of 17
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
1/17
BLOCK 11
Physiology of Bilirubin Metabolism
dr. Andreanyta Meliala, Ph.D
Dept Of Physiology
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
2/17
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
3/17
Extravascular Pathway for RBC Destruction
(Liver, Bone marrow,& Spleen)
Hemoglobin
Globin
Amino acids
Amino acid pool
Heme Bilirubin
Fe2+
Excreted
Phagocytosis & Lysis
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
4/17
Handling of Free (Intravascular) Hemoglobin
Purposes: 1. Scavenge iron2. Prevent major iron losses
3. Complex free heme (very toxic)
Haptoglobin: hemoglobin-haptoglobin complex is readilymetabolized in the liver and spleen forming an iron-globincomplex and bilirubin. Prevents loss of iron in urine.
Hemopexin: binds free heme. The heme-hemopexin complex
is taken up by the liver and the iron is stored bound toferritin.
Methemalbumin: complex of oxidized heme and albumin.
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
5/17
DEGRADATION OF HEME TO BILIRUBIN
P450cytochrome
75% is derived from RBCs
In normal adults thisresults in a daily load of
250-300 mg of bilirubinNormal plasmaconcentrations are less then1 mg/dL
Hydrophobic transportedby albumin to the liver forfurther metabolism prior toits excretion
unconjugated bilirubin
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
6/17
NORMAL BILIRUBINMETABOLISM Uptake of bilirubin by the liver is mediated bya carrier protein (receptor)
Uptake may be competitively inhibited byother organic anions
On the smooth ER, bilirubin is conjugated withglucoronic acid, xylose, or ribose
Glucoronic acid is the major conjugate -catalyzed by UDP glucuronyl tranferase
Conjugated bilirubin is water soluble and issecreted by the hepatocytes into the biliarycanaliculi
Converted to stercobilinogen (urobilinogen)(colorless) by bacteria in the gut
Oxidized to stercobilin which is colored
Excreted in feces
Some stercobilin may be re-adsorbed by thegut and re-excreted by either the liver orkidney
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
7/17
HYPERBILIRUBINEMIA
Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when
there is an imbalance between its production and excretionRecognized clinically as jaundice
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
8/17
Prehepatic (hemolytic) jaundice
Results from excessproduction of bilirubin (beyondthe livers ability to conjugateit) following hemolysis
Excess RBC lysis is commonly
the result of autoimmunedisease; hemolytic disease ofthe newborn (Rh- or ABO-incompatibility); structurallyabnormal RBCs (Sickle celldisease); or breakdown of
extravasated blood
High plasma concentrations ofunconjugated bilirubin (normalconcentration ~0.5 mg/dL)
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
9/17
Intrahepatic jaundice
Impaired uptake,
conjugation, or secretionof bilirubin
Reflects a generalized
liver (hepatocyte)dysfunction
In this case,hyperbilirubinemia is
usually accompanied byother abnormalities inbiochemical markers ofliver function
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
10/17
Posthepatic jaundice
Caused by an obstruction ofthe biliary tree
Plasma bilirubin is conjugated,and other biliary metabolites,such as bile acids accumulate in
the plasma
Characterized by pale coloredstools (absence of fecalbilirubin or urobilin), and darkurine (increased conjugatedbilirubin)
In a complete obstruction,urobilin is absent from theurine
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
11/17
Diagnoses of Jaundice
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
12/17
Neonatal Jaundice Common, particularly in premature infants
Transient (resolves in the first 10 days)
Due to immaturity of the enzymes involved in bilirubin conjugation
High levels of unconjugated bilirubin are toxic to the newborn due to itshydrophobicity it can cross the blood-brain barrier and cause a type of
mental retardation known as kernicterus
If bilirubin levels are judged to be too high, then phototherapy with UVlight is used to convert it to a water soluble, non-toxic form
If necessary, exchange blood transfusion is used to remove excess bilirubin
Phenobarbital is oftentimes administered to Mom prior to an induced laborof a premature infant crosses the placenta and induces the synthesis ofUDP glucuronyl transferase
Jaundice within the first 24 hrs of life or which takes longer then 10 daysto resolve is usually pathological and needs to be further investigated
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
13/17
Causes of Hyperbilirubinemia
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
14/17
Benign liver disorder
of the affected individuals inherited it
Characterized by mild, fluctuating increases in
unconjugated bilirubin caused by decreased abilityof the liver to conjugate bilirubin oftencorrelated with fasting or illness
Males more frequently affected then females
Onset of symptoms in teens, early 20s or 30s
Can be treated with small doses of phenobarbital
to stimulate UDP glucuronyl transferase activity
Gilberts Syndrome
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
15/17
Autosomal recessive
Extremely rare < 200 cases worldwide gene frequency is < 1:1000
High incidence in the plain people of Pennsylvania (Amish andMennonites)
Characterized by a complete absence or marked reduction inbilirubin conjugation
Present with a severe unconjugated hyperbilirubinemia thatusually presents at birth
Afflicted individuals are at a high risk for kernicterus
Condition is fatal when the enzyme is completely absent
Treated by phototherapy (10-12 hrs/day) and liver transplant by
age 5
Crigler-Najjar Syndrome
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
16/17
Characterized by impaired biliarysecretion of conjugated bilirubin
Present with a conjugatedhyperbilirubinemia that is usually mild
Dubin-Johnson and Rotors Syndromes
8/12/2019 ORYN Heme Degradation and Hyperbilirubinemias
17/17
Regulation of iron metabolism
