Bilirubin and jaundice

Introduction

Bilirubin is a yellow pigment produced from the breakdown of haemoglobin in red blood cells. It undergoes a multi-step process involving hepatic uptake, conjugation, and excretion via bile. Disruption in any part of this pathway can lead to hyperbilirubinaemia and jaundice.

Bilirubin Metabolism

1. Formation of Unconjugated (Indirect) Bilirubin

• Haem breakdown occurs in the reticuloendothelial system (mainly in the spleen and liver).
• Haem oxygenase converts haem into biliverdin.
• Biliverdin reductase reduces biliverdin to unconjugated bilirubin.
• Unconjugated bilirubin is lipid-soluble and bound to albumin in the blood.
• It is transported to the liver for further processing.

2. Hepatic Conjugation

• Hepatocytes take up unconjugated bilirubin.
• UDP-glucuronosyltransferase (UGT1A1) conjugates bilirubin with glucuronic acid, making it water-soluble.
• This forms conjugated (direct) bilirubin, which can be excreted into bile.

3. Excretion and Enterohepatic Circulation

• Conjugated bilirubin is secreted into bile and enters the small intestine.
• In the colon, gut bacteria convert it into urobilinogen.
  • Some urobilinogen is reabsorbed and excreted in urine as urobilin, giving urine its yellow colour.
  • The remainder is oxidised and excreted in faeces as stercobilin, giving stool its brown colour.

Types of Bilirubin

• Unconjugated (Indirect) Bilirubin
  • Lipid-soluble
  • Bound to albumin
  • Not excreted in urine
• Conjugated (Direct) Bilirubin
  • Water-soluble
  • Excreted in bile and urine

Peak Incidence

• Dependent on cause:
  • Pre-hepatic (e.g. haemolysis): often affects younger individuals with inherited or acquired haemolytic anaemia.
  • Hepatic (e.g. viral hepatitis): any age, often 20–40 years.
  • Post-hepatic (e.g. gallstones, malignancy): typically in middle-aged or elderly adults.

Pathophysiology

Jaundice results when bilirubin metabolism is disrupted at one of the following stages:

• Pre-hepatic: Excess production of unconjugated bilirubin from haemolysis or ineffective erythropoiesis exceeds hepatic conjugation capacity.
• Hepatic: Hepatocyte dysfunction or enzyme defects impair conjugation or excretion of bilirubin, leading to a mixed picture.
• Post-hepatic: Obstruction of bile flow causes accumulation of conjugated bilirubin in the liver and blood.

Symptoms

• Yellowing of the sclerae (scleral icterus) and skin.
• Pale stools and dark urine (in obstructive causes).
• Pruritus (particularly in cholestatic or post-hepatic causes).
• Fatigue, abdominal discomfort, anorexia, or nausea in hepatic causes.

Signs

• Pre-hepatic: Pallor, splenomegaly (due to haemolysis).
• Hepatic: Tender hepatomegaly, stigmata of chronic liver disease (e.g. spider naevi, palmar erythema, ascites).
• Post-hepatic: Jaundice, scratch marks, dark urine, pale stools, palpable gallbladder (Courvoisier’s sign in malignancy).

Classification of Hyperbilirubinaemia

1. Pre-hepatic (Unconjugated)

• Cause: Excess haemolysis, ineffective erythropoiesis, Gilbert’s or Crigler-Najjar syndrome
• Bloods: ↑ Unconjugated bilirubin; normal LFTs
• Urine: No bilirubin (unconjugated is not water-soluble)
• Stools: Normal

2. Hepatic (Mixed)

• Cause: Hepatitis, cirrhosis, drug-induced liver injury, Dubin-Johnson syndrome, Rotor syndrome
• Bloods: ↑ Conjugated & unconjugated bilirubin, ↑ ALT/AST
• Urine: Dark (conjugated bilirubin)
• Stools: Normal or pale

3. Post-hepatic (Conjugated)

• Cause: Gallstones, cholangiocarcinoma, pancreatic cancer, PSC, PBC
• Bloods: ↑ Conjugated bilirubin, ↑ ALP/GGT
• Urine: Dark
• Stools: Pale

Diagnosis

History and Examination

• Timing and progression of jaundice
• Risk factors: travel, alcohol, medication, blood transfusion, autoimmune disease, malignancy
• Signs of chronic liver disease or haemolysis

Laboratory Tests

• Serum bilirubin (total, direct, indirect)
• Liver function tests: ALT/AST (hepatocellular), ALP/GGT (cholestatic)
• FBC and reticulocyte count: Anaemia and reticulocytosis suggest haemolysis
• Peripheral blood smear: Spherocytes (hereditary spherocytosis), schistocytes (microangiopathic)
• LDH, haptoglobin: Raised LDH and low haptoglobin in haemolysis
• Coombs test: Positive in autoimmune haemolytic anaemia
• Autoantibodies: ANA, ASMA, AMA
• Iron studies: Ferritin, transferrin saturation
• Hepatitis serology

Urine Testing

• Urinary bilirubin: Present if conjugated
• Urobilinogen: Absent in post-hepatic; elevated in haemolysis

Imaging

• Ultrasound: Gallstones, ductal dilation, liver texture
• MRCP: Detailed view of biliary and pancreatic ducts
• CT abdomen: For suspected masses
• ERCP: Diagnostic and therapeutic in obstructive jaundice

Liver Biopsy

• Consider if diagnosis remains unclear and autoimmune or metabolic liver disease is suspected

Genetic Testing

• Consider in hereditary disorders (e.g. Gilbert’s, Crigler-Najjar, hereditary spherocytosis)

Complications

• Pre-hepatic: Severe anaemia, gallstones (from increased bilirubin turnover)
• Hepatic: Liver failure, hepatic encephalopathy, coagulopathy
• Post-hepatic: Cholangitis, biliary cirrhosis, sepsis, secondary malignancy (e.g. cholangiocarcinoma)

Management

• Pre-hepatic jaundice:
  • Treat underlying cause (e.g. immunosuppression for autoimmune haemolysis, blood transfusion in severe cases).
• Hepatic jaundice:
  • Supportive care (fluids, nutrition)
  • Treat cause (e.g. antivirals for hepatitis, corticosteroids for autoimmune hepatitis)
  • Consider transplant if decompensated cirrhosis or acute liver failure
• Post-hepatic jaundice:
  • ERCP for stone extraction
  • Stenting or surgery for strictures and malignancies
  • Ursodeoxycholic acid for primary biliary cholangitis