◘ Izatty Lim ◘ 0308188 ◘ 11 April 2014 ◘
• Clinical Features
• Lab findings
• Cholestatic liver disease
Pathogenesis of Jaundice Causes of Jaundice
yellow discoloration of skin & sclerae
systemic retention of bilirubin ( serum level above 2.0mg/dL)
Impaired bile flow
systemic retention of not only bilirubin but also other solutes eliminated
in bile ( bile salts & cholesterol)
2 major function of hepatic bile:
o Constitutes the 1° pathway for elimination of
bilirubin, excess cholesterol & xenobiotics
o Secreted bile salts and phospholipid molecules
promote emulsification of dietary fat
Bilirubin end product of heme degradation
Daily production 0.2 – 0.3g
• Breakdown of senescent red cells within mononuclear phagocytes
• Turnover of hepatic hemoproteins
Heme Biliverdin Bilirubin
Bilirubin formed outside the liver in cells of mononuclear phagocyte system
is released & bound to serum albumin
Bilirubin & Bile Acids
Hepatocellular processing of bilirubin:
1) Carrier-mediated uptake at the sinusoidal membrane
2) Cytosolic protein binding and delivery to the endoplasmic reticulum
3) Conjugation with one or two molecules of glucuronic acid by bilirubin uridine
4) Excretion of the water-soluble, nontoxic bilirubin glucuronides into bile.
• Most bilirubin glucuronides deconjugated by gut bacterial β-glucuronidases &
degraded to colorless urobilinogens.
• Urobilinogens & the residue of intact pigment are largely excreted in feces.
• ≈ 20% of the urobilinogens are reabsorbed in the ileum & colon returned to liver
reexcreted into bile.
• Conjugated & unconjugated bile acids also are reabsorbed in the ileum returned to
the liver by enterohepatic circulation.
(1) Normal bilirubin production (0.2 to 0.3
g/day) is derived primarily from the
breakdown of senescent circulating red cells,
with a minor contribution from degradation of
tissue heme-containing proteins.
(2) Extrahepatic bilirubin is bound to serum
albumin and delivered to the liver.
Hepatocellular uptake (3) and glucuronidation
(4) by glucuronosyltransferase in the
hepatocytes generate bilirubin
monoglucuronides & diglucuronides, which
are water-soluble and readily excreted into
(5) Gut bacteria deconjugate the bilirubin and
degrade it to colorless urobilinogens. The
urobilinogens and the residue of intact
pigments are excreted in the feces, with some
reabsorption & reexcretion into bile.
In the normal adult,
• rate of systemic bilirubin production = rates of hepatic uptake, conjugation, and
• Equilibrium between bilirubin production and clearance disrupted Jaundice
More than one mechanism may operate to cause jaundice
• Especially in hepatitis, when both unconjugated and conjugated
bilirubin may be produced in excess.
• In severe disease, bilirubin levels may reach 30 - 40 mg/dL.
Of these various causes of jaundice,
• MC: hepatitis, obstruction to the flow of bile & hemolytic anemia.
Neonatal jaundice or physiologic jaundice of the newborn
• almost every newborn develops transient & mild
• hepatic machinery for conjugating & excreting bilirubin
does not fully mature until about 2 weeks of age
Jaundice also may result from inborn errors of metabolism
• Gilbert syndrome, a relatively common (7% of the population), benign, somewhat
heterogeneous inherited condition
• Manifest as mild, fluctuating unconjugated hyperbilirubinemia.
• Primary cause : ↓ hepatic levels of glucuronosyltransferase (mutation in the encoding gene)
• Polymorphisms in the gene variable expression of this disease.
• not associated with any morbidity.
• Dubin-Johnson syndrome
• Result from autosomal recessive defect in the transport protein responsible for
hepatocellular excretion of bilirubin glucuronides across the canalicular membrane.
• Affected persons exhibit conjugated hyperbilirubinemia.
• Other than having a darkly pigmented liver (from polymerized epinephrine metabolites, not
bilirubin) and hepatomegaly, patients are otherwise without functional problems
Pathologic condition of impaired bile flow, leading to accumulation of bile
pigment in the hepatic parenchyma
Can be caused by extrahepatic or intrahepatic obstruction of bile channels, or
by defects in hepatocyte bile secretion
• May manifest as jaundice
• Sometimes pruritus
• Skin xanthomas (focal accumulations of cholesterol) sometimes appear, the
result of hyperlipidemia and impaired excretion of cholesterol.
• Symptoms related to intestinal malabsorption, including nutritional deficiencies
of the fat-soluble vitamins A, D, or K.
Pathogenesis remains obscure
A characteristic laboratory finding:
• ↑ serum alkaline phosphatase (enzyme in bile duct epithelium & canalicular
membrane of hepatocytes reflects the detergent action of retained bile salts on
• ↑ γ-glutamyl transpeptidase (GGT, canalicular ectoenzyme) reflects the
detergent action of bile salts retained in the luminal space of the bile canaliculus
on the apical membranes of hepatocytes & bile duct epithelial cells
depend on its severity, duration, and underlying cause
Common to both obstructive & non-obstructive cholestasis is the accumulation of
bile pigment within the hepatic parenchyma
Elongated green-brown plugs of bile visible in dilated bile canaliculi Rupture of
canaliculi bile extravasation phagocytosed by Kupffer cells.
Droplets of bile pigment also accumulate within hepatocytes fine, foamy
appearance (feathery degeneration).
In the parenchyma (upper panel),
Enlarged cholestatic hepatocytes (1) with
dilated canalicular spaces (2).
Apoptotic cells (3)
Kupffer cells (4) with regurgitated bile
In the portal tracts of obstructed liver (lower panel),
bile ductular proliferation (5), edema, bile pigment
retention (6), and eventually neutrophilic
inflammation (not shown).
Surrounding hepatocytes (7) are swollen &
Obstruction of the biliary tree distention of upstream bile ducts and
ductules by bile.
• The bile stasis and backpressure proliferation of the duct epithelial cells and
looping & reduplication of ducts & ductules.
• Unlike the extensive ductular reaction in the setting of massive hepatic necrosis,
in obstruction, the ductular proliferation is confined to portal tracts.
• The labyrinthine ductules reabsorb secreted bile salts, serving to protect the
downstream obstructed bile ducts from the toxic detergent action of bile salts.
• Associated histologic findings include portal tract edema and periductular
infiltrates of neutrophils.
Extrahepatic biliary obstruction frequently is amenable to surgical correction.
By contrast, cholestasis caused by diseases of the intrahepatic biliary tree
cannot be treated surgically (short of transplantation)
• the patient's condition may be worsened by an operative procedure.
• urgency in identifying the cause of jaundice and cholestasis.
Primary biliary cirrhosis (PBC)
chronic inflammatory intrahepatic liver disorder that slowly destroys the small-
to-medium-sized bile ducts.
When these ducts are damaged, bile builds up in the liver (cholestasis) and over
time damages liver tissue.
Primary sclerosing cholangitis (PSC)
extrahepatic cholestatic liver disease (affecting the part of the bile duct that is
outside of the liver) that damages the bile ducts both inside and outside of the
In both diseases,
inflammation leads to progressive thickening, scarring, and destruction of the
The buildup of bile, bile salts, and cholesterol in the liver causes damage to cell
membranes in the liver, reduced production of bile salts, and fibrosis
(development of scar tissue).
Fibrosis is both a marker of liver damage and a potential contributor to liver
failure. Continuing damage causes scarring or cirrhosis (the liver slowly
deteriorates and malfunctions), and prevents proper liver function and impaired
blood circulation in the intestines.
Cholestatic liver diseases