52 Bile Acids and Jaundice Quiz

What is Bile?

• Bile is a fluid produced by the liver, approximately 500mL/day in adults.
• It is typically yellow-green and alkaline (pH 7.5-8).
• It is stored in the gallbladder and released in response to cholecystokinin (CCK).
• CCK is released from I cells in the duodenum after eating a meal containing nutrients.
• Bile is essential for fat digestion and absorption, excretion of excess cholesterol and metabolites, and neutralisation of stomach acid.

Bile Composition

• Bile contains bile acids, bile pigments, cholesterol, drugs and their metabolites, and particulate matter.
• Particulate matter is removed from the bloodstream by Kupffer cells in the liver.

Bile and Fat Digestion

• Bile acids act as detergents, emulsifying fats in food.
• Bile acids are amphipathic, with hydrophilic and hydrophobic regions.
• They form micelles around fat droplets, with the hydrophobic sides facing the fat and the hydrophilic sides facing outwards.
• Pancreatic amylase can enter micelles and digest triglycerides into monoglycerides and fatty acids.

Bile Acid Metabolism

• Primary bile acids, cholic acid and chenodeoxycholic acid, are synthesised in the liver from cholesterol.
• They are conjugated to glycine or taurine, forming conjugated primary bile acids, and stored in the gallbladder.
• They are released in response to a meal to facilitate fat digestion and absorption.
• Primary bile acids are converted to secondary bile acids by bacteria in the colon.
• Bile acids provide a pathway for excess cholesterol excretion from the body.

Bilirubin

• Bilirubin is a natural degradation product of haem.
• Red blood cells (RBCs) have a lifespan of 60-120 days.
• Most senescent RBCs are destroyed extravascularly (in the liver, spleen, or bone marrow) through phagocytosis or lysis.
• Intravascular haemolysis is rare, usually occurring as a consequence of disease.
• Released haem is toxic, requiring detoxification through metabolism to bilirubin.
• 75% of bilirubin is derived from RBCs, the remainder from other heme-containing proteins (eg., myoglobin, cytochromes).

Formation of Bilirubin

• Haemoglobin from RBCs is broken down into globin, haem, and bilirubin during phagocytosis and hemolysis.
• Iron (Fe2+) is recycled for erythropoiesis.
• Bilirubin is a waste product that needs to be excreted.

Handling of Free Haemoglobin

• Free haem in the blood is toxic.
• Detoxification occurs by binding to serum proteins.
• Haptoglobin binds to free haemoglobin, forming a complex that is metabolised in the liver and spleen, producing iron-globin and bilirubin. This complex also prevents iron loss in the urine.
• Haemopexin binds to the free haem, forming a complex that is taken up by the liver for iron storage.
• Albumin binds to oxidized haem, forming Met-haemalbumin.

Degradation of Haem to Bilirubin

• Degradation occurs mostly in the spleen, requiring two enzymes: heme oxygenase (HMOX) and biliverdin reductase (BVRA).
• Haem is converted to biliverdin (green pigment) by HMOX.
• Biliverdin is then converted to bilirubin (yellow pigment) by BVRA.

Metabolism of Bilirubin

• The liver takes up bilirubin through facilitated diffusion via the OATP transporter.
• Bilirubin binds to cytoplasmic proteins (ligandin and protein Y) in hepatocytes, preventing efflux back into the blood.
• Bilirubin is conjugated with glucuronic acid by UDP-glucuronyl transferase (UDP-glucuronosyltransferase), making it water-soluble.

Metabolism of Bilirubin (Continued)

• Conjugated bilirubin is secreted into bile ducts through active transport via MRP-3.
• Bile is excreted from the liver into the gut.
• Glucuronidases in colonic bacteria de-conjugate bilirubin to urobilinogen (colourless).
• Urobilinogen is either oxidized by bacteria to stercobilin (brown pigment) and excreted in feces, or reabsorbed into the portal blood.
• Reabsorbed urobilinogen is partially excreted in urine as urobilin.

Summary of Bilirubin Formation and Fate

• Haem from RBC hemolysis is converted to bilirubin.
• Bilirubin is transported in the bloodstream bound to albumin.
• The liver takes up bilirubin, conjugates it, and excretes it into bile.
• Bilirubin is converted to urobilinogen in the intestinal tract.
• Urobilinogen is either reabsorbed and excreted in urine as urobilin or excreted in feces as stercobilin.

Jaundice

• Jaundice presents as yellowing of the skin, whites of the eyes, and mucous membranes due to hyperbilirubinemia.
• Typically occurs when serum bilirubin levels exceed 35 µM/L (normal 17 µM/L).
• Usually indicates underlying disease involving abnormal heme metabolism, liver dysfunction, or biliary tract obstruction.
• Can cause complications such as urticaria, abdominal pain, pale feces, dark urine, and neurological damage (kernicterus).
• Treatment depends on the underlying cause.

Classification of Jaundice

• There are three categories of jaundice based on the site of pathology.
• Pre-hepatic (haemolytic): Bilirubin production exceeds the liver’s uptake capacity.
• Intra-hepatic (hepatocellular): Bilirubin cannot be taken up, conjugated, or excreted due to hepatocellular damage.
• Post-hepatic (cholestatic): Obstruction to biliary flow causes conjugated bilirubin to be regurgitated back into circulation.

Pre-hepatic Jaundice

• Also known as haemolytic jaundice or hematogenous jaundice.
• Excess bilirubin production following haemolysis.
• Excess RBC lysis is often due to autoimmune disease.
• High plasma levels of unconjugated bilirubin.

Intra-hepatic Jaundice

• Also known as hepatocellular jaundice.
• Impaired uptake, conjugation, or secretion of bilirubin.
• Reflects generalized liver cell (hepatocyte) dysfunction.
• Hyperbilirubinaemia is often accompanied by other abnormal biochemical markers of liver function.

Post-hepatic Jaundice

• Also known as obstructive jaundice or choleostatic jaundice.
• Caused by obstruction to the biliary tract.
• Plasma bilirubin is conjugated.
• Other bile constituents also accumulate in the plasma.
• Characterized by pale stools and dark urine.

Differential Diagnosis of Jaundice:

• Pre-hepatic
  • Conjugated bilirubin: Present
  • ALT or AST: Normal
  • Alkaline phosphatase (ALP): Normal
  • Urine bilirubin: Absent
  • Urine urobilinogen: Present
• Intra-hepatic
  • Conjugated bilirubin: Increased
  • ALT or AST: Increased
  • Alkaline phosphatase (ALP): Normal
  • Urine bilirubin: Present
  • Urine urobilinogen: Present
• Post-hepatic
  • Conjugated bilirubin: Increased
  • ALT or AST: Normal
  • Alkaline phosphatase (ALP): Increased
  • Urine bilirubin: Present
  • Urine urobilinogen: Absent

Newborn Jaundice

• Common, particularly in premature infants.
• Occurs 2-4 days after birth due to immature enzymes involved in bilirubin conjugation.
• Typically resolves within 10 days of life.

Complications of Newborn Jaundice

• Kernicterus: Occurs when unbound unconjugated bilirubin deposits in the brain, causing encephalopathy.
• Aggravating factors: Haemolysis, breastfeeding, sulphonamides, antibiotics.

Treatment of Newborn Jaundice

• Often resolves without treatment.
• Phototherapy: Converts bilirubin to a water-soluble, non-toxic form.
• Phenobarbitone: Induces synthesis of UDP-glucuronyl transferase.
• Exchange blood transfusion: Removes excess bilirubin.
• Pathological jaundice (within 24 hours of birth or lasting over 10 days) indicates an underlying condition.

Gilbert’s Syndrome

• Most common inherited disorder of bilirubin conjugation, presenting with mild, fluctuating unconjugated hyperbilirubinaemia.
• Onset typically during adolescence due to sex hormone changes.
• Caused by reduced UDP-glucuronyl transferase activity, preventing bilirubin conjugation.
• Often treated with phenobarbitone to stimulate UDP-glucuronyl transferase activity.

Crigler-Najjar Syndrome

• Rare autosomal recessive disorder presenting with severe unconjugated hyperbilirubinemia from birth.
• Caused by mutations in the UDP-glucuronyl transferase gene.
• Type I: Complete absence of the enzyme.
• Type II: Marked reduction in enzyme activity.
• High risk of kernicterus.
• Treatment: Liver transplant (Type I), phenobarbitone or phototherapy (Type II).

Dubin-Johnson Syndrome

• Benign genetic disorder presenting with conjugated hyperbilirubinaemia.
• Presents with mild, recurrent jaundice.
• Caused by a mutation in the gene coding for MRP-2, resulting in impaired biliary secretion of conjugated bilirubin.
• Jaundice can worsen with aggravating factors.
• Treatment: Not usually necessary.