2. JAUNDICE—GENERAL
• Jaundice or icterus refers to the yellow pigmentation of the skin or sclerae
by bilirubin.
• Bilirubin pigment has high affinity for elastic tissue and hence jaundice is
particularly noticeable in tissues rich in elastin content.
• Jaundice is the result of elevated levels of bilirubin in the blood termed
hyperbilirubinemia.
• Normal serum bilirubin concentration ranges from 0.3-1.3 mg/dl, about
80% of which is unconjugated.
• Jaundice becomes clinically evident when the total serum bilirubin
exceeds 2 mg/dl.
• A rise of serum bilirubin between the normal and 2 mg/dl is generally not
accompanied by visible jaundice and is called latent jaundice.
3. • NORMAL BILIRUBIN METABOLISM
• Normal metabolism of bilirubin can be conveniently described under
4 main headings—source, transport, hepatic phase and intestinal
phase
1.SOURCE OF BILIRUBIN
About 80-85% of the bilirubin is derived from the catabolism of
hemoglobin present in senescent red blood cells.
The destruction of effete erythrocytes at the end of their normal
lifespan of 120 days takes place in the reticuloendothelial system in
the bone marrow, spleen and liver.
4. • The remaining 15-20% of the bilirubin comes partly from non-haemo globin
haem-containing pigments such as myoglobin, catalase and cytochromes, and
partly from ineffective erythropoiesis.
• In either case, haem moiety is formed which is converted to biliverdin by
microsomal haem oxygenase for which oxygen and NADPH are essential
requirements.
• Bilirubin is formed from biliverdin by biliverdin reductase.
5. 2. TRANSPORT OF BILIRUBIN :
• Bilirubin on release from macrophages circulates as unconjugated
bilirubin in plasma tightly bound to albumin.
• Certain drugs such as sulphonamides and salicylates compete with
bilirubin for albumin binding and displace bilirubin from albumin, thus
facilitating bilirubin to enter into the brain in neonates and increase the
risk of kernicterus.
• Bilirubin is found in body fluids in proportion to their albumin content
such as in CSF, joint effusions, cysts etc
6.
7. 3. HEPATIC PHASE
On coming in contact with the hepatocyte surface, unconjugated
bilirubin is preferentially metabolised which involves 3 steps: hepatic
uptake, conjugation and secretion in bile.
i) Hepatic uptake Albumin-bound unconjugated bilirubin upon entry
into the hepatocyte, is dissociated into bilirubin and albumin. The
bilirubin gets bound to cytoplasmic protein glutathione-S-
transferase (GST) (earlier called ligandin).
8. Before considering the features and types of jaundice, it is essential to review the normal bilirubin metabolism
9. • Conjugation :
Unconjugated bilirubin is not water-soluble but is alcohol-soluble and
is converted into water-soluble compound by conjugation.
Conjugation occurs in endoplasmic reticulum and involves conversion
to bilirubin mono- and diglucuronide by the action of microsomal
enzyme, bilirubinUDP-glucuronosyl transferase.
The process of conjugation can be induced by drugs like phenobarbital.
10. • Conjugated bilirubin is bound to albumin in two forms:
reversible and irreversible.
Reversible binding is similar to that of unconjugated bilirubin. However,
when present in serum for a long time (e.g. in cholestasis, long-
standing biliary obstruction, chronic active hepatitis), conjugated
bilirubin is bound to albumin irreversibly and is termed delta bilirubin
or biliprotein.
This irreversible conjugated delta bilirubin is not excreted by the
kidney, and remains detectable in serum for sufficient time after
recovery from the diseases.
11. iii) Secretion into bile:
• Conjugated (water-soluble) bilirubin is rapidly transported directly into bile
canaliculi by energy dependent process and then excreted into the bile.
4. INTESTINAL PHASE
Appearance of conjugated bilirubin in the intestinal lumen is followed by
either direct excretion in the stool as stercobilinogen which imparts the
normal yellow colour to stool, or may be metabolised to urobilinogen by the
action of intestinal bacteria.
Conjugated bilirubin is normally not reabsorbable whereas its metabolic
product, urobilinogen, is reabsorbed from the small intestine and reaches
enterohepatic circulation.
Some of the absorbed urobilinogen in resecreted by the liver into the bile
while the rest is excreted in the urine as urobilinogen.
12.
13.
14. Predominantly Unconjugated Hyperbilirubinemia
• This form of jaundice can result from the following three sets of
conditions:
1. INCREASED BILIRUBIN PRODUCTION (HAEMOLYTIC, ACHOLURIC
OR PREHEPATIC JAUNDICE)
• This results from excessive red cell destruction as occurs in intra- and
extravascular haemolysis or due to ineffective erythropoiesis.
• There is increased release of haemoglobin from excessive breakdown
of red cells that leads to overproduction of bilirubin.
Hyperbilirubinaemia develops when the capacity of the liver to
conjugate large amount of bilirubin is exceeded.
15. • In premature infants, the liver is deficient in enzyme necessary for
conjugation while the rate of red cell destruction is high.
• This results in icterus neonatorum (Icterus neonatorum is taken to
mean the presence of clinical jaundice in infants during the
first 3-4 weeks of life.)
which is particularly severe in haemolytic disease of the newborn due
to maternal isoantibodies.
• Bile pigment being unconjugated type is absent from urine (acholuric
jaundice). acholuric jaundice , jaundice without bilirubinemia,
associated with elevated unconjugated bilirubin that is not excreted
by the kidney. Familial acholuric jaundice is another name for the
hereditary form of hemolytic jaundice.
16. 2. DECREASED HEPATIC UPTAKE
The uptake of bilirubin by the hepatocyte that involves dissociation of
the pigment from albumin and its binding to cytoplasmic protein, GST
or ligandin, may be deranged in certain conditions e.g. due to drugs,
prolonged starvation and sepsis.
17. 3. DECREASED BILIRUBIN CONJUGATION
• This mechanism involves deranged hepatic conjugation due to defect
or deficiency of the enzyme, glucuronosyl transferase.
• This can occur in certain inherited disorders of the enzyme (e.g.
Gilbert’s syndrome and Crigler-Najjar syndrome), or acquired defects
in its activity (e.g. due to drugs, hepatitis, cirrhosis).
• However, hepatocellular damage causes deranged excretory capacity
of the liver more than its conjugating capacity .
• The physiologic neonatal jaundice is also partly due to relative
deficiency of UDP-glucuronosyl transferase in the neonatal liver and
is partly as a result of increased rate of red cell destruction in
neonates.
18. II. Predominantly Conjugated Hyperbilirubinaemia
(Cholestasis)
• This form of hyperbilirubinaemia is defined as failure of normal amounts
of bile to reach the duodenum.
• Morphologically, cholestasis means accumulation of bile in liver cells and
biliary passages.
• The defect in excretion may be within the biliary canaliculi of the
hepatocyte and in the microscopic bile ducts (intrahepatic cholestasis or
medical jaundice), or there may be mechanical obstruction to the
extrahepatic biliary excretory apparatus (extra hepatic cholestasis or
obstructive jaundice).
19. • It is important to distinguish these two forms of cholestasis since
extrahepatic cholestasis or obstructive jaundice is often treatable
with surgery,
• whereas the intrahepatic cholestasis or medical jaundice cannot be
benefitted by surgery but may in fact worsen by the operation.
• Prolonged cholestasis of either of the two types may progress to
biliary cirrhosis.
20. 1. INTRAHEPATIC CHOLESTASIS
• Intrahepatic cholestasis is due to impaired hepatic excretion of bile and
may occur from hereditary or acquired disorders.
i) Hereditary disorders producing intrahepatic obstruction to biliary
excretion are characterised by ‘pure cholestasis’ e.g. in Dubin-Johnson
syndrome, Rotor syndrome, fibrocystic disease of pancreas, benign familial
recurrent cholestasis, intrahepatic atresia and cholestatic jaundice of
pregnancy.
ii) Acquired disorders with intrahepatic excretory defect of bilirubin are
largely due to hepatocellular diseases and henceare termed
‘hepatocellular cholestasis’ e.g. in viral hepatitis, alcoholic hepatitis, and
drug-induced cholestasis such as from administration of chlor promazine
and oral contraceptives.
22. 2. EXTRAHEPATIC CHOLESTASIS
• Extrahepatic cholestasis results from mechanical obstruction to large
bile ducts outside the liver or within the porta hepatis.
• The common causes are gallstones, inflammatory strictures,
carcinoma head of pancreas, tumours of bile duct, and congenital
atresia of extrahepatic ducts.
• The obstruction may be complete and sudden with eventual
progressive obstructive jaundice, or the obstruction may be partial
and incomplete resulting in intermittent jaundice.
23. • The features of
extrahepatic cholestasis
(obstructive jaundice), like
in intrahepatic cholestasis,
are: predominant
conjugated
hyperbilirubinaemia,
bilirubinuria, elevated
serum bile acids causing
intense pruritus, high
serum alkaline
phosphatase and
hyperlipidaemia.
B:Extrahepatic cholestasis shows characteristic
bile lakes due to rupture of canaliculi in the
hepatocytes in the centrilobular area.
24. General Aspects of Jaundice
• Jaundice is yellow pigmentation of the skin or sclerae by bilirubin.
• It is due to rise in bilirubin level in the blood (hyperbilirubinaemia) above
normal (0.3-1.3 mg/dl).
• Normally, bilirubin formed in the body is transported and metabolised
through the liver, and excreted through the intestines and kidneys.
• All forms of liver cell injury result in necrosis of liver cells in the hepatic
lobule which may be diffuse (submassive to massive), zonal and focal.
Zonal necrosis may pertain to respective zone: centrilobular (zone 1),
midzonal (zone 2) and periportal (zone 3).
• Predominantly unconjugated hyperbilirubinaemia is due to increased
production and decreased hepatic uptake and conjugation, while reduced
excretion causes mainly conjugated hyperbilirubinaemia.
25. Causes of neonatal jaundice
A. UNCONJUGATED HYPERBILIRUBINAEMIA
1. Physiologic and prematurity jaundice
2. Haemolytic disease of the newborn and kernicterus
3. Congenital haemolytic disorders
4. Perinatal (whole pregnancy period) complications (e.g.
haemorrhage, sepsis)
26. 5. Gilbert’s syndrome :
• This is the commonest of the familial, genetically-determined
diseases of the liver affecting 2-5% of the population.
• Gilbert’s syndrome is characterised by mild, benign, unconjugated
hyperbilirubinaemia (serum bilirubin 1-5 mg/dl) which is not due to
haemolysis.
• The condition is inherited as an autosomal dominant character.
• The defect in bilirubin metabolism is complex and appears to be
reduced activity of UDPglucuronosyl transferase with decreased
conjugation, or an impaired hepatic uptake of bilirubin.
• The jaundice is usually mild and intermittent.
27. 6. Crigler-Najjar syndrome (type I and II)
• Crigler-Najjar syndrome is a rare form of familial non-haemolytic
jaundice with very high unconjugated hyperbilirubinaemia. There are 2
forms of this condition: type I and type II.
Type I Crigler-Najjar syndrome
This is inherited as an autosomal recessive disorder. There is complete
absence of conjugating enzyme UDP-glucuronosyl transferase in the
hepatocytes and hence no conjugated bilirubin is formed.
There is extreme elevation of unconjugated bilirubin (usually more than
20 mg/dl) with high risk of developing permanent CNS damage from
kernicterus. The prognosis is generally fatal, with death coming from
kernicterus usually in the first year of life.
28. • Type II Crigler-Najjar syndrome
• This is inherited as an autosomal dominant disease.
• There is deficiency of enzyme UDP-glucuronosyl transferase but not
complete absence.
• Thus, unconjugated hyperbilirubinaemia is generally mild to
moderate (usually less than 20 mg/dl).
• Occurrence of kernicterus is exceptional and patients respond well to
phenobarbital therapy. (The major effect of phenobarbital is to
increase hepatic glucuronosyl transferase (UGT) activity and the
conjugation of bilirubin)
29. B. CONJUGATED HYPERBILIRUBINAEMIA
1. Hereditary (Dubin-Johnson syndrome, Rotor’s syndrome)
Dubin-Johnson syndrome is autosomal recessive disorder characterised
by predominant conjugated hyper bilirubinaemia (usually less than 5
mg/dl) with genetic defect in canalicular excretion of conjugated bilirubin.
ROTOR’S SYNDROME
There is mild chronic jaundice similar to Dubin-Johnson syndrome but
differs from it in having no brown pigment in the liver cells. The disease
has autosomal recessive inheritance. The defect probably lies in
intrahepatic storage of bilirubin and no cholestasis but the exact
molecular basis is not known.
31. 5. Biliary atresia (intrahepatic and extrahepatic) : Biliary atresias, also
called as infantile cholangiopathies, are a group of intrauterine
developmental abnormalities of the biliary system. Though they are
often classified as congenital, the abnormality of development in most
instances is extraneous infection during the intrauterine development
or shortly after birth that brings about inflammatory destruction of the
bile ducts.
32. 6. Reye’s syndrome
• Reye’s syndrome is defined as an acute postviral syndrome of
encephalopathy and fatty change in the viscera.
• The syndrome may follow almost any known viral disease but is most
common after influenza A or B and varicella.
• Viral infection may act singly, but more often its effect is modified by
certain exogenous factors such as by administration of salicylates,
insecticides.
• These effects cause mitochondrial injury and decreased activity of
mitochondrial enzymes in the liver.
• This eventually leads to rise in blood ammonia and accumulation of
triglycerides within hepatocytes.