12- Liver Metabolism and Urea Cycle

Direct Bilirubin

Normal Amount: <0.2 mg/dL

Dissolves in water

Conjugated

Indirect Bilirubin

Normal Amount: <1.0 mg/dL

Insoluble in water

Unconjugated

Hyperbilirubinemia

Above 1.2 mg/dL

Jaundice

Bilirubin >2.0 mg/dL

Icterus

Bilirubin >3.0 mg/dL

Kernicterus

Unconjugated Bilirubin 12-20 mg/dL

Enters CNS, mental retardation, motor issues, brain damage, cerebral palsy

DDX Jaundice Conjugated

Extrahepatic

Intrahepatic

DDX Jaundice Unconjugated

Increased production

Decreased uptake

Decreased conjugation

Neonatal Jaundice

• Pre-Hepatic (hemolysis & decreased conjugation)

• Decreased UDP (decreased conjugation)

• Precipitates in basal ganglia

Causes of Neonatal Jaundice

• ABO Incompatibility

• Breast Milk Jaundice

ABO Incompatibility

• This form of jaundice occurs when there is incompatibility between blood types of the mother and fetus

• This leads to increased bilirubin levels from the breakdown of the fetus red cells (hemolysis)

Breast Milk Jaundice

• This form of jaundice occurs in breastfed newborns and usually appears at the end of the first week of life.

• Certain chemicals in breast milk are thought to be responsible for inhibition of UDP Glucuronyl transferase.

• It is usually a harmless condition that resolves spontaneously

Inherited Disorders of Bilirubin Metabolism

• Gilbert’s Syndrome

• Crigler-Najjar (Type I)

• Crigler-Najjar (Type II)

• Dubin-Johnson

• Rotor’s Syndrome

Crigler-Najjar Syndrome Type I

• Total Serum Bilirubin: 18-45 (>20)

• Unconjugated is high

• Severely defective UDPGT

• Kernicterus in infancy if untreated

• Death in infancy

Crigler-Najjar Syndrome Type II

• Total Serum Bilirubin: 6-25 (<20)

• Unconjugated high

• Conjugation Defective UDPGT

Gilbert’s Syndrome

• Total Serum Bilirubin: <4

• Unconjugated high

• Mild jaundice during illness/stress/fasting

Dubin-Johnson Syndrome

• Conjugated high

• Impaired canalicular export of conjugated bili.

• Liver grossly black!

Rotor’s Syndrome

• Conjugated high

• Impaired canalicular export of conjugated bili.

• Normal Liver!

Hyperammonemia

• Ammonia is highly toxic to the liver

• Normal number is <50µmol /L, and an increase to only 100 µmol /L can lead to consciousness issues

• 200 µmol /L is associated with coma and convulsions

Mitochondria

Cytosol

The first 2 reactions of the urea cycle happen in THIS, the rest in THIS.

Kidneys

Urea from liver is transported to the blood and then to THIS where it is excreted into the urine.