Ep 10: Bilirubin Metabolism

Learning Objectives

By the end of this episode, NICU Grads will be able to:
1. Review bilirubin biochemistry and physiology, including biological properties bilirubin and pathways of synthesis, transport, metabolism and excretion
2. Discuss in detail the role of enterohepatic circulation of bilirubin in neonatal serum bilirubin excretion

Guest Speaker
Lauren Miyares, MD FAAP
Neonatal-Perinatal Fellow

Bilirubin Metabolism

What is bilirubin?

• Derived from red blood cell breakdown and heme 
  • 75% from catabolism of circulating RBCs 
  • 25% from ineffective erythropoiesis (red cell catabolism in bone marrow) and turnover of heme protein and free heme 

Does it have a purpose?

• There is no known physiologic function for bilirubin
• It possibly serves as an antioxidant
• The placenta can remove indirect bilirubin, but not biliverdin, so there is a fetal advantage to make bilirubin 

How is it broken down/metabolized?

• STEP 1 = Heme Degradation 
  • Heme oxygenase-1 (HO-1)= enzyme found in cells of the liver and other organs that converts heme to biliverdin 
  • Bilirubin reductase= enzyme that breaks down biliverdin to unconjugated bilirubin
• STEP 2 = Bilirubin Plasma Transportation
  • In plasma, unconjugated bilirubin binds to albumin
  • Albumin bound bilirubin cannot cross the blood brain barrier and is lipid-solute
• STEP 3 = Hepatic Uptake
  • Bilirubin dissociates from albumin before entering the liver cell via passive diffusion and/or membrane carrier molecules.
  • Unconjugated bilirubin is selectively taken up across the basolateral membrane of the hepatocyte by a carrier-mediated process involving the organic anion-transporting polypeptide-2 (OATP-2)
  • Bilirubin binds to ligandin/other binding-proteins and is transported to the smooth endoplasmic reticulum (SER)
• STEP 4 = Bilirubin Conjugation
  • What is conjugation?
    • Process of by which unconjugated bilirubin is conjugated to a polar water-soluble substance, bilirubin glucuronides
  • What is purpose of conjugation?
    • Allows for excretion of bilirubin as water-soluble substances (e.g. stercobilin and urobilin)
  • Who does the conjugation?
    • UGT1A1
      • Uridine diphosphoglucuronate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) 
        • Also known as glucuronosyl transferase or glucuronyl transferase
  • Where is the site of conjugation?
    • Smooth endoplasmic reticulum (SER)
• STEP 5 = Elimination
  • Excreted into the bile, which enters intestines and is ultimately eliminated from the body
  • Small percentage eliminated in the urine as urobilin
  • NOT ALL OF THE CONJUGATED BILIRUBIN GETS ELIMINATED
    • Enterohepatic recirculation
      • Some conjugated bilirubin gets reabsorbed into the blood
      • MOA:
        • Presence of intestinal beta glucoronidase + decreased microflora –> Increased enterohepatic circulation–> Increased unconjugated bilirubin load
        1. Intestinal beta glucoronidase
           • Present in both term and premature neonates in high concentrations
           • Located in the brush border of the intestine
           • Reduces conjugated bilirubin back to unconjugated state via hydrolysis of the bilirubin glucuronide
        2. Relative lack of bacterial flora in the newborn bowel
           • Leads to the decreased ability compared to older children and adults to convert conjugated bilirubin stercobilin or urobilirubin to be excreted from the body

References: 

1. Ronald J. Wong, David K. Stevenson, Charles E. Ahlfors, Hendrik J. Vreman. Neonatal Jaundice:Bilirubin Physiology and Clinical Chemistry. Neoreviews 2007; 8(2):e58-e67; DOI: 10.1542/neo.8-2-e58
2. Richard J. Martin, Avroy A. Fanaroff, Michele C. Walsh. (2015). Fanaroff and Martin’s neonatal-perinatal medicine: diseases of the fetus and infant. Philadelphia, PA: Elsevier/Saunders.
3. Brodsky, Dara, and Camilia Martin. Brodsky and Martin’s Neonatology Review Series. 3rd ed., Lulu, 2020.
4. Brodsky, Dara. Neonatology Review: Q&A. 3rd ed., Lulu, 2016.
5. Chess, Patricia. Avery’s Neonatology Board Review: Certification and Clinical Refresher. 1 ed., Elsevier, 2019.
6. Polin, Richard A., and Mervin C. Yoder. Workbook in Practical Neonatology. 5th ed., Saunders, 2014.

Credits

• Written and Produced by: Neena Jube-Desai MD, MBA FAAP
• Cover Art by: Neena Jube-Desai MD, MBA FAAP
• Infographic by: Mekala Neelakantan
• Host: Neena Jube-Desai MD, MBA FAAP
• Editor: Neena Jube-Desai MD, MBA FAAP
• Guest: Lauren Miyares, MD FAAP