reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 


Zhang AY, Blondet N, Cruz M , Masur S, Chiu C, Berk J. “#65: Liver Lovers Unite! An Approach to Pediatric and Adolescent Hyperbilirubinemia”. The Cribsiders Pediatric Podcast. https:/ October 5, 2022


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The Cribsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit and search for this episode to claim credit.

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