Jaundice

Definition
Accumulation of yellow pigment in
the skin and other tissues (Bilirubin)

Bilirubin Metabolism

Bilirubin formation

Transport of bilirubin in plasma

Hepatic bilirubin transport

Hepatic uptake

Conjugation

Biliary excretion

Enterohepatic circulation

Bilirubin formation
RBCs
Chiefly
70+%

Bilirubin

120ds

Senecent RBCs

Iron
hemoglobin
Globin

R
C
Bilirubin CBR
Biliverdin MHO
heme
20%

nonhemoglobin heme
Hepatic Hemoproteins nonhemoglobin hemoprotein

1-5%

Premature destruction of newly formed RBCs

Transport of Bilirubin in Plasma

Albumin + UB

UB ~ Albumin Complex

H affinity binding sites

2:1

Bilirubin

Molar
Ratio
>2:1

L affinity binding sites

Plasma protein
Albumin

Bilirubin
can be replaced by

Other organic anions

PH

UB

Hepatic Bilirubin Transport

1. Hepatic uptake of Bilirubin
UCB~Albumin Complex Separated
Bilirubin

(be) taken up
MTA (receptor ?)

Plasma membrane of the liver

2.Conjugation of Bilirubin
ligation (Y protein)

UCB

(lipid soluble)

Transfer across
Microvillar membrane

ER
Conjugation
(catalized by
UDPGT)

Z protein

3.Biliary Excretion of Bilirubin

CB

transfer

carrier
protein

(be) bound to

CB

CBGA

(water soluble)

Bile canaliculus

 UDPGT: Uridine Diphosphate Glucuronyl

Transferase
UCB: because of its tight albumin binding
and lipid solubility, it is not excreted in
urine.
CB: is less tightly bound to albumin and is
water soluble, so it is filtered at the
glomerulus and appears in the urine.

Entero-hepatic circulation
CB

mostly

B and I

be degraded
Bacterial Enzymes

feces (feceal urobilinogens)

90%

20%

Urobilinogens (coloress)

Reabsorbed

50-200 mg/d
liver

re-excreted

Bile

excreted

feces

plasma
trace

4 mg/d

circulation

kidneys
urine urobilinogen

The serum of normal adults contains 1 mg of bilirubin per 100 ml.

In healthy adults

The direct fraction is usually <0.2 mg/100 ml

The indirect fraction is usually <0.8 mg/100 ml

Pathophysiologic classification of
Jaundice

Hemolytic Jaundice

Hepatic Jaundice

Obstructive Jaundice(Cholestasis)

Congenital Jaundice

Jaundice classification
predominantly unconjugated
hyperbilirubinaemia
predominantly conjugated
hyperbilirubinaemia

Hemolytic Jaundice
Pathogenesis

Overproduction
Hemolysis (intra and extra vascular)

inherited or genetic disorders

acquired immune hemolytic anemia
(Autoimmune hemolytic anemia)
nonimmune hemolytic anemia
(paroxysmal nocturna Hemoglobinruia)

Ineffective erythropoiesis

Overproduction may overload the liver with UB

Hemolytic Jaundice
Symptoms
weakness, Dark urine, anemia,
Icterus, splenomegaly

Lab

UB without bilirubinuria
fecal and urine urobilinogen
hemolytic anemia
hemoglobinuria (in acute intravascular
hemolysis)
Reticulocyte counts

Hemolytic Jaundice
(pre-hepatic)

Serum / blood:
bilirubin (micormoles/l) 50-150; normal
range 3-17
AST I.U. < 35; normal range <35
ALP I.U. <250; normal range <250
gamma GT I.U. 15-40; normal range
15-40
albumin g/l 40-50; normal range 40-50
reticulocytes(%) 10-30; normal range
<1
prothrombin time (seconds) 13-15;
normal range 13-15

Hemolytic Jaundice
(pre-hepatic)

urinary changes:
bilirubin: absent
urobilinogen: increased or
normal
faecal changes:
stercobilinogen: normal

Obstructive Jaundice
Pathogenesis
it is due to intra- and extra hepatic
obstruction of bile ducts
intrahepatic Jaundice: Hepatitis, PBC,
Drugs
Extra Hepatic Biliary Obstruction:
Stones, Stricture, Inflammation, Tumors,
(Ampulla of Vater)

Etiology of Obstructive
Jaundice
Intrahepatic-Liver cell Damage/Blockage of
Bile Canaliculi

Drugs or chemical toxins

Dubin-Johnson syndrome
Estrogens or Pregnancy
Hepatitis-viral,chemical
Infiltrative tumors
Intrahepatic biliary hypoplasia or atresia
Primary biliary cirrhosis

Etiology of Obstructive
Jaundice
Extrahepatic-Obstructive of bile Ducts
Compression obstruction from tumors
Congenital choledochal cyst
Extrahepatic biliary atresia
Intraluminal gallstones
Stenosis-postoperative or inflammary

cholestasis
clinical features
pain, due to gallbladder
disease, malignancy, or
stretching of the liver capsule
fever, due to ascending
cholangitis
palpable and / or tender
gallbladder
enlarged liver, usually smooth

General signs of cholestasis

xanthomas: palmar creases, below the
breast, on the neck. They indicate
raised serum cholesterol of several
months. Xanthomas on the tendon
sheaths are uncommonly associated
with cholestasis.
xanthelasma on the eyelids
scratch marks: excoriation
finger clubbing
loose, pale, bulky, offensive stools
dark orange urine

Obstructive Jaundice
Lab Findings

Serum Bilirubin
Feceal urobilinogen (incomplete obstruction)
Feceal urobilinogen absence (complete obstruction)
urobilinogenuria is absent in complete obstructive
jaundice
bilirubinuria
ALP
cholesterol

Obstructive Jaundice
extrahepatic

serum / blood
bilirubin (micromoles/l) 100-500;
normal range 3-17
AST I.U. 35-400; normal range <35
ALP I.U. >500; normal range <250
gamma GT I.U. 30-50; normal range
15-40
albumin g/l 30-50; normal range 40-50
reticulocytes(%) <1; normal range <1
prothrombin time (secs) 15-45; normal
range 13-15
( " + parenteral vitamin K) falls

Obstructive Jaundice
extrahepatic

urinary changes
bilirubin: increased
urobilinogen: reduced or absent
faecal changes
stercobilinogen: reduced or
absent

Hepatic Jaundice
Due to a disease affective hepatic
tissue either congenital or acquired
diffuse hepatocellular injury

Hepatic Jaundice

Pathogenesis
Impaired or absent hepatic conjugation of bilirubin

decreased GT activity (Gilberts syndrome)

hereditary absence or deficiency of UDPGT (Grigler-Najjar
Syndrome)

Familiar or hereditary disorders

Dubin-Johnson Syndrome
Rotor syndrome

Acquired disorders

hepatocellular necrosis
intrahepatic cholestasis
(Hepatitis, Cirrhosis, Drug-related)

Gross specimen of cirrhosis of

the liver

Hepatic Jaundice
Symptoms
weakness, loss appetite, hepatomegaly, palmar
erythema, spider

Lab Findings
liver function tests are abnormal
both CB and UCB
Bilirubinuria

Hepatic Jaundice

serum / blood
bilirubin (micromoles/l) 50-250; normal
range 3-17
AST I.U. 300-3000; normal range <35
ALP I.U. <250-700; normal range <250
gamma GT I.U. 15-200; normal range
15-40
albumin g/l 20-50; normal range 40-50
reticulocytes(%) <1; normal range <1
prothrombin time (secs) 15-45; normal
range 13-15
( " + parenteral vit. K) 15-45

Hepatic Jaundice
urinary changes
bilirubin: normal or increased
urobilinogen: normal or reduced
faecal changes
stercobilinogen: normal or
reduced

Jaundice
diagnosis(1)
history and examination
urine, stools
serum biochemistry
bilirubin
transaminases - AST, ALT
albumin
alkaline phosphatase

Jaundice
diagnosis(2)
haematology

haemoglobin
WCC
platelets
prothrombin time +/- parenteral
vitamin K
abdominal ultrasound and chest X-ray
further investigations - determined by
the basis of the jaundice, e.g. prehepatic, hepatic, extra-hepatic

conjugated hyperbilirubinaemia
the liver is able to conjugate bilirubin, but
the excretion is impaired.
failure of bilirubin excretion by
hepatocytes:
Dubin-Johnson syndrome
Rotor's syndrome
obstruction to biliary flow i.e. cholestasis,
both intra-hepatic and extra-hepatic

The proportion of conjugated

bilirubin to the total raised
bilirubin
20-40% of total: more suggestive of
hepatic than posthepatic jaundice
40-60% of total: occurs in either hepatic
or posthepatic causes
> 50% of total: more suggestive of
posthepatic than hepatic jaundice
less than 20% :secondary to haemolysis
or constitutional e.g. Gilbert's disease,
Crigler-Najjar syndrome

unconjugated
hyperbilirubinaemia
increased bilirubin formation
failure of bilirubin
uptake(Gilbert's disease)
failure of bilirubin
conjugation

unconjugated
hyperbilirubinaemia
increased bilirubin formation

haemolysis
ineffective erythropoiesis:
megaloblastic anaemia
iron deficiency
haemoglobinopathies

unconjugated
hyperbilirubinaemia
failure of bilirubin conjugation

neonatal jaundice
Crigler Najjar syndrome
drug inhibition e.g.
chloramphenicol
extensive hepatocellular
disease e.g. hepatitis,
cirrhosis

Cholestasis
diagnosis
elevated serum bilirubin - in proportion
to duration of cholestasis; returns to
normal once cholestasis is relieved
raised serum alkaline phosphatase - to
more than 3X upper limit of normal;
LFTs - aminotransferases mildly raised;
raised gamma GT
increased urinary bilirubin
urinary urinobilinogen is excreted in
proportion to amount of bile reaching the
duodenum i.e. absence of urinobilinogen
indicates complete biliary obstruction

Identification of cause
dilated ducts on ultrasound percutaneous transhepatic
cholangiograpy
undilated ducts on ultrasound endoscopic retrograde cholangiopancreatography
needle biopsy of the liver

Hepatocellular carcinoma

Primary sclerosing cholangitis in

childhood

Accompanied Symptoms

Fever
Pain,Charcot syndrome
Hepatomegaly
Spleenmegaly
Ascites
GI bleeding
itch

Jaundice- Differential diagnosis

1. Once Jaundice is recognized, it is important to
determine whether hyperbilirubinemia is
predominantly CB or UCB?
2. Differentiation of hemolitic from other type of
Jaundice is usually not difficult.
3. The laboratory findings are in constant in partial
biliary obstruction and differentiation from
intrahepatic cholestesis is particularly difficult.

Jaundice- Differential diagnosis

Differential Diagnosis

UCB or CB
Exclude UCB (e.g. hemolysis or Gilbert Synd.)
Distinguish hepatocellular from obstructive
Distinguish intrahepatic from extra hepatic
cholestasis

Case Study1
History: 68-year-old,jaundice,stomach pain,
dark urine,itching of the
skin,rapid weight loss of 21lb
Lab data
CBC within narmal limits
Total bilirubin:238mol/l
GGT:300U/l
ALP:360U/l
AST:80u/l
ALT:75u/l
Urinalysis:positive bilirubin,normal urobilinogen
Serum amylase:elevated

Case Study1
Question:
What is the most probable diagnosis for this
patient?
Which labtory tests provided the most
information,and which provided the least?

Case Study2
History:38-year-old white
female,jaundice,right upper
quadrant abdominal
pain,nausea,vomiting,itching
skin.She has a history of
intravenous drug use and alcohol
abuse.

Case Study2
Lab data
elevated total bilirubin(136 mol/l)
elevated conjugated bilirubin(102mol/l)
Urine:orange-brown,3+bilirubin,normal
urobilinogen
elevated
ALP(1.5ULT),GGT(3ULT),ALT,AST(5ULT)
Modest increase:Serum cholesterol and
triglyceride

Case Study2
Question
What is the probable diagnosis for this
patient?Why?
What other laboratory test would
recommend to confirm this diagnosis?
Which laboratory tests ordered provided the
most information?Why?

SUMMARY

Have the patient had an isolated elevation

of serum bilirubin?

SUMMARY

Is the bilirubin elevation due to an increased

unconjucated or conjucated fraction?

SUMMARY

Is the hyperbilirubinemia hepatocellular or

cholestatic?

SUMMARY

If cholestatic,is it intra-or extrahepatic?