dr vivek joshi, md. heme catabolism commonly occurs in liver and spleen done by...
DESCRIPTION
Steps of Heme Catabolic pathway 3 Formation of Indirect bilirubin Release of Indirect Bilirubin in the Blood Uptake of Indirect bilirubin by the liver parenchymal cells Conjugation of bilirubin in the liver forming bilirubin diglucuronide Secretion of conjugated bilirubin into the bile Formation of urobilinogen and stercobilinogen in the intestineTRANSCRIPT
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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