Step 1 · Gastrointestinal

Bilirubin Metabolism & Jaundice

Name: Bilirubin Metabolism & Jaundice
Creator: Veli Bakalov, MD

Follow one heme molecule from macrophage to urine and every jaundice pattern falls out

Gastrointestinal·Physiology·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Heme → biliverdin (heme oxygenase, releasing CO and iron) → unconjugated bilirubin (biliverdin reductase), carried to the liver on albumin.
UGT conjugates bilirubin with glucuronic acid; only conjugated (direct) bilirubin is water-soluble and appears in urine, so bilirubinuria always means conjugated hyperbilirubinemia.
Gut bacteria convert bilirubin to urobilinogen: stercobilin colors stool brown; reabsorbed urobilinogen is recycled or excreted in urine as urobilin.
Prehepatic (hemolytic) jaundice: unconjugated bilirubin, ↑ urine urobilinogen, no urine bilirubin, normal liver enzymes, ↑ LDH, ↓ haptoglobin.
Posthepatic (obstructive) jaundice: conjugated bilirubin, dark urine, pale stools, ↓ urine urobilinogen, ↑ alkaline phosphatase and GGT, pruritus; hepatocellular jaundice raises both fractions with ↑ AST/ALT.
Gilbert syndrome: UGT activity ~30% of normal → benign intermittent unconjugated hyperbilirubinemia with fasting, stress, or illness; affects ~5–10% of people.
Crigler-Najjar type I (absent UGT) causes kernicterus and death in infancy without liver transplant; type II (reduced UGT) responds to phenobarbital.
Dubin-Johnson (MRP2/ABCC2 secretion defect, grossly black liver) and Rotor (uptake/storage defect, liver not black) are benign conjugated hyperbilirubinemias.
Physiologic neonatal jaundice appears on days 2–4; jaundice in the first 24 hours is pathologic; kernicterus = basal ganglia deposition; phototherapy converts bilirubin to lumirubin.

From heme to urobilinogen

Making bilirubin. Senescent red cells are engulfed by macrophages of the reticuloendothelial system, mainly in the spleen. Heme oxygenase opens the heme ring to form biliverdin, releasing carbon monoxide and iron; biliverdin reductase then produces unconjugated bilirubin, which travels to the liver bound to albumin. The carbon monoxide released is why massive hemolysis can transiently raise carboxyhemoglobin.

Conjugation. In the hepatocyte, UDP-glucuronosyltransferase (UGT, encoded by UGT1A1) attaches glucuronic acid, producing water-soluble conjugated bilirubin that is secreted into bile. Deficient or defective UGT is the lesion in Gilbert and Crigler-Najjar syndromes.

The gut and back. In the intestine, bacteria convert bilirubin to urobilinogen. Most is oxidized to stercobilin, which colors stool brown. Some urobilinogen is reabsorbed and either recycled through the liver (enterohepatic circulation) or excreted by the kidney as urobilin, which gives urine its yellow color.

HemeFrom senescent red cells, in splenic macrophages
BiliverdinHeme oxygenase; releases CO and iron
Unconjugated bilirubinBiliverdin reductase; carried on albumin
Conjugated bilirubinUGT in the liver; water-soluble, secreted into bile
UrobilinogenGut bacteria → stercobilin (stool) and urobilin (urine)

One heme molecule's journey

Direct vs indirect bilirubin

Unconjugated (indirect) bilirubin. Lipophilic and water-insoluble, so it circulates tightly bound to albumin and cannot be filtered or excreted in urine. Its lipid solubility lets the unbound fraction cross the blood-brain barrier in neonates and deposit in the basal ganglia (kernicterus). Drugs that displace bilirubin from albumin, such as sulfonamides, raise that risk in newborns.

Conjugated (direct) bilirubin. Water-soluble, so when it backs up into blood it is filtered into urine. The van den Bergh reaction splits total bilirubin into these fractions: direct = conjugated, indirect = unconjugated.

Only conjugated bilirubin enters urine, so bilirubinuria always signals a conjugated (direct) hyperbilirubinemia; dark urine in intravascular hemolysis is hemoglobinuria, not bilirubin. Unconjugated causes are hemolysis, Gilbert, and Crigler-Najjar; conjugated causes are obstruction, Dubin-Johnson, and Rotor.

Localizing jaundice

Prehepatic (hemolytic). Hemolysis delivers more bilirubin than the liver can conjugate, raising unconjugated bilirubin. The liver still conjugates and excretes at full speed, so more urobilinogen is made and urine urobilinogen rises, but bilirubin is absent from urine ("acholuric jaundice"). Liver enzymes are normal; look for anemia, high LDH, and low haptoglobin.

Hepatic (hepatocellular). Viral hepatitis or cirrhosis impairs both conjugation and secretion, so unconjugated and conjugated bilirubin both rise. AST and ALT are elevated, urine bilirubin is present, and urine urobilinogen is normal or decreased.

Posthepatic (obstructive). Stones or tumor block bile flow, raising conjugated bilirubin with high alkaline phosphatase and GGT. Bilirubinuria darkens the urine. Because bilirubin no longer reaches the gut, stools turn pale (acholic) and urine urobilinogen falls. Retained bile salts cause pruritus.

Lab patterns of jaundice

Feature	Prehepatic	Hepatic	Posthepatic
Main bilirubin	Unconjugated	Both	Conjugated
Urine bilirubin	Absent	Present	Present (dark urine)
Urine urobilinogen	↑	Normal or ↓	↓
Stool	Normal or dark	Normal or pale	Pale (acholic)
Other labs	Anemia, ↑ LDH, ↓ haptoglobin	↑ AST and ALT	↑ Alkaline phosphatase and GGT; pruritus

Hereditary hyperbilirubinemias

Gilbert syndrome. UGT activity is reduced to about 30% of normal, usually from a UGT1A1 promoter variant. Unconjugated bilirubin rises intermittently with stress, fasting, illness, exertion, or even a hangover, while liver enzymes and blood counts stay normal. It is common (about 5–10% of people), entirely benign, and needs no treatment. Because UGT also inactivates the chemotherapy drug irinotecan, patients with Gilbert variants are prone to its toxicity.

Crigler-Najjar syndrome. Type I has absent UGT: severe unconjugated hyperbilirubinemia from birth, kernicterus, and death in infancy without treatment. Phototherapy and plasmapheresis buy time; liver transplant is definitive. Type II is milder, with residual UGT that phenobarbital can induce.

Dubin-Johnson and Rotor syndromes. Dubin-Johnson syndrome is a defect of MRP2 (ABCC2), the canalicular transporter that secretes conjugated bilirubin into bile, causing benign conjugated hyperbilirubinemia and a grossly black liver from retained pigment. Rotor syndrome is similar but milder, reflects defective hepatic uptake and storage, and the liver is not black.

Hereditary hyperbilirubinemias

Syndrome	Bilirubin	Defect	Key features
Gilbert	Unconjugated	UGT activity ~30% of normal	Jaundice with fasting or illness; benign
Crigler-Najjar I	Unconjugated	Absent UGT	Kernicterus; fatal in infancy without transplant
Crigler-Najjar II	Unconjugated	Reduced UGT	Milder; responds to phenobarbital
Dubin-Johnson	Conjugated	MRP2 (ABCC2) secretion defect	Grossly black liver; benign
Rotor	Conjugated	Uptake and storage defect	Milder; liver not black

Neonatal jaundice and kernicterus

Physiologic jaundice. Newborns combine immature UGT with high red-cell turnover, so unconjugated bilirubin rises and jaundice appears on days 2–4. Jaundice within the first 24 hours is pathologic and needs workup, often for hemolysis.

Kernicterus. Unconjugated bilirubin deposits in the basal ganglia (especially the globus pallidus) and causes lethargy, hypertonia, and permanent neurologic injury.

Treatment. Phototherapy isomerizes unconjugated bilirubin to water-soluble forms such as lumirubin, which are excreted without conjugation. Severe cases need exchange transfusion.

Conjugated hyperbilirubinemia in a newborn is never physiologic: persistent jaundice with pale stools and dark urine suggests biliary atresia.