HEME CATABOLISM

Dr Vivek Joshi, MD

Heme catabolism

Commonly occurs in liver and spleen Done by reticuloendothelial cells Most of the heme for degradation comes from senescent/old RBCs Rest comes from immature RBC & cytochromes from extraerythroid

tissues

Hemoglobin in RBCs

GlobinHeme

Amino acids

Iron

Porphyrin

May be reused

Degraded

Steps of Heme Catabolic pathway

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Formation of Indirect bilirubinRelease of Indirect Bilirubin in the BloodUptake of Indirect bilirubin by the liver parenchymal cellsConjugation of bilirubin in the liver forming bilirubin diglucuronideSecretion of conjugated bilirubin into the bileFormation of urobilinogen and stercobilinogen in the intestine

Reticuloendothelial system

Carried out by the heme oxygenase system

Substrate inducibleLocated near the

electron transport chain

Requires oxygen and NADPH

Produces biliverdin, CO, iron, NADP+

Green

+

+Red purple

Formation of Indirect bilirubin

Biliverdin reductase acts on biliverdin(green color) converting it into bilirubin(yellowish orange color)

Changing color of the bruise- intermediates.

This bilirubin formed is unconjugated- indirect bilirubin

Yellow orange

Formation of Indirect bilirubin

Requires Albumin for transport Transports bilirubin to the liver from RES Has 2 binding sites for bilirubin

High-affinity site Can accommodate about 25 mg of bilirubin per

100 ml plasma Low-affinity site

Binds bilirubin loosely when exceeds 25 mg/100 ml in plasma

Bilirubin can easily be displaced by anionic drugs(Salicylates and sulfonamides) and diffuse into the CNS- Kernicterus in the newborn

Release of Indirect Bilirubin in the Blood

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Release of Indirect Bilirubin in the Blood

Uptake of Indirect bilirubin by liver parenchymal cells Occurs at the sinusoidal surface of the hepatocytes

Occurs via a facilitated transport system with a very large capacity

Allows the equilibrium of bilirubin across the sinusoidal membrane of the hepatocyte

Dependent upon removal of bilirubin by subsequent metabolic pathways

Gilberts syndrome # Inherited Unconjugated hyperbilirubinemia-AD # Defective uptake of bilirubin -No Conjugation of bilirubin # Mild jaundice

Addition of glucuronic acid to bilirubin converts the non-polar bilirubin to more water-soluble derivatives

Catalyzed by microsomal bilirubin glucuronyltransferase using UDP-glucuronic acid as glucuronate donor

Bilirubin glucuronyltransferase (Can be induced by phenobarbital)

Conjugation of bilirubin in the liver

forming bilirubin diglucuronide

Crigler Najjar- I Crigler Najjar -II

Complete UDP Glucuronyl transferase deficiency

Partial UDP Glucuronyl transferase deficiency

Poor survival Compatible

Inherited Unconjugated hyperbilirubinemia

Secretion into the bile

Occurs by an active transport mechanism

Rate-limiting for the entire process of hepatic bilirubin metabolism

Inducible by the same drugs that are capable of inducing the conjugation of bilirubin

Conjugation and excretion system for bilirubin behave as a functional unit

Dubin –Johnson syndrome

Rotors syndrome

Defect in the excretion of bilirubin in the bile

Defect in the excretion of bilirubin in the bile

Black pigmented liver Liver-No pigmentation

Inherited Conjugated hyperbilirubinemia

Bilirubin diglucuronide

β glucuronidases

Glucuronic acid

BilirubinUrobilinogen Oxidized

to stercobilin

Excreted in feces(250 mg/day ;Brown color

to the stools)

Reabsorbed and reexcreted to the

liver( Enterohepatic urobilinogen

cycle )

Excreted in urine as urobilin(1 mg/day)

Formation of urobilinogen and stercobilinogen in the intestine

Bilirubin is hydrolyzed and reduced by bacteria to yield urobilinogen.

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Bilirubin

Conjugated Bilirubin Unconjugated Bilirubin

Water soluble Soluble in methanol

Can be Present in urine Absent in urine

Excreted in bile Not excreted in bile

0-0.2 mg/dl 0.2-0.6 mg/dl

Total Bilirubin:, 1 .0 mg/dl

Hyperbilirubinemia When bilirubin in blood exceeds 1 mg/dL (17.1

µmol/L)-Hyperbilirubinemia May be due to :

Production of more bilirubin than the normal liver can handle

Failure of a damaged liver to conjugate and excrete bilirubin produced in normal amounts

Obstruction to the excretory ducts of the liver When Serum Bilirubin >2 mg/dl - Jaundice (Icterus)

Jaundice Yellowish discoloration of

skin,nail beds and sclera due to deposition of bilirubin

High Serum bilirubin levels measured by Van den Bergh reaction:

Conj.Bil combines with diazotized sulfanilic acid-Red azobilirubin(Direct positive-Conjugated Bil)

Reaction carried out with methanol- Total bilirubin

Unconjugated Bil –Obtained by substracting total from the conjugated

Hemolytic /Pre Hepatic Jaundice

# Normal Capacity of the Liver to conjugate and excrete bilirubin (3000 mg/day)# Normal bilirubin production (300 mg/day)# Massive lysis of the red blood cells-Bilirubin produced faster than conjugated

Causes for unconjugated hyperbilirubinimia

# Massive hemolysis seen in: Malaria Sickle cell anemia G6PD Deficiency Pyruvate kinase deficiency Hereditary spherocytosis

# Biochemical findings Increased serum unconjugated bilirubin Increased urine urobilinogen Bilirubin absent in urine

Damage to the liver cells leading to Decreased conjugation of bilirubin in the liver/Intra hepatic obstruction-

Rise in unconjugated bilirubin Seen in Cirrhosis / HepatitisPatient has anorexia and vomiting

Bilirubin when conjugated is not efficiently secreted (Intra hepatic obstruction) into the bile- Rise in conjugated bilirubin

Biochemical findings: Increased levels of Unconjugated /conjugated

bilirubin Normal or Decreased urine urobilinogen Bilirubin in urine - Dark colored urine (Intra hepatic

obstruction) Plasma levels of ALT and AST are elevated

Hepatocellular Jaundice

Obstructive jaundiceResults from the obstruction of the bile duct-Blocks the passage of bilirubin into the intestineSeen in case of Hepatic tumor/Bile stones or strictureBiochemical findings

Increased conjugated bilirubin in the blood Complete obstruction of the bile duct -No

urobilinogen in urine and stercobilinogen in faeces (Pale, clay

colored Stools)Bilirubin present in the urine (Liver “regurgitates”

conjugated bilirubin into the blood which is excreted into the urine

Prolonged obstruction of bile duct can lead to liver

damage and a subsequent rise in unconjugated bilirubin

Physiological Jaundice 2nd -3rd day of birth Unconjugated

hyperbilirubinemia seen in premature babies

Transient condition Results from an

accelerated hemolysis and an immature hepatic system for the uptake, conjugation, and secretion of bilirubin

UDP-glucuronyl transferase activity is low in newborns and specially in premature babies

Jaundice of the newborn

Pathological Jaundice Rise in Unconjugated

bilirubin concentration in plasma (>25 mg/dl)

Bilirubin is bound to low affinity binding site of albumin-Easily removed

Can penetrate the blood-brain barrier and cause kernicterus (Deposition of bilirubin in the brain leading to neurologic sequelae)

Seen in cases of Rh /ABO incompatibility/Hereditary spherocytosis

Jaundice of the newborn

Jaundice of the newborn

Treatment- Blue fluorescent light (phototherapy) which converts bilirubin to more polar, water-soluble isomers which can be excreted without conjugation to glucuronic acid

Jaundice of the newborn

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