Jaundice (pathophysiology)

Reference
--Kawthalkar Essentials of Clinical Pathology - 2010 ed
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1. Jaundice

Jaundice (from French jaune , meaning yellow) or icterus
refers to yellow discoloration of skin, sclera, and mucous
membranes due to increased level of serum bilirubin.
Jaundice becomes clinically evident when serum
bilirubin level exceeds 2.0 mg/dl.

There are various methods for classification of
jaundice as follows:

1. According to the main type of bilirubin increased
in plasma:

• Predominantly unconjugated hyperbilirubinemia:
Indirect or unconjugated bilirubin is > 85% of total;
causes are hemolysis, resorption of a large
hematoma, ineffective erythropoiesis, Gilbert’s
syndrome, physiologic jaundice of newborn, and
Crigler-Najjar syndrome.
• Predominantly conjugated hyperbilirubinemia:
Direct or conjugated bilirubin is >50% of total;
causes are hepatitis, cirrhosis, cholestasis, drugs
(anabolic steroids, oral contraceptives), toxins,
Dubin-Johnson syndrome, and Rotor syndrome.

• Mixed (conjugated + unconjugated) hyperbilirubinemia:
Conjugated bilirubin is 20-50% of total;
it results from viral or alcoholic hepatitis.

2. 2. According to etiology:

• Hemolytic: The increased rate of red cell destruction
causes increased haemoglobin breakdown to
bilirubin in reticuloendothelial cells; this exceeds
the capacity of conjugation in liver.

• Hepatocellular: Inability of hepatocytes to conjugate
and/or excrete bilirubin.

• Obstructive: Failure of excretion of conjugated
bilirubin into the intestine, causing its
regurgitation in circulation.

3. According to site of disease:
• Prehepatic
• Hepatic
• Posthepatic

A simple classification is division of jaundice into
three main types: prehepatic, hepatic, and
posthepatic. This classification is the basis for
identifying the cause of jaundice

1. Prehepatic jaundice: There is excessive formation of
bilirubin exceeding the capacity of the liver to
conjugate it for excretion. The type of bilirubin
increased in serum is of unconjugated type. Bilirubin
is absent in urine since unconjugated bilirubin is
water-insoluble. Urobilinogen is increased in urine and feces.

3. Jaundice is usually mild (serum bilirubin<5.0 mg/dl;
conjugated bilirubin is <15% of total).
The cause can usually be identified by examination
of a stained blood smear and hematological
investigations. In jaundiced newborns, rapidly rising
unconjugated bilirubin needs careful management to
prevent kernicterus.

2. Hepatic jaundice: In hepatic disease, unconjugated,
conjugated, or both are increased.

a. Unconjugated hyperbilirubinemia:
1. Defective uptake of bilirubin by liver cells from
blood: Gilbert’s syndrome is the most common
cause of unconjugated hyperbilirubinemia,
affecting 5% of general population. It is a
familial, benign disease with autosomal dominant
mode of inheritance. Raised bilirubin is
usually noticed during routine laboratory
examination. There is defective uptake by
hepatocytes and mild deficiency of glucuronyl
transferase. Jaundice is mild and fluctuating,
and may go unnoticed for years. Jaundice
becomes noticeable during illness or after
fasting. Mildly elevated serum bilirubin is the
sole abnormality; other LFTs are normal.

2. Defective conjugation of bilirubin:
Crigler-Najjar syndrome: This is of two types.

4. Type I is characterized by autosomal recessive
mode of inheritance, complete absence of
glucuronyl transferase, severe unconjugated
hyperbilirubinemia, and kernicterus (deposition
of bilirubin in basal ganglia of brain). Type II is a
less severe disease in which some amount of
enzyme activity is present.
Physiologic jaundice of newborn: This is a transient
increase of unconjugated bilirubin which is
observed in almost all newborns. It usually
develops during the 2nd to 4th day after birth
with return to normal bilirubin level by 7th to
10th day. It is because of deficiency of glucuronyl
transferase leading to impaired conjugation
during the first few days of life.

b. Conjugated hyperbilirubinemia:

1. Hepatocellular disease: Liver enzymes (aspartate
aminotransferase and alanine aminotransferase)
are markedly elevated, and serum
bilirubin is usually in the range of 4.0 to 8.0
mg/dl. Conjugated bilirubin is 20-50% of total
bilirubin. In hepatocellular injury, both conjugated
and unconjugated bilirubins are increased.
Unconjugated bilirubin is increased due
to reduced ability of liver cells to conjugate

5. bilirubin. Conjugated bilirubin is raised from
cholestasis due to hepatocyte swelling.

2. Intrahepatic cholestasis: In intrahepatic cholestasis,
there may be
(1) impairment of secretion
of bilirubin from hepatocytes into the biliary
canaliculi;
(2) obstruction of bile flow in
canaliculi by swollen hepatocytes;
or
(3) damage to intrahepatic canaliculi.
In Dubin-Johnson syndrome, there is a
defect in the excretion of bilirubin by hepatocytes,
and liver is darkly pigmented due to
accumulation of polymerized epinephrine
metabolites. Bromosulphthalein excretion test
is abnormal. In Rotor syndrome, there is impaired
excretion of bilirubin but without pigmentation
of liver; bromosulphthalein test is
normal. Alkaline phosphatase is normal in both
conditions.
Drugs commonly associated with cholestatic
injury are oral contraceptives, anabolic
steroids, oral anti-diabetics, phenothiazines,
and erythromycin.
In primary biliary cirrhosis, there is autoimmune
destruction of intrahepatic bile ducts.
It predominantly occurs in middle-aged
females and is characterized by chronic elevation
of alkaline phosphatase and positive antimitochondrial

6. antibody in serum. There is an
association with other autoimmune disorders.
Primary sclerosing cholangitis is an autoimmune
disorder occurring in young to
middle-aged men in whom there is inflammation
and destruction of both intrahepatic
and extra-hepatic bile ducts. Associated
inflammatory bowel disease is often present.
Serum alkaline phosphatase is elevated and
many patients have circulating perinuclear
antineutrophil cytoplasmic antibodies.

3. Posthepatic jaundice: This is also called as
obstructive jaundice, surgical jaundice, or
extrahepatic cholestasis.
Obstruction of extrahepatic biliary tract
prevents flow of bile into the duodenum. This
causes “regurgitation” of conjugated bilirubin
into the circulation. (Biliary canaliculi distend
and rupture due to backpressure of bile and
conjugated bilirubin escapes into the
sinusoids). Conjugated bilirubin is usually
>50% of total in posthepatic jaundice. Urinary
and fecal urobilinogen are decreased, faeces are
clay-colored, and bilirubin (being conjugated
and water-soluble) appears in urine.
The tests employed to assess excretory function of
liver are serum/urine bilirubin and urine/fecal
urobilinogen.

7. Classification of jaundice according to the site of disease
Prehepatic jaundice
• Hemolytic anemia
• Ineffective erythropoiesis (megaloblastic anemia, thalassemias)
• Resorption of a large hematoma
Hepatic jaundice
• Predominantly unconjugated hyperbilirubinemia
– Gilbert’s syndrome
– Crigler-Najjar syndrome
– Physiologic jaundice of newborn
• Predominantly conjugated hyperbilirubinemia
– Hepatocellular diseases: viral hepatitis, toxic hepatitis,
alcoholic hepatitis, active cirrhosis
– Intrahepatic cholestasis: Dubin-Johnson syndrome, drugs,
primary biliary cirrhosis, primary sclerosing
cholangitis, biliary atresia
Posthepatic jaundice
• Carcinoma of head of pancreas
• Carcinoma of ampulla of Vater
• Secondaries in porta hepatis
• Gallstones in or stricture of common bile duct