Biochemistry · Metabolic pathway
Heme breakdown and bilirubin !
Heme from old red cells becomes bilirubin; the liver conjugates it and bile carries it to the gut, where it colours the stool.
Updated 2026-11-01
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Key facts
- About 250–350 mg of bilirubin is made per day; roughly 80 % comes from hemoglobin of old red cells removed by spleen macrophages.
- Heme oxygenase opens the ring and releases CO (almost all the body's endogenous CO) and Fe²⁺, which is recycled.
- Unconjugated (indirect) bilirubin is water-insoluble and travels bound to albumin; it does not appear in urine.
- Liver UGT1A1 adds glucuronic acid (conjugated or direct bilirubin); MRP2 pumps it into bile, the slowest step.
- Colonic bacteria turn it into urobilinogen: part is reabsorbed and leaves in urine as urobilin (yellow); the rest is oxidised to stercobilin (brown).
- Also called
- Heme catabolism
Regulation
- Heme oxygenase 1 is inducible: its substrate (heme), oxidative stress, hypoxia and inflammation switch it on.
- Phenobarbital induces UGT1A1 (useful in Crigler-Najjar type 2).
- Newborns have little UGT1A1 in the first days: the basis of physiological jaundice.
The steps, one by one
- Step 1 · Heme oxygenase (inducible HO-1, constitutive HO-2) irreversible Heme + o2 + NADPH → Biliverdin + Carbon monoxide (CO) + Ferrous iron (Fe²⁺) + nadpIn the macrophage endoplasmic reticulum it breaks the heme ring: green biliverdin, CO and iron come out.If it fails: HO-1 deficiency is very rare: severe hemolysis, inflammation and endothelial damage.
- Step 2 · Biliverdin reductase irreversible Biliverdin + NADPH → Bilirubin + nadpIn the cytosol it reduces the central bridge of biliverdin, giving yellow bilirubin.If it fails: Its absence (very rare) leaves biliverdin unreduced: greenish skin and serum (green jaundice).
- Step 3 · UDP-glucuronosyltransferase 1A1 (UGT1A1) irreversible Bilirubin + UDP-glucuronic acid → Bilirubin glucuronide (conjugated bilirubin) + UDPBilirubin reaches the liver on albumin, enters the hepatocyte, and UGT1A1 attaches one or two glucuronic acids: it becomes water-soluble.If it fails: Activity down to ~30 %: Gilbert syndrome. Absent or nearly absent: Crigler-Najjar types 1 and 2. Immature: neonatal jaundice. Crigler-Najjar syndrome →
- Step 4 · MRP2 (ABCC2), canalicular transporter irreversible Bilirubin glucuronide (conjugated bilirubin) + ATP → Conjugated bilirubin in bile + ADP + phosphate (Pi)It pumps conjugated bilirubin from the hepatocyte into the bile canaliculus using ATP; it is the rate-limiting step of the whole liver pathway.If it fails: Without MRP2: Dubin-Johnson syndrome (conjugated hyperbilirubinemia, black liver). When OATP1B1/1B3 reuptake fails: Rotor syndrome. Dubin-Johnson syndrome →
- Step 5 · Colonic bacterial β-glucuronidases and reductases irreversible Conjugated bilirubin in bile → UrobilinogenIn the gut, bacteria strip the glucuronide and reduce bilirubin to colourless urobilinogen; part returns to the liver (enterohepatic circulation).If it fails: In the newborn, the nearly sterile gut and mucosal β-glucuronidase send bilirubin back to the blood and add to jaundice. Neonatal jaundice →
- Step 6 · Urobilinogen oxidation (colonic bacteria and kidney) irreversible Urobilinogen → Stercobilin (stool) + Urobilin (urine)In the colon stercobilin forms and colours the stool; urobilinogen that reaches the kidney leaves as urobilin, the yellow of urine.If it fails: Pale stools and dark urine mean bilirubin is not reaching the gut: cholestasis or biliary obstruction. Gallstones (cholelithiasis) →
Clinical notes
- Overproduction (hemolysis) or failed uptake or conjugation: unconjugated hyperbilirubinemia, with no bilirubin in urine.
- Failed excretion or biliary obstruction: conjugated hyperbilirubinemia, with dark urine and, if blocked, pale stools.
- In complete biliary obstruction no bilirubin reaches the gut: urinary urobilinogen disappears.
- The colour changes of a bruise (red-purple → green → yellow) show the pathway: heme → biliverdin → bilirubin.
Related conditions
- Gilbert syndrome
- Crigler-Najjar syndrome
- Dubin-Johnson syndrome
- Rotor syndrome
- Neonatal jaundice
- Sickle cell disease
- Gallstones (cholelithiasis)
- Cirrhosis
Related
- Heme oxygenase
- Biliverdin reductase
- UGT1A1 (bilirubin UDP-glucuronosyltransferase)
- Heme
- Bilirubin
- Hemoglobin and 2,3-BPG
- Heme synthesis
- Iron metabolism
- Myoglobin
Test yourself
Think of the answer, then tap the question to see it.
Which enzyme opens the heme ring, and what does it release?
Heme oxygenase: it releases biliverdin, carbon monoxide and Fe²⁺.
Why does unconjugated bilirubin not appear in urine?
It is water-insoluble and travels bound to albumin, which is not filtered by the glomerulus.
What gives stool its brown colour?
Stercobilin, which colonic bacteria form from urobilinogen.
What is the slowest step in liver handling of bilirubin?
Excretion of conjugated bilirubin into bile by MRP2; that is why liver disease usually raises the conjugated fraction.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Reactome | Heme degradation (Reactome, 2026); Bilirubin blood test: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Jaundice | Icterus | MedlinePlus (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.