Thamer A. Bin Traiki
Introduction
 Jaundice (icterus) is yellowish discoloration of the
skin & sclera as a result of raised level of serum
bilirubin .
 A careful clinical examination cannot detect jaundice
until the serum bilirubin is more than 2 mg/dL (34
µmol/liter), twice the normal upper limit.
 The yellow discoloration is best seen in the periphery
of the ocular conjunctivae and in the oral mucous
membranes (under the tongue, hard palate).
Cont…
 The normal serum bilirubin concentration in children
and adults is less than 1 mg/dL (17 µmol/liter).
 Less than 5 percent of which is present in
conjugated form.
 The measurement is usually made using diazo
reagents and spectrophotometry.
Cont…
 Conjugated bilirubin reacts rapidly ("directly") with the
reagents.
 The measurement of unconjugated bilirubin requires the
addition of an accelerator compound.
 Elevated serum bilirubin concentrations can be due to
three causes which can sometimes coexist:
 Overproduction of bilirubin
 Impaired uptake, conjugation, or excretion of bilirubin
 Backward leakage from damaged hepatocytes or bile ducts
FORMATION OF BILIRUBIN
 Bilirubin is formed by breakdown of heme present in
hemoglobin, myoglobin, cytochromes, catalase,
peroxidase and tryptophan pyrrolase.
 80% of the daily bilirubin production (250 to 400 mg in
adults) is derived from hemoglobin .
 The remaining 20 % being contributed by other
hemoproteins and a rapidly turning-over small pool of
free heme.
 Enhanced bilirubin formation is found in all conditions
associated with increased red cell turnover such as
intramedullary or intravascular hemolysis.
Cont…
 Heme consists of a ring of four pyrroles joined by
carbon bridges and a central iron atom
(ferroprotoporphyrin IX).
 Bilirubin is generated by sequential catalytic
degradation of heme mediated by two groups of
enzymes:
 Heme oxygenase
 Biliverdin reductase
Cont…
 Heme oxygenase
 Initiates the opening of the porphyrin ring of heme by
catalyzing the oxidation of the alpha-carbon bridge .
 This leads to formation of the green pigment, biliverdin
 Biliverdin reductase
 Reduce the biliverdin to the orange-yellow pigment
bilirubin .
 Iron is released in this process.
 The oxidized alpha-bridge carbon is eliminated as
carbon monoxide (CO).
 Bilirubin is very poorly soluble in water at physiologic
pH because of internal hydrogen bonding .
 Conversion of bilirubin to a water-soluble form, by
disruption of the hydrogen bonds, is essential for the
elimination by the liver and kidney.
 This is achieved by glucuronic acid conjugation of
the propionic acid side chains of bilirubin.
Albumin Binding of Bilirubin in Plasma
 Binding to albumin and, to a much lesser degree,
high density lipoprotein, keeps bilirubin in solution in
plasma.
 Only a small fraction of bilirubin circulates in the
unbound state.
 Binding to high density lipoprotein may become
significant in states of severe hypoalbuminemia.
Cont…
 Albumin binding keeps bilirubin in the vascular
space, thereby preventing its deposition into
extrahepatic tissues, including sensitive tissues such
as the brain, and minimizing glomerular filtration.
 It also transports bilirubin to the sinusoidal surface of
the hepatocyte, where the pigment dissociates from
albumin and enters the hepatocyte .
Cont…
 Albumin binding of bilirubin is usually reversible.
 The usual tight but reversible binding to albumin
precludes glomerular filtration of unconjugated bilirubin.
 In contrast, conjugated bilirubin is less strongly bound to
albumin and can be excreted in the urine.
 Thus, the finding of bilirubin in the urine, in the absence
of albuminuria, indicates the presence of an increased
amount of conjugated bilirubin in the plasma.
Cont…
 However, irreversible binding can occur in the presence
of prolonged conjugated hyperbilirubinemia, eg, during
biliary obstruction.
 The bilirubin fraction irreversibly bound to albumin (delta-
bilirubin) is not cleared by the liver or the kidney .
Uptake and Storage of Bilirubin by
Hepatocytes
 In the liver sinusoids, the albumin-bilirubin complex
dissociates, and the bilirubin is taken up efficiently by
the hepatocyte while the albumin remains in the
circulation.
 Bilirubin is taken up by hepatocytes by a process of
facilitated diffusion, which is not energy-consuming;
as a result, transport cannot occur against a
concentration gradient, and is bidirectional.
Cont…
 Sinusoidal bilirubin uptake requires inorganic anions,
such as chloride, and is thought to be mediated by
carrier proteins .
 Within the hepatocyte, bilirubin and other organic
anions bind to glutathione S-transferases (GSTs).
 GST-binding reduces the efflux of the internalized
bilirubin, thereby increasing net uptake .
Conjugation of Bilirubin
 Glucuronidation of bilirubin by the enzyme glucuronyl
transferase in the hepatocyte particularly in the endoplasmic
reticulum .
 Bilirubin diglucuronide is the predominant pigment in normal adult
human bile, representing over 80%of the pigment.
 Bilirubin glucuronides are water-soluble and are readily excreted in
bile.
 Unconjugated bilirubin accounts for only 1 to 4 % of pigments in
normal bile.
Execretion of Conjugated Bilirubin
 Conjugated bilirubin is secreted across the bile
canalicular membrane of the hepatocyte against a
concentration gradient with active transport .
 Enhanced bile flow (eg, infusion of bile salts) or
phenobarbital treatment increases the excretory
capacity.
Degradation of Bilirubin in the
Digestive Tract
 Bile pigment appearing in bile is mostly (more than 98
percent) conjugated.
 Conjugated bilirubin is water soluble and is not absorbed
across the lipid membrane of the small intestinal
epithelium .
 The unconjugated bilirubin fraction is partially reabsorbed
and undergoes enterohepatic circulation .
Cont…
 Bilirubin is reduced by bacterial enzymes in the colon to a
series of molecules termed urobilinogens .
 The two major urobilinoids found in stool, urobilinogen
and stercobilinogen, are colorless and turn orange-yellow
only after oxidation to urobilins.
 Urobilinogens and their derivatives are partly absorbed
from the bowel, undergo enterohepatic recycling, and are
eventually excreted in urine and feces .
Cont…
 In conditions associated with elevated conjugated
plasma bilirubin concentrations (eg, intrahepatic or
extrahepatic cholestasis), the kidney is responsible
for 50 to 90 % of conjugated bilirubin excretion.
Ann Surg 1966; 163:330
N Engl J Med 1966; 274:231
 However, bile remains the main excretion route for
unconjugated hyperbilirubinemia.
Cont…
 In complete biliary obstruction or severe intrahepatic
cholestasis (eg, in the early phase of acute viral
hepatitis), feces may take the appearance of china
clay.
 Thus, the absence of urobilinogen in stool and urine
in a jaundiced patient indicates complete biliary
obstruction.
 The intestinal microflora influence serum levels of
bilirubin.
 In a study in Gunn rats (which have a congenital deficiency of bilirubin
UDB-glucuronsyltransferase), treatment with oral clindamycin and
neomycin resulted in the disappearance of fecal urobilinoids while
serum bilirubin increased dramatically.
 Intestinal colonization with C. perfringens led to reappearance of fecal
urobilinoid production accompanied by a partial decrease in serum
bilirubin levels.
 The authors speculated that prolonged use of certain
antibiotics may lead to an increase in serum bilirubin
levels in humans & patients with abnormal bilirubin
conjugation may be at particular risk.
J Hepatol 2005; 42:238.
Delta Bilirubin
 Albumin-linked bilirubin fraction .
 Formed in the serum when hepatic excretion of
bilirubin glucuronides is impaired.
 Delta bilirubin constituted 8 to 90% of total bilirubin in
patients with hepatocellular and cholestatic jaundice.
 Because of its covalent binding to albumin, the
clearance of delta bilirubin is approximately the
same as albumin rather than the short half-life of
conjugated bilirubin that is not albumin bound (12 to
24 days versus 4 hours).
JAMA 1971; 218:216
 Because conjugated bilirubin is excreted in the urine, patients with
conjugated hyperbilirubinemia develop bilirubinuria.
 Some patients with conjugated hyperbilirubinemia do not exhibit
bilirubinuria during the recovery phase of their disease because delta
bilirubin.
 Late in the recovery phase of hepatobiliary disorders, virtually all the
conjugated bilirubin may be in the albumin-linked form.
 As a result, elevated serum bilirubin levels decline more slowly than
expected in some patients who otherwise appear to be recovering
satisfactorily.
Cont…
 Because delta-bilirubin gives a "direct" diazo(reagents
causes breakdown of the tetrapyrrole to two azodipyrroles which can be
readily measured spectrophotometrically)
reaction, this may give
a false impression of a persistent blockage of the
bile ducts .
 The presence of delta-bilirubin can be inferred by the
absence of bilirubin excretion in the urine despite the
apparent presence of direct hyperbilirubinemia and
can be identified by high performance liquid
chromatography of serum .
Urine Bilirubin
 The presence of bilirubin in the urine reflects direct
hyperbilirubinemia and therefore underlying hepatobiliary
disease.
 In contrast to conjugated bilirubin, unconjugated bilirubin
is tightly bound to albumin & it is not filtered by the
glomerulus.
 Conjugated bilirubin may be found in the urine when the
total serum bilirubin concentration is normal
 because the renal reabsorptive capacity for conjugated
bilirubin is low and the methods used can detect urinary
bilirubin concentrations as low as 0.05 mg/dL (0.9
micromol/L).
Cont…
 Thus, bilirubinuria may be an early sign of liver or
biliary disease, while the clearance of bilirubin
from the urine may be an early sign of recovery
since, as delta bilirubin is protein-bound.
 For clinical purposes, the predominant type of bile
pigments in the plasma can be used to classify
hyperbilirubinemia into two major categories .
 Plasma elevation of predominantly unconjugated
bilirubin due to

The overproduction of bilirubin, impaired bilirubin uptake by
the liver, or abnormalities of bilirubin conjugation
 Plasma elevation of both unconjugated and
conjugated bilirubin due to

hepatocellular diseases, impaired canalicular excretion, and
biliary obstruction
Unconjugated Hyperbilirubinemia
Hx
 Age?
 Duration of the
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complaint?
Fever or rigors?
Recent outbreak of
jaundice?
Recent consumption of
shellfish?
IVDA?
Sexual contact?
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Blood transfusion?
Alcohol consumption?
Drugs recently?
Recent travel?
Anesthesia?
Family hx (is it gilberts)
Recent biliary surgery?
Hx of hemolytic
diseases?
Specific Symptoms
 Articaria
 Pruritis
 Dark urine
 Pale stool
 Abdominal pain
 charcot’s triad??
Signs
 Is it really jaundice or
psudo?
1.carotenemia:(palms , soles
& NL folds)
2.Uremic Pigmentation Chronic uremics retain the
yellow urochrome
pigments which normally
color urine amber.
3. Industrial Staining of Skin
- In a number of industries
yellow pigments used may
stain the exposed portions
of the skin of the workers
Cont…
 ascites, splenomegaly (tipped), spider angiomata, and
gynecomastia
 Hepatomegaly
 Palplable GB
 Courvoisier sign :
palpable GB+ jaundice=CA (not GS)
 Murphey’s sign
 hyperpigmentation in hemochromatosis.
 a Kayser-Fleischer ring in Wilson's disease.
 xanthomas in primary biliary cirrhosis.
 Cold sores (HSV-hepatitis)
Ultrasonography
 The sensitivity of US for the detection of dilated bile ducts
and biliary obstruction ranges in various studies from 55
to 91 % .
 The sensitivity increases with the serum bilirubin
concentration and the duration of jaundice. Radiology 1979; 133:39
 US can also demonstrate cholelithiasis and gallbladder
stones; however, common duct stones may not be well
seen since gas in the duodenum can obscure
visualization of the distal common duct.
 The advantages of US are that it is noninvasive, portable,
and relatively inexpensive.
Endoscopic ultrasound (EUS)
 By placing an ultrasound transducer directly in the duodenum,
EUS allows complete visualization of the common bile duct
without the hindrance of overlying bowel gas, which limits
traditional ultrasound.
 EUS has a similar accuracy to ERCP for detection of small
common bile duct stones but does not carry the risk of
inducing pancreatitis.
 EUS is also highly accurate for detecting pancreatic tumors,
especially small (<3cm) tumors which are difficult to see with
helical CT.
 The main disadvantages of EUS
 the semi-invasive nature of the test
 The inability to directly remove stones found in the bile duct.
CT scan
 Conventional CT and US are equally effective for the
recognition of obstruction and identification of the level of
obstruction.
 Helical (spiral) CT has improved the accuracy of CT and
may emerge as the preferred technique for hepatobiliary
imaging .
 Helical CT offers a more comprehensive analysis of the
liver and extrahepatic abdomen and pelvis.
 CT in comparison to US
 Not as sensitive in detecting cholelithiasis because only
calcified stones are visualized.
 It is more expensive .
ERCP
 ERCP permits direct visualization of the biliary tree
and pancreatic ducts.
 It is clearly superior to US and CT for the detection of
extrahepatic obstruction .
 It is the procedure of choice when there is suspicion
of choledocholithiasis.
 Another advantage of ERCP is that a therapeutic
intervention, such as stone extraction or papillotomy,
can be performed during the procedure
Cont…
 ERCP is more expensive than US and CT .
 Invasive
 Associated with a finite rate of mortality (0.2 %)
 Complications such as bleeding, cholangitis, and
pancreatitis (3 %)
MRCP
 MRCP is a potential alternative to ERCP.
 Although contrast material is administered,
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cholangiographic images can be obtained similar to those
obtained with ERCP.
In patients with dilated ducts, a MRCP cholangiogram is
diagnostic in 90 to 100 percent of patients.
It reveals the level of obstruction in 80 to 100%
Has a sensitivity and specificity of 90 to 100 % for the
detection of choledocholithiasis and bile duct stenosis.
MRCP is as accurate as ERCP for detecting
choledocholithiasis .
Cont…
 MRCP is expensive and may eventually replace
diagnostic ERCP.
 However, it is unlikely to replace US or helical CT as
the initial imaging test in the diagnostic evaluation of
jaundice .
 ERCP is preferred in the patient with cholangitis
because it permits therapeutic drainage of the
obstruction.
Percutaneous transhepatic
cholangiography
 Requires passage of a needle through the skin into
the hepatic parenchyma and advancement into a
peripheral bile duct.
 Injection of contrast media provides close to 100 %
sensitivity and specificity for the diagnosis of biliary
tract obstruction .
Cont…
 It is similar to ERCP in cost and morbidity .
 Particularly useful when the level of obstruction is
proximal to the common hepatic duct or ERCP is
precluded for anatomic reasons.
 However, it may be technically limited in the absence
of dilatation of the intrahepatic ducts .