Bilirubin Overview and Metabolism

Bilirubin Overview

• Bilirubin is a byproduct of heme metabolism.
• It's produced in the liver.
• It's stored in the gallbladder.
• It's secreted into the duodenum after a meal.
• Primarily composed of water, phospholipids, and electrolytes.
• Bile salts are crucial for lipid absorption.
• Bilirubin is the body's method of excreting waste.
• It's a brown/yellow color.

Bilirubin Metabolism

• Heme is released from aged red blood cells and myoglobin, and cytochromes.
• Macrophages process residual heme.
• The heme is converted to biliverdin then to bilirubin.

Bilirubin in Blood

• Bilirubin has poor water solubility.
• It's transported through the bloodstream by albumin to the liver.

Bilirubin Conjugation in the Liver

• The liver conjugates bilirubin with glucuronic acid.
• UDP-glucuronyltransferase adds glucuronic acid to bilirubin, making it more soluble in water.
• Bilirubin monoglucuronide and bilirubin diglucuronide are water-soluble compounds.
• Increased water solubility allows excretion with bile.

Bilirubin Metabolism in the Intestines

• Bacteria convert bilirubin back to unconjugated bilirubin in the intestines.
• Enzymes called beta-glucuronidase facilitate this conversion.
• Unconjugated bilirubin is converted to urobilinogen.
• This takes place in the distal small intestine and colon.

Urobilinogen Fate

• Urobilinogen is excreted in feces (~80-90%); converted to stercobilin, which makes stool dark.
• A smaller portion (10-20%) is reabsorbed by the intestines.
• Most is taken up by the liver.
• A small amount is excreted in urine; converted to urobilin, which makes urine yellow.

Clinical Measurements of Bilirubin

• Van den Bergh reaction: Coupling bilirubin with a diazonium salt to form a colored complex.
• Serum conjugated bilirubin is water-soluble and can undergo the reaction directly.
• Serum unconjugated bilirubin is not water-soluble and must be mixed with alcohol before reacting.
• Urine bilirubin (conjugated only) is normally absent.
• Urine urobilinogen is typically present in small amounts.

Jaundice

• Jaundice is characterized by yellowing skin, conjunctiva, and mucous membranes.
• Scleral icterus (yellowing of the whites of the eyes) is often the first sign.
• Visible early in the area under the tongue.
• Normal total bilirubin is <1.0 mg/dL.
• Jaundice usually occurs when total bilirubin is >3.0 mg/dL.

Dark Urine

• Dark urine is associated with elevated conjugated bilirubin, which is water-soluble.
• Other causes of dark urine include rhabdomyolysis, hematuria, and dehydration.

Bilirubin Metabolism Clinical Assessment

• Serum bilirubin (total, direct, indirect)
• Urine urobilinogen
• Urine bilirubin (conjugated)

Hyperbilirubinemia

• This is an excess of bilirubin in the blood
• Possible causes include hemolysis, biliary obstruction, and liver disease.

Hyperbilirubinemia - Hemolysis

• ↑ heme from breakdown of RBCs.
• ↑ unconjugated bilirubin.
• No urine bilirubin (conjugated).
• Increased urine urobilinogen.

Hyperbilirubinemia - Biliary Obstruction

• Lack of bile flow (cholestasis).
• Extrahepatic (outside the liver): Gallstones, pancreatic mass.
• Intrahepatic (within the liver): Alcoholic liver disease, viral hepatitis.
• ↑ direct bilirubin.
• Clay-colored stools (lack of stercobilin).
• ↑ urine bilirubin.
• Absent urobilinogen.

Hyperbilirubinemia - Primary Liver Diseases

• Unconjugated hyperbilirubinemia: Significant damage to hepatocytes (liver cells). Chronic hepatitis, advanced cirrhosis.
• Conjugated hyperbilirubinemia: Damage to bile ducts. Viral hepatitis, alcoholic hepatitis, NASH.

Special Causes of Hyperbilirubinemia

• Rifampin/Probenecid: Competition for liver uptake; mild ↑unconjugated bilirubin.
• Gilbert's syndrome: ↓ UDP-glucuronyltransferase function; mild ↑ unconjugated bilirubin.
• Crigler-Najjar syndrome (type I and II): Severely reduced/absent UGT enzyme; ↑ unconjugated bilirubin.
• Dubin-Johnson syndrome: Defective liver excretion of conjugated bilirubin; ↑ conjugated bilirubin; black liver.
• Rotor's syndrome: Similar to Dubin-Johnson but without a black liver; milder.
• Neonatal jaundice: ↓ UDP-glucuronyltransferase enzyme activity in newborns leading to ↑unconjugated bilirubin.

Neonatal Jaundice Treatment

• Phototherapy exposes skin to specific wavelengths, converting bilirubin to lumirubin, which is more water-soluble and excreted easily.

Bilirubin Algorithm

• This is a diagnostic flowchart to determine the kind of bilirubin problem.