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What is Bilirubin?
Is a bile pigment
Is lipid soluble
Is a product of heme metabolism
Metabolisme Heme
Hemoglobin 80%
O2
Myoglobin
Cytochrome P450s
Hemoproteins
Heme
Fe3+ + CO
Heme
Oxygenase
NADP+
NADPH + H+
Biliverdin
Macrophage of the
reticuloendothelial system at
spleen
Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).
Biliverdin
Reductase
Bilirubin
Hepa
r
Blood
Hepatic Cell
Bile
Alb
B
?
Alb
B + GST
B :GST
B + UDPGA
UGT1A1
CB
sER
Alb = albumin
B = bilirubin
GST = glutathione-S-transferase
UDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubin
UGT1A1 = UDP-glucuronosyltransferase 1A1
MRP2 = Multi-drug Resistance Protein 2
Adapted from Harrisons 15th Ed. Principles of Internal Medicine, 2001.
MRP2
Bilirubin Excretion
Liver
Enterohepatic
circulation
CB
Bile
CB
B-glucoronidase
Bacteria usus
Intestines
Bacteria
Urobilinogen ox
Stercobilinogen
Urobili
n
Stercobilin
feces
Bilirubin Excretion
Liver
CB
Kidney
Enterohepatic
circulation
Bile
B-glucoronidase
CB
Urobilinogen
bacteria
bacteria
Urobilinogen
ox
Urobili
n
Urine
ox
Urobilin
Stercobilingogen Stercobilin
Intestines
feces
NORMAL BILIRUBIN
METABOLISM
Hyperbilirubinemia
Interferences at any one of the points of
bilirubin processing described above can lead
to a condition known as
HYPERBILIRUBINEMIA.
As the name implies this disease is
characterized by abnormally elevated levels of
bilirubin in the blood.
HYPERBILIRUBINEMIA
Intrahepatic jaundice
Impaired uptake,
conjugation, or secretion
of bilirubin
Reflects a generalized
liver (hepatocyte)
dysfunction
In this case,
hyperbilirubinemia is
usually accompanied by
other abnormalities in
biochemical markers of
liver function
Posthepatic jaundice
Caused by an obstruction of the
biliary tree
Plasma bilirubin is conjugated,
and other biliary metabolites,
such as bile acids accumulate in
the plasma
Characterized by pale colored
stools (absence of fecal bilirubin
or urobilin), and dark urine
(increased conjugated bilirubin)
In a complete obstruction,
urobilin is absent from the urine
Diagnoses of Jaundice
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 its
hydrophobicity it can cross the blood-brain
barrier and cause a type of mental
retardation known as kernicterus
Neonatal Jaundice
If bilirubin levels are judged to be too high, then
phototherapy with UV light 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 labor of a premature infant crosses the placenta and
induces the synthesis of UDP glucuronyl transferase
Jaundice within the first 24 hrs of life or which takes longer
then 10 days to resolve is usually pathological and needs to be
further investigated
Causes of Hyperbilirubinemia
SYMPTOMS
o Yellowing of the skin, scleras (white of the eye), and
mucous membranes (jaundice)
o Detectable when total plasma bilirubin levels exceed
2-3mg/100mL
AHHH!!! I have symptoms
of hyperbilirubinemia!!!
Causes:
1.
2.
3.
4.
5.
Increased bilirubin
production
Reduced bilirubin uptake
by hepatic cells
Disrupted intracellular
conjugation
Disrupted secretion of
bilirubin into bile
canaliculi
Intra/extra-hepatic bile
duct obstruction
Lead to increases in
free (unconj.) bilirubin
1)
Other
2)
Plasma
Alb
Bile
B
B + GST
Alb
B :GST
B + UDPGA
CB
UGT1A1
sER
MRP2