Jaundice

Yellowish discolouration of body tissue such as skin, sclera, mucous membranes and
deep tissues that occurs when levels of free (unconjugated) or conjugated bilirubin in
plasma is elevated above 2mg/dl (34mol/l)
Normal bilirubin level in a normal adult is 0.3 - 1.2 mg/dl
Jaundice becomes evident when the serum bilirubin levels rise above 2.0 to 2.5 mg/dl;
levels as high as 30 to 40 mg/dL can occur with severe disease.
Conjugated bilirubin

Unconjugated bilirubin

Water soluble

Insoluble in water at physiological PH

Loosely bound to albumin

Tighty bound to albumin

Non toxic

Small amount of albumin-free-bilirubin

that exists in plasma as anions can easily
diffuse in to tissues, particularly the brain
in infants, and produce toxic injury.

Excess levels in plasma can be excreted in

urine
With prolonged conjugated hyperbilirubinemia
(cholestasis, long standing biliary obstruction,
chronic active hepatitis) results in portion of
the circulating pigment to covalently bind to
albumin (termed as bilirubin delta fraction).
They are not excreted by the kidney.

The unbound plasma fraction may

increase in severe hemolytic disease or
when protein-binding drugs displace
bilirubin from albumin. Hence, hemolytic
disease of the newborn (erythroblastosis
fetalis) may lead to accumulation of
unconjugated bilirubin in the brain,
which can cause severe neurologic
damage, referred to as kernicterus

Formation of bilirubin

Bilirubin is the end product of heme degradation

Daily production of bilirubin is around 0.2-0.3 g
Breakdown of senescent erythrocytes is the major source for production of bilirubin
Theres a little contribution from the turnover of hepatic hemoproteins and also from
premature destruction of erythrocytes in the bone marrow (this latter pathway is
important in hematologic disorders associated with excessive intramedullary
hemolysis of defective erythrocytes)
Heme is oxidised to biliverdin by heme oxigenase enzyme
Biliverdin is then reduced into bilirubin by biliverdin reductase
Both heme oxygenase and biliverdin reductase can be found in mononuclear
phagocyte system (including the spleen)
Formation of bilirubin takes place in mononuclear phagocyte system outside the liver
Release bilirubin in to blood
Bilirubin then tightly binds to serum albumin, but they can disassociate in the liver

Hepatocellular processing of bilirubin involves

o Carrier mediated uptake at the sinusoidal membrane by a member of the
organic anion transporting polypeptide (OATP) family
o Then disassociate into bilirubin and albumin
o Bilirubin then binds to proteins (glutathione S-transferase) in the
cytoplasm and is transported to the endoplasmic reticulum
o Conjugation with glucuronic acid catalysed by uridine diphosphate
glucuronosyl transferase (UDP- glucuronosyltransferase/glucuronyl
transferase) where each bilirubin molecule reacts with two uridine
diphosphoglucuronic acid (UDPG) molecules to form bilirubin
diglucuronide.
o This process of conjugation can be induced by drugs like phenobarbital
o This glucuronide, which is more water-soluble than the free bilirubin, is
then transported against a concentration gradient most likely by an active
transporter known as multidrug resistance protein-2 (MRP-2) into the bile
canaliculi.

A small amount of the bilirubin glucuronide escapes into the blood

Bilirubin glucuronoid is bound less tightly to albumin than free bilirubin, and is
excreted in the urine.
Thus, the total plasma bilirubin normally includes free bilirubin plus a small amount
of conjugated bilirubin.
Most of the bilirubin glucuronide passes via the bile ducts to the intestine.
Most bilirubin glucuronoids are deconjugated by gut bacterial -glucuronidases and
degraded to colourless urobilinogens
The intestinal mucosa is relatively impermeable to conjugated bilirubin
The intestinal mucosa is permeable to unconjugated bilirubin and to urobilinogens
So urobilinogens and unconjugated/free bilirubin is largely excreted in feces.
Some of the bile pigments and urobilinogens (20%) are reabsorbed in the portal
circulation.
Some of the reabsorbed substances are again excreted by the liver (enterohepatic
circulation), but small amounts of urobilinogens enter the general circulation and are
excreted in the urine.

In a normal adult
The rate of systemic bilirubin production = the rate of hepatic uptake, conjugation and
biliary excretion
So theres an equilibrium between bilirubin production and bilirubin clearance in a normal
person
Mechanisms that disturbs this equilibrium can lead to jaundice
These mechanisms are;
excessive production of bilirubin
reduced hepatic uptake

 impaired conjugation
decreased hepatocellular excretion
impaired intrahepatic or extrahepatic bile flow
Excessive production of bilirubin, reduced hepatic uptake and impaired conjugation
predominately causes unconjugated hyperbilirubinemia
Decreased hepatocellular excretion, impaired intrahepatic or extrahepatic bile flow
predominately causes conjugated hyperbilirubinemia
More than one of these mechanism can operate together to cause jaundice
example : In hepatitis conjugated and unconjugated hyperbilirubinemia are both evident
But in general one form of mechanism predominates and the predominate form of plasma
bilirubin is helpful to evaluate the possible cause of hyperbilirubunemia
Predominantly Unconjugated Hyperbilirubinemia
Excess Production of Bilirubin
Hemolytic anemias
Resorption of blood from internal hemorrhage
(e.g., alimentary tract bleeding, hematomas)
Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia)
Reduced Hepatic Uptake
Uptake of bilirubin that involes hepatic disassociation of the pigment from albumin and its
binding to cytoplasmic protein maybe disturbed.
Drug interference with membrane carrier systems
Diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis, cirrhosis)
Prolonged starvation
Sepsis
Impaired Bilirubin Conjugation
This happens due to defect or deficiency of the enzyme glucuronosyl transferase.
Inherited disorders of the enzyme (Gilberts syndrome, Crigler-Najjar syndrome)
Acquired defects in enzyme activity due to drugs, hepatitis, cirrhosis
Physiologic jaundice of the newborn
Predominantly Conjugated Hyperbilirubinemia
Decreased Hepatocellular Excretion
Deficiency in canalicular membrane transporters
Drug-induced canalicular membrane dysfunction (e.g., oral contraceptives, cyclosporine)
Hepatocellular damage or toxicity
(e.g., viral or drug-induced hepatitis, total parenteral nutrition, systemic infection)
Impaired Intra- or Extrahepatic Bile Flow
Inflammatory destruction of intrahepatic bile ducts
(e.g., primary biliary cirrhosis, primary sclerosing cholangitis, graft-versus-host disease,

liver transplantation)
gall stones
carcinoma of the pancreas
How can you tell if its conjugated hyperbilirubanemia or unconjugated hyperbilirubanemia?
If bilirubin is present in urine its conjugated hyperbilirubanemia!
unconjugated bilirubin cannot be filtered by the glomerulus (maybe because unconjugated
bilirubin is insoluble in water???)

Case Scenario :
Tom is a first year medical student, whose father complained of ;
Loss of appetite
Abdominal pain
Itching (pruritus)
Yellowish discolouration of eyes (Icterus)
Passing pale stools
Tea coloured urine
Tom suspects jaundice and take his father to the hospital immediately. For the
investigations, the doctor asks his father to get the following test done.
- Total Bilirubin/ Serum bilirubin levels
Report of Toms father
Total Bilirubin

Patient
30 mol/l

Reference range
2-17 mol/l

The doctor interprets the report and says that it seems to be jaundice
Clinical Features

Yellowish discolouration of skin (jaundice) and sclera (icterus)

Tea coloured urine
Passing pale stools
Itching (pruritus)
Loss of appetite
Abdominal pain

Physiological and biochemical basis for the clinical features

Yellowish discolouration of skin (jaundice) and sclera (icterus)
High amounts of bilirubin in blood

Elevated deposition of bilirubin in skin and sclera

Yellowish discolouration of skin and sclera

Tea coloured urine

Reflux of conjugated bilirubin in to blood from hepatocytes

High amounts of conjugated bilirubin in blood

Saturation of albumin protein by bilirubin and therefore excessive high

amounts of free (non albumin bound) conjugated bilirubin in blood

Elevated filtration of conjugated bilirubin by the glomerular membrane

conjugated bilirubin excreted via urine

Conjugated bilirubin is oxidized by air

Tea coloured urine

Pale stools
Bile duct obstruction (so no conjugated bilirubin)
or
No production of bilirubin (so no conjugated bilirubin is made)

No bile enters in to the duodenum

or
No bilirubin in bile that entered the duodenum

No bilirubin to be degraded in to urobilinogen by gut bacteria

Pale stools

Itching (Pruritus)

Reflux of conjugated bilirubin in to blood from hepatocytes

carries bile salts as well

Deposition of bile salts in subcutaneous tissues

Irritation of nerve fibres

Itching (Pruritis)

Due to continuous itching

Polished nails

Abdominal Pain
Obstruction of bile duct

Bacteria ascends to the bile duct due to absence of bile

Inflammation of the bile duct

Pain in the right upper quadrant of the abdomen

Loss of appetite
Bile duct obstruction (so no bile is secreted in to the duodenum)

Deposition of bile salts in

blood extends to tongue

No bile to emulsify fat

No fat digestion

Fat remains for a longer time in GI tract

Fullness of the stomach

Bitter taste in tongue

Loss of appetite

Three types of jaundice

1' Haemolytic jaundice
2' Hepatocellular jaundice
3' Obstructive jaundice/ Cholestasis jaundice

Haemolytic jaundice

Increased destruction of red blood cells or its precursors in reticulo-endothelial system due to
diseases like sickle cell anaemia, immune mediated haemolytic anaemia
Therefore the disturbance to the equilibrium occurs before unconjugated bilirubin enters the
liver
So the mechanism is also known as Pre-hepatic
Excessive haemolysis of RBC

Increased unconjugated bilirubin

Supersaturates the binding sites of Albumin

Unconjugated bilirubin
remains in the circulation

Liver conjugation

Increased conjugation of
bilirubin

Deposition of unconjugated
bilirubin in tissue

Urobilinogen

Changes seen in Full Blood Test

Patient
8g/dl
40 - 54

Haemoglobin
Haematocrit

Reference range
13-18g/dl
30

Excessive haemolysis cause the number of functional RBC to reduce. Therefore reducing
the haematrocrit (Packed Cell Volume) and the amount of haemoglobin.

Other changes seen in blood tests

Patient
1001019/l
12 14 sec

Reticulocyte count
Prothrombin Time

Reference range
25-851019/l
12 sec

Normal

Low amount of Haemoglobin

Low O2 supply to the tissues

Stimulate the production of erythropoietin

Increased number of haemopoietic stem cells

Causes the cells to pass rapidly through the stages of erythropoiesis

Reticulocytes in blood

Changes seen in urine

Bilirubin
Urobilinogen
Haemoglobinuria
Colour

Patient
Absent
5mol/l for 24 hours

Reference range
Normal
<4.2mol/l for 24
hours

Present
Dark

Pale yellow

Abnorma
l
Abnorma
l

Why is bilirubin absent in urine?

When unconjugated bilirubin is made they are insoluble in water, and are bound to albumin.
So they cannot pass the glomerular membrane. Inside the liver cell it becomes conjugated
with glucuronoid acid and is secreted in to the duodenum along with bile. But in the ileum
conjugated bilirubin is not reabsorbed, so they are excreted in faeces. Therefore bilirubin is
not seen in urine of a patient with haemolytic jaundice

Why is urobilinogen amount in urine is increased?

Increased production of conjugated bilirubin leads to increased production of urobilinogen by
gut bacteria. This leads to increased reabsorption of urobilinogen in to the circulatory system
which leads to excretion of excessive urobilinogen via urine. So urine gets dark on standing
due to increased levels of urobilinogen.

Why is haemoglobinuria is caused?

In a normal healthy adult, no haemoglobin is present in urine. Haemoglobinuria is termed as
presence of haemoglobin in urine.

Excessive red blood cell breakdown causes haemoglobin to be released. Extra-corpuscular

Hb binds to haptoglobin.
When all the haptoglobins are saturated free plasma haemoglobin levels increase
There for haemoglobin is filtered by the kidney and then excreted via urine

Stools are dark in colour due to increased amount of stercobilin in it.

Haemolytic jaundice is usually mild since hepatic bilirubin conjugation capacity is very high.

Hepatocellular jaundice

In hepatocellular jaundice theres damage to the hepatocytes due to inflammation of

destruction.

Eg : Acute parenchymal liver disease

Chronic parenchymal liver disease
These may result in
1. Reduced uptake of conjugated bilirubin in to hepatocytes
2. Reduced conjugation
3. Reduced secretion of conjugated bilirubin
without obstruction of bile canaliculi
with obstruction of bile canaliculi

In blood concentrations of both conjugated bilirubin and unconjugated bilirubin are

increased.
Proportion depends on the nature of damage.

Damage to hepatocytes without obstruction of bile canaliculi

Damaged hepatocytes

Reduced uptake of unconjugated bilirubin or reduced conjugation

Accumulation of unconjugated bilirubin in plasma

Deposition in tissue

Jaundice

Damaged hepatocytes with obstruction to bile canaliculi

Due to reduced
uptake

Regurgitation of conjugated
bilirubin

Low levels of
High levels of unconjugated
conjugated
bilirubin in plasma
bilirubin in
bile

High levels of conjugated

bilirubin in plasma

Jaundice

In hepatocellular jaundice disturbance to the equilibrium of bilirubin metabolism occurs

within the liver. Eg : Hepatitis
Therefore his mechanism is also known as Hepatic