This document discusses pathophysiology of jaundice. It begins by defining jaundice as a yellowish discoloration of tissues caused by bilirubin deposition. Jaundice can be caused by liver disease or hemolytic disease leading to hyperbilirubinemia. The document then discusses the classification, causes, clinical features and metabolic pathways involved in different types of jaundice including prehepatic (hemolytic), hepatic, and obstructive jaundice. It also summarizes various congenital hyperbilirubinemias like Crigler-Najjar syndrome, Gilbert's syndrome and Dubin-Johnson syndrome.
2. Introduction….
Jaundice (french: Jaune-Yellow) or icterus
Is a yellowish discolouration of tissue resulting
from the deposition of bilirubin .
Tissue deposition of bilirubin occurs only in the
presence of serum hyperbilirubinemia is a sign of
either liver disease or a hemolytic disease.
( Reference : Harrisons textbook of medicine/16th ed/vol.1 /238-240)
3. Carotenemia and use of the drug Quinacrine are few other
causes of yellow coloration of tissue .
Carotenemia can be distinguished from jaundice by sparing
of sclera.
In 4-37% patients treated with Quinacrine , yellowish
discolouration of skin is seen .
Unlike carotenemia ;quinacrine can cause discolouration of
sclera.
4. Slight increase in serum bilirubin are best detected by
examining the Sclera as sclera is rich in elastin and the
bilirubin has high affinity for the elastin .
The normal plasma concentration of bilirubin is less
than 21 μmol/L (1.2 mg/dL).
The presence of scleral icterus indicates a serum
bilirubin of atleast 3.0 mg/dl.
(Reference: Harrisons textbook of medicine/16thed/vol.1 /238-240)
5. Under steady state normal metabolic conditions
about 3.9 mg/kg or 250 to 350 mg of bilirubin is
produced each day from breakdown of Haem from
RBC in spleen and liver.
1gm of hemoglobin yields 36.2 mg of bilirubin .
Reference :API textbook of Medicine/7th ed/page-580.
7. The breakdown of haeme produces bilirubin (an
insoluble waste product) Bilirubin must be made water
soluble to be excreted. This transformation can be
studied in 5 broad steps;-
1. Heme degradation & Formation of bilirubin
2. Plasma transport
3. Liver uptake & Conjugation
4. excretion of bilirubin
5. Formation and excretion of urobilinogen
8. Reference : Bilirubin metabolism: Applied physiology : X. Wang et al: Current
Paediatrics (2006) 16, 70–74
Heme degradation & Formation of bilirubin
9. Reference: Harrison’s Internal Medicine/17thed/fig:297-1:
Hepatocellular bilirubin transport : Albumin-bound bilirubin in sinusoidal blood passes
through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both
facilitated and simple diffusional processes. Within the cell it is bound to glutathione-S-transferases
and conjugated by bilirubin-UDP-glucuronosyltransferase (UGT1A1) to mono- and diglucuronides,
which are actively transported across the canalicular membrane into the bile
ABBREVIATIONS :
ALB: albumin
UCB :unconjugated bilirubin
UGT1A1: bilirubin-UDP
glucuronosyltransferase
BMG: bilirubin monoglucuronide
GST: glutathione-S-transferase
MRP2: multidrug resistance–
associated protein 2
BDG : bilirubin diglucuronide
BT :proposed bilirubin transporter
12. Van Den Berg test
It is helpful in determining the type of bilirubin present in
serum.
normal serum gives a negative van den berg test.
When diazo reagent is added to serum containing
conjugated bilirubin (water soluble) a purple coloration is
obtained within 30 seconds .This is called Direct positive
van den berg reaction.
It is performed using the diazo reagent (mixture of
sulphanilic acid , hydrochloric acid and sodium nitrite).
13. When diazo reagent is added to serum containing
mainly unconjugated biluruibin (water insoluble ), no
colour is obtained but with addition of solvent like
alcohol , purple colouration is obtained .This is
Indirect positive van den berg reaction .
14. If the serum contains both unconjugated and
conjugated bilirubin in high concentration the
purple color is produced immediately (direct
positive) which is further intensified by the
addition of alcohol (indirect positive).
This type of reaction is known as biphasic.
Reference for van den berg test : Biochemistry : U.Satyanarayan
:Elseveir: 4rth ed:chap 20/Pg 455
17. 4. Congenital Hyperbilirubinemia :
A. Unconjugated :
1. Disturbance of bilirubin transport : Gilbert syndrome
2. Disturbance of bilirubin conjugation: Crigler Najjar
Syndrome.
B. Conjugated :
Distrubance in excretion of Bilirubin : Dubin Johnson
syndrome , Rotor’s Syndrome
Reference: Practical Medicine : P.J .Mehta /16th ed/18-19
18. Van den
berg test
Indirect positive
reaction
Biphasic reaction Direct positive
reaction
Mechanism
of Production
Excessive
breakdown of RBCs
producing
unconjugated
bilirubin in the
amounts more than
the healthy liver can
conjugate and
excrete.
Inability of liver to
efficiently
conjugate and
transport bilirubin
into the bile due to
liver cell damage .
Obstruction of the bile
ducts so conjugated
bilirubin can’t flow
through the biliary
tract freely resulting in
increased serum
conjugated bilirubin.
Type of
serum
bilirubin
accumulated
unconjugated
hyperbilirubenemia.
Both unconjugated
& conjugated
bilirubin is
increased in serum
conjugated
hyperbilirubenemia.
Hemolytic Jaundice
(Prehepatic)
Hepatic Jaundice Obstructive Jaundice
(Post hepatic)
19. Urine
urobilinogen
Increases
(liver excrete lot of
conjugated bilirubin in the
intestine with the bile so
more urobilinogen is
formed part of it is
reabsorbed and goes to
general circulation thus
urine urobilinogen is
increased.)
Decreases
(Damaged liver
cells produce &
excrete less of
conjugated
bilirubin so less
urobilinogen is
formed.)
Markedly
decreased/absent
(due to
obstruction,
conjugated
bilirubin is not
released into the
intestine thus no
urobilinogen is
formed.
Hemolytic Jaundice
(Prehepatic)
Hepatic Jaundice Obstructive
Jaundice
(Post hepatic)
Urine
Bilirubin
Absent
(Unconjugated bilirubin is
water insoluble
transported in plasma in
bound form with albumin
.Since albumin is not
filtered in urine
,unconjugated is too not
filtered into urine so this
is called Acholuric
Jaundice.)
Present
(conjugated
bilirubin is water
soluble and
present in plasma
in dissolved form
and gets filtered
in urine , such
jaundice is
called choluric
jaundice)
Present
(Since
conjugated
bilirubin is
filtered in urine)
20. Hemolytic
Jaundice
(Pre hepatic)
Hepatic
Jaundice
Obstructive
Jaundice
(Post hepatic)
Faecal
Fat level
normal
(as bile is
present in gut
for normal
digestion of fat )
Increased
(bile deficiency in the
intestine so
emulsification and
absorption of fat is
inadequate thus
producing bulky ,pale
greasy and foul smelling
faeces called
steatorrhoea )
Increased
Faecal
Stercobilinogen
markedly
increased
reduced Absent
Peripheral
blood film
Anemia
,reticulocytosis
Normal Normal
22. Clinical
characterstics
Hemolytic
Jaundice
(Pre hepatic)
Hepatic
Jaundice
Obstructive
Jaundice
(Post hepatic)
Pruritis Absent Transient Marked
Tender Liver Absent May be present Absent
Spleen Present may be present Absent
Gall bladder Not Palpable Not Palpable May be Palpable
Urine colour Normal Deep yellow Deep yellow
stool colour Dark brown
coloured stool
Pale faeces Clay coloured
stool
Reference :PJ Mehta : Practical Medicine :16th ed : Page 20 & Indu
Khurana :Textbook of Physiology :Table 3.2-3 Page.161.
23. FIG.20.1 (A) Normal Bilirubin Metabolism (B) alterations in bilirubin
metabolism along with enzymes in 3 types of jaundice.
Note: RED-changes in hemolytic jaundice . Green – changes in hepatic
jaundice . Blue – changes in obstructive jaundice
Reference : Biochemistry :U.Satyanarayan:fig.20.1/chap20/457
24. Crigler-Najjar Syndrome (Type I)
Is a rare genetic disorder and is caused by complete
absence of UDP-glucuronyltransferase (UGT1A1)
It is inherited as an autosomal recessive trait.
Severe hyperbilirubenemia develops within the first 72
hours of life.
Serum bilirubin levels are >30 mg/dl resulting into
kernicterus .
25. Management is by repeated exchange transfusion
and phototherapy to keep the serum bilirubin <20
mg/dl .
There is no response to the treatment of
phenobarbitone
Liver transplantation is an efficacious therapy and it
requires life-long immune suppression .
Reference :Ghai essential pediatrics/6th ed/170-73
26. Crigler-Najjar Syndrome (Type II)
Is a rare autosomal dominant disorder.
It is characterized by partial deficiency of UDP-
glucuronyltransferase.
Unconjugated bilirubin is usually < 20 mg/dl.
Unlike Crigler-Najjar Type I, Type II responds
dramatically to Phenobarbital & a normal life can be
expected.
28. Is benign, often familial condition characterized by recurrent
but asymptomatic mild unconjugated hyperbilirubinemia in the
absence of haemolysis or underlying liver disease.
If, it becomes apparent, it is not until adolescence and then
usually in association with stress such as intercurrent illness,
fasting or strenuous exercise.
There is decreased level of UDP Glucuronosyl transferase,
also there is evidence for a defect in hepatic uptake of bilirubin
Gilbert syndrome
29. Hyperbilirubinemia is mild .Serum bilirubin concentrations <3
mg/dL although both higher and lower values are frequent.
Diagnosis of Gilbert syndrome can be made in the
presence of :
1.Unconjugated hyperbilirubinemia noted on several occasions
2.Normal results on CBC, reticulocyte count, and blood smear
3.Normal liver function test results; and absence of other
disease processes.
Reference: A case report of Gilbert Syndrome:Manandhar SR:Kathmandu
University Medical Journal (2003) Vol. 1, No. 3, 187-189
30. Dubin Johnson Syndrome
Autosomal recessive
Defective excretion of conjugated bilirubin
Conjugated bilirubin in blood is increased
Mutation in MRP-2 protein responsible for transport
of conjugated bilirubin in bile.
Bilirubin deposits in liver and liver appears black
The condition is referred to as Black liver jaundice.
Reference:Textbook of Biochemistry:D.M Vasudevan:7th ed:Page279-280
31. Rotor Syndrome
Similar condition but the exact defect is not identified
Bilirubin excretion is defective
No staining of liver
Autosomal recessive
Reference:Textbook of Biochemistry:D.M Vasudevan:7th ed:Page279-280
34. Physiological jaundice of new born
Appears after 24 hours
Maximum intensity by 4th-5th day in term & 7th
day in preterm
Serum level less than 15 mg / dl
Clinically not detectable after 14 days
Note: Baby should, however, be watched for
worsening jaundice.
35. 1.Excessive destruction of RBC occurs in first few days after
birth causing increase in serum bilirubin.
Mechanism of production of Physiological Jaundice
2. Hepatic immaturity in first few (7-10 ) days after birth also
contributes to increased serum bilirubin .
In the fetus bilirubin produced is cleared by the placenta
and eliminated by the maternal liver.
Immediately after birth, the neonatal liver must assume
responsibility for bilirubin clearance and excretion but it
takes 7-10 days to mature.
36. Levels of UGT1A1 are low, and alternative excretory
pathways allow passage of unconjugated bilirubin into the
gut.
The intestinal flora that convert bilirubin to urobilinogen are
also undeveloped, an enterohepatic circulation of
unconjugated bilirubin ensues.
As a consequence, most neonates develop mild
unconjugated hyperbilirubinemia .
Reference: Harrison's Internal Medicine /17th ed/Chapter 297 and Ghai essential
pediatrics/6th ed/170-71 and Indu Khurana Textbook of Physiology /section 3/162
37. It is presumed to be due to inhibitory substances in the
breastmilk that interfere with bilirubin conjugation like
preganaediol and free fatty acids.
Breastmilk Jaundice
Reference: Ghai essential pediatrics/6th ed/170-71
Temporary interruption of breastmilk feed reduces the
serum levels of bilirubin.
A bilirubin level of over 20 mg/dl may be attained.
Few babies exclusive breast feed develop jaundice in 2nd
week of life and may continue in 3rd month.
38. Pathological jaundice in newborns
Appears within 24 hours of age
Increase of bilirubin > 5 mg / dl /24 hrs
Total Serum bilirubin > 15 mg /dl
Direct bilirubin > 2 mg /dl
Reference: Ghai essential pediatrics/6th ed/170-71
39. Increased production
1.Fetomaternal blood group incompatibility :Rh ,ABO
2.Hereditary spherocytosis
3.G6PD deficiency , vitamin K induced hemolysis
4.Sepsis
5.Increased enterohepatic circulation : pyloric stenosis or
large bowel obstruction
Decreased clearance
Criggler-najjar syndrome type I and II
Causes of unconjugated hyperbilirubinemia
Reference: Ghai essential pediatrics/6th ed/170-71
40. This condition results from incompatibility betweeen
maternal and fetal blood groups.
Rh+ve fetus may produce antibodies in Rh -ve mother
In Rh incompatibility first child often escapes and
subsequent child would be affected .
Sometime the child is born with severe hemolytic disease
often referred to as erythroblastosis foetalis.
When blood level is more than 20 mg/dl the capacity of
albumin to bind bilirubin is exceded.
Hemolytic Jaundice in Newborn
41. In young children before the age of 1 year the blood brain
barrier is not fully matured and free bilirubin enters the
brain(kernicterus) deposited in brain leading to convulsions
, toxic encephalitis and spasticity.
Treatment :
Exchange transfusion along with phototherapy and
barbiturates.
Phototherapy with blue light(440nm) isomerise insoluble
bilirubin to soluble isomers,can be excreted through urine
without conjugation.
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Notes de l'éditeur
Carotenemia and use of the drug Quinacrine are few other causes of yellow coloration of tissue .Carotenemia can be distinguished from jaundice by sparing of sclera. In 4-37% patients treated with Quinacrine , yellowish discolouration of skin is seen .Unlike carotenemia quinacrine can cause discolouration of sclera.
Slight increase in serum bilirubin are best detected by examining the Sclera as Sclera is rich in ELASTIN and the bilirubin has high affinity for the elastin
other organ rich in elastin is ear drum, which also is yellow during jaundince..
The normal plasma concentration of bilirubin is less than 21 μmol/L (1.2 mg/dL)
The presence of scleral icterus indicates a serum bilirubin of atleast 3.0 mg/dl. (Harrisons textbook of medicine/16th ed/vol.1 /238-240)
Under steady state normal metabolic conditions about 3.9 mg/kg or 250 to 350 mg of bilirubin is produced each day from breakdown of haem from rbc in spleen and liver.
1gm of hemoglobin yields 36.2 mg of bilirubin .(API textbook of Medicine/7th ed/page-580.)