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1
Bilirubin and Jaundice
Pathways of Bilirubin Synthesis and Catabolism
Porphogens
Fe
Heme
Globin
Hgb
+
+
Urobilinogen StercobilinFecalPigments
UrineUrobilinogen
Heme PrecursorsMyoglobinNon-Hgb HemeProteins
ShuntPathwayFree Bilirubin – Albumin Complex
ConjugatedBilirubin
Hgb
Biliverdin
Bilirubin
Fe
Globin
RBCsBone
MarrowReticuloendothelial
System (RES)
2mg
70mg
68mg
2
Labeling of RBC hemoglobin and fecal stercobilin
0.3
0.2
0.1
0.1
0.08
0.06
0.04
0.02
20 40 60 80 100 120 140 160 180
A:
Ato
m %
exc
ess
15N
of
ster
cob
ilin
B:
Ato
m %
exc
ess
15N
of
hae
min
B
A
Times ( days)
Labeling of red cell hemoglobin and fecal stercobilinin a normal human given 15N orally
X
X X
X X X
XX
X
X X
X
X
X
X
Sources of bilirubin production in the rat
Early Bilirubin15%
0-3 Days
Late Bilirubin65%
40-80 Days
Non-HemoglobinSources (liver)
Red CellSenescence
IncreasedErythropoiesis
Sources of bilirubin production in the rat, as adduced from studies of thelabeling of plasma bilirubin in Gunn rats and bile bilirubin in normal rats.
3
NN
N NFe
COO COO
C
NN
N N
OOC COO
OH HO
H H
H
NN
NH N
OOC COO
OH HO
H
NADPH NADP
O2NADPHNADP
Fe (II)O2 CO
Biliverdin
reductase
NADPHNADP
Hemin +
heme-oxygenase complex
hydroxyheme-oxygenase complex
biliverdin
bilirubin
NN
N NFe
COO COO
OH
4
OATP MDR2
(ligandin)
A.
B.
5
N NH
NNHFe
Me
CH
CHCH2
Me
CH2 CH2 CO2H
MeMe
H2C CH2 CH2 CO2H
A B
CD
γ
β
α
δ
NH
NH
NH
CH CH2CH
NH
O
MeCH2MeCHMe Me CH
O
CH2
C
CH2
CH2
CCH2
OO O OO O
OH
OHHO
COOH COOH
OHHO
HOCH2
NH
NH
NH
CH CH2CH
NH
O
MeCH2MeMe Me CH
OA B C D
CHCH2 CH2
CO2H
CH2
CH2
CO2HCH2
A B
C
D
BILIRUBIN - IX α DIGLUCURONIDE
BILIRUBIN – IX α (convoluted structure)
BILIRUBIN – IX α (planar structure)
A.
B.
C.
CO (excreted via lungs)
Fe (reutilized)
HN
HN
NH
NH
C OO
C
C
OO
OO
H
H
HN
HN
NH
NH
C OO
C
C
OO
OO
H
GA
HN
HN
NH
NH
C OO
C
C
OO
O
GA
OGAConjugation prevents
internal H-bonding by the-COOH groups of Bilirubin
BILIRUBINS:
UNCONJUGATED (UCB)
MONO-GLUCURONIDE
(BMG)
DIGLUCURONIDE(BDG)
2
1
BILIRUBIN CONJUGATION IN MICROSOMESINVOLVES TWO STEPS, MEDIATED BY
ONE BILIRUBIN-UDPGA TRANSFERASE
UDPGA
UDP
UDPGA
UDP
UDPGATRANSFERASE
6
OATP MDR2
(=cMOAT)
UROBILINOGENS ARE FORMED BY DECONJUGATION AND REDUCTION OF BILIRUBINS BY INTESTINAL BACTERIA
CONJUGATED BILIRUBIN
UNCONJUGATEDBILIRUBIN
Deconju-gation
A UROBILINOGEN
Reduction
NHN
HH
N HN
COOGA COOGA
M
MV
M VO O
M
NHN
HH
N HN
COOH COOH
M
MV
M VO O
M
NHN
HH
N HN
H2C CH2
COOH COOH
M
ME
M EO O
M
H H
2 GA + 8HM = MethylE = EthylV = Vinyl
7
Slow
Fast
FRACTIONAL DIAZO REACTION OF PLASMA
R R
Directreaction
Indirectreaction
CONJUGATEDBILIRUBIN
UNCONJUGATEDBILIRUBIN
N+
N
SO3H
+
N+
N
SO3H
+
DIA
ZO
RE
AG
EN
T
8
R R
CONJUGATEDBILIRUBIN
UNCONJUGATEDBILIRUBIN
N+
N
SO3H
+ + ACCELERATOR
(ALCOHOL, CAFFEINE)
TOTAL – DIRECT INDIRECT=
TOTAL DIAZO REACTION OF PLASMA
Bilirubinuria in Jaundice
UNCONJUGATED PLASMA BILIRUBIN (B) CONJUGATED
NO BILIRUBIN BILIRUBIN ++
URINE
PLASMA
(A=ALBUMIN)
9
10
Phototherapy for neonatal jaundice
Treatment for Neonatal JaundicePrevention of kernicterus
11
NH
NH
NH
CH CH2CH
NH
O
MeCH2MeMe Me CH
OA B C D
CHCH2 CH2
COOH
CH2
CH2
COOHCH2
NH
NH
NH
CH CH2CH
NH
O
CH2MeMe Me CH
O
CH2
COOHCH2
CH2
CH2
COOH
Me CHCH2
Structure of the α and β isomers of bilirubin IX. In the IXβ isomer (and in the γ and δ isomers, not shown) the propionic acid groups are moved to positions other than those indicated on the central pyrrole rings B and C of bilirubin IXα.
Bilirubin IX α
Bilirubin IX β
2.5
2.0
1.5
1.0
0.5
16
12
8
4
0 8 16 24 0 2 4 6 8 10
LiverCo-PPLiverSn-PP
Hem
e O
xyge
nase
(nm
ol b
ilirub
in/m
g ph
Effect of Sn-protoporphyrin (Sn-PP) and CO-protoporphyrin (Co-PP) when administeredonce at a dose of 50 μmol/kg body wt on hepatic heme oxygenase activity in the rat.
Time(hours) (days)
12
18
16
14
10
-4 0 2 4 0 1 2 3 4 5 6 7
12
2.5
5.0
7.5
10.0
Effect of Sn-protoporphyrin (Sn-PP) (100 μmol/kg body wt) administeredat 4d before and on the day of surgery on hyperbilirubinemia in the
bile-duct-ligated rat. Effect of Sn-PP (2 x 0.25 μmol/kg body wt) on the levels of serum bilirubin in a patient with primary biliary cirrhosis (PBC).
Time (days)
Bile-DuctLigation
RAT PBC(50 )
Sn-PP
Pla
sma
Bilir
ubin
mg/
dl Control
Sn-PP
UGT1 gene
1J 1I 1H 1G 1F 1E 1D 1C 1B 1A 2 3 4 5
5’ 3’
mRNA B-UGT1
Phenol
UGTs
NH2 COOH
enzymesubstrate binding site UDPGA
binding sitemembranespanningregion
285 amino acids 246 amino acids
13
UDPGT promoter A(TA)6TAA
UDPGT nullMutation
Bolivian Squirrel MonkeyGunn ratAnimal Model
BenignKernicterusPrognosis
2-7% of populationRarePrevalence
Increased proportion of monoglucuronide
Small amounts of unconjugatedbilirubin
Pigments in bile
ReductionNo effectEffect of Phenobarbital on plasma bilirubin
30-50% of normalUndetectableHepatic bilirubin-UDPGT activity
Usually normal; elevated in a minority of cases
NormalPlasma BSP retention at 45 min
50-85 μM (fluctuates)340-860 μMPlasma bilirubin
Gilbert SyndromeCrigler-Najjar Type ICharacteristics
Unconjugated Hyperbilirubinemia
MRP2Mutation
BenignBenignPrognosis
RareUncommon (1:1300 in Persian Jews)Prevalence
Autosomal recessiveAutosomal recessiveMode of inheritance
Elevated total; elevated proportion of coproporphyrin I but <80%
Normal total >80% as coproporphyrin IUrinary coproporphyrin
Elevated; no secondary rise at 90 min
Normal or elevated; secondary rise at 90 min45-min plasma BSP retention
Normal except for bilirubinNormal except for bilirubinRoutine liver function tests
Elevated, usually between 2 and 5 mg%, occasionally as high as 20 mg%; predominantly direct-reacting
Elevated, usually between 2 and 5 mg%, occasionally as high as 20 mg%; predominantly direct-reacting
Serum bilirubin
NormalDark pigment; predominantly in centrilobular areas; otherwise normal
Conversion of protoheme (ferroprotoporphyrin IX) to bilirubin IXα. Cleavage of the protoporphyrin ring occurs selectively at the α-methene bridge. The bridge carbon atom is oxidized to carbon monoxide.