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Approach To

Petrus Irianto

Bilirubin Metabolism

Bilirubin breakdown of mature RBCs in the RES.

15% of bilirubin comes from the catabolism of other haemcontaining proteins, such as myoglobin.

250 300 mg of bilirubin are produced daily.

Biliverdin is formed from the haem and this is reduced to

form bilirubin.

The bilirubin produced is unconjugated and is transported to

the liver attached to albumen.

Jaundice is a common feature of both acute

and chronic liver diseases as well as
disorders of a non-hepatic origin.

Jaundice can be recognized clinically at

serum bilirubin levels of 3mg/dl or more.

Besides a rise in the bilirubin level,

yellowness of the skin can be due to
carotenoderma, use of drug quinacrine &
excessive exposure to phenols.

Jaundice can occur in four different ways:

1- Increased bilirubin load as in haemolysis.
2- Disturbance in the hepatic uptake &
of bilirubin within the hepatocytes
3- Defects in conjugation.
4- Defects in the excretion of conjugated
bilirubin across the canalicular cell
membrane or an obstruction of the large
biliary channels.


The onset of Jaundice in viral hepatitis is

associated with a prodrome of ANV, malaise &

The onset of cholestasis is insidious, it is

associated with pruritus.

A history of fever with rigors, Rt upper abd. pain

or a past history of biliary surgery suggest

Dark urine & pale stool exclude the possibility of

haemolytic jaundice.

A history of multiple sex partners, travel, ethanol

intake, drugs, bl. transfusion, needlestick
exposure & tattooing is also important.

Recent surgery with subsequent jaundice

after one week may suggest halothane

Previous biliary surgery with subsequent

jaundice may suggest stricture, residual
stones or hepatitis.

A family history of jaundice or liver disease

suggests the possibility of hereditary
hyperbilirubinaemia or genetic disorder such
as Wilson disease.

The clinical assessment & basic biochemical

parameters lead to three broad subgroups of

1- Isolated elevation of s. bilirubin: when AST,

ALT & ALP levels are normal.

2- Hepatocellular jaundice: when the AST & ALT

levels are elevated out of proportion to the

3- Cholestatic jaundice: when the ALP level is

elevated out of proportion to the AST & ALT

Isolated elevation of serum Bilirubin

Unconjugated Hyperbilirubinaemia
* Increase bil. production (e.g. haemolysis,
resorptionof haematoma)
* Decrease hepatocellular uptake (e.g.
* Decrease conjugation (Gilbert S, Crig.
Nagar S)
Conjugated Hyperbilirubinemia
* Dubin-Junson syndrome
* Roter syndrome

Hepatocellular Jaundice
Acute or subacute hepatocellular injury
Viral hepatitis, alcohol, drugs, ischemic hepatitis, Wilson's disease,
acute fatty liver of pregnancy

Chronic hepatocellular Disease:

Viral hepatitis, alcoholic, autoimmune hepatitis, Wilson dis.,
Haemochromatosis, NASH, alpha 1 antitrypsin deficiency.

Hepatic disorders with prominent cholestasis.

* Diffuse infiltrative disorders (e.g. granulomat dise. as TB,
sarcoidosis, lymphoma, drugs) Amyloidosis, malignancy.
* Inflammation of intrahepatic bile ductules (PBC), GVHD, Drugs
* Miscellaneous e.g. use of oestrogen & steroids, TPN, bact.

Obstruction of The bile duct

Choledocholithiasis, 1ry SC, AIDS, pancreatitis
Carcinoma gallbladder, periampullary carcinoma,
cholangiocarcinoma, Cancer head of pancreas

Isolated elevation
of serum Bilirubin


Type of Jaundice

Cause of Jaundice

* Bil. production (e.g. haemolysis, resorption
of haematoma)
Hepatocellular uptake (e.g. rifampcin)
conjugation (e.g. Gilbert S, Crig. Nagar S)
* Dubin-Junson sundrome
* Roter syndrom
Acute or subacute
Viral hepatitis, alcohol, drugs, ischemic hepatiti
hepatocellular injury Wilsons disease, acute fatty liver of pregnancy
Chronic hepatocellu Viral hepatitis, alcoholic, autoimmune hepatitis
Haemochromatosis, Wilson dis., NASH, alpha
1 antitrypsin deficiency.
Hepatic disorders
with prominent

Obstruction of
The bile duct

* Diffuse infiltrative disorders (e.g. granulomat

dise. As TB, sarcoidosis, lymphoma, drugs)
Amyloidosis, malignancy.
* Inflammation of intrahepatic bile ductules
(PBC), GVHD, Drugs (chloropromazine)
* Miscellaneous e.g. use of oestrogen &
steroids, TPN, bact. Infection.


Choledocholithiasis, 1ry SC, AIDS, pancreatitis


Carcinoma gallblader, periampullary carcinoma

cholangiocarcinoma, Cancer head of pancreas

Physical Examination:

-Stigmata of CLD J. is hepatocellular in origin.

-High fever, right upper abd. tenderness cholangitis
& choledocholithiasis.
-Palpable abdominal mass Malignant obstructive J.
-Rt. upper abd. scar or palpable gallbladder Obst. J.
-Certain physical findings may suggest a particular liver
*Hyperpigmentation haemochromatosis.
*Xanthoma PBC.
*Kayser-Fleischer rings Wilson disease.

-A systemic illness should be excluded e.g.

distended jugular veins in constrictive
pericarditis or Rt. Heart F in patient with
hepatomegaly & ascites.
-Hard nodular liver 1ry or 2ry malignancy.
-Diffuse lymphadenopathy infectious
mononucleosis or lymphoma.

Laboratory, Radiological & Histological Evaluation:

*Serum Biochemical Tests:
-The normal serum bilirubin is <1.5mg/dl of which
<0.5% is conjugated.
-In haemolysis or genetic disorders e.g. Gilbert synd., there is
unconjugated hyperbilirubinaemia (>90%).
-In hepatocellular j. >50% of bilirubin is conjugated.
-In obstructive j., the circulating bilirubin is mainly conj.
* The degree of elevation of s. bil., correlates poorly with
clinical severity.
* Unconjugated bil is not excreted in the urine & thus in
unconjugated hyperbilirubinaemia, bil. is absent in urine.

Serum Enzymes:
Enzymes raised in hepatocellular injury:
Aminotransferases include ALT (located in cytosol) &
AST (located in mitochondria & cytosol).
ALT is found mainly in liver while AST is also found in
other tissues such as skeletal & cardiac muscle.
ALT is more specific than AST in detecting liver dise.
AST & ALT are released following hepatocyte necrosis.
A marked raise in transaminases > 1000 U/L, is seen in
AVH, ischaemic hepatitis & drug-induced liver disease.
In alcoholic liver disease, the enzyme levels are rarely
> 200-300 U/L, with AST:ALT ratio >2:1.

Enzymes raised in cholestasis:

Alkaline Phosphatase (ALP), gamma-glutamyl

transpeptidase (GGT) & 5-nucleotidase
ALP isoenzymes are also present in bone &
Increase in ALP, GGT & 5NT hepatobiliary
GGT levels are often disproportionately
elevated in alcoholic liver disease.


Albumen is synthesized by liver & has a half-life of 1520 days.

Decreased level of albumen are seen in advanced
hepatic cirrhosis & signify severe hepatic
S. albumen usually remain normal in acute hepatitis;
falling values in this setting imply an unusual sever
Non-specific diffuse elevation is common in CLD.
There is a disproportionate elevation of IgG in
autoimmune hepatitis, IgM in PBC & IgA in alcoholic
liver disease.

International normalized ratio (INR) &

Prothrombin time (PT):
INR/PT is a valuable index of the ability of liver
to synthesize vit. K-dependent clotting factors.
An increasing INR/PT implies relatively severe
hepatocellular dysfunction.
The INR/PT may be deranged in cholestasis as
well, but this is due to the malabsorption of
vit. K & is rapidly corrected by parenteral
administration of vit K.

Other tests:
-Serological/replicative markers for specific
diagnosis of acute or chronic viral hepatitis.
-Antimitochondrial antibody (AMA) for PBC;
antinuclear factor (ANA), anti-smooth muscle
antibody (ASMA) & anti-liver kidney microsome
(LKM) antibody seen in autoimmune hepatitis;
alpha-fetoprotien, which is raised in HCC & s.
caeruloplasmin for Wilson disease.

Imaging Procedures:
Radiological imaging is important for the
diagnosis of a focal liver mass or biliary
disease. However, imaging plays little role in
the evaluation of diffuse hepatocellular e.g.

Ultrasonography (US):
It is a valuable but operator-dependent
It has sensitivity of 55-91% & specificity of
82-95% for biliary obstruction.
Although US may not detect stones in the
extrahepatic bile duct, which may be
obscured by overlying gas, it reliably
establishes the presence of a dilated bile

Ultrasonography (US):


Beside it can differentiate intrahepatic from

extrahepatic cholestasis, US can also
detect the associated abnormalities such
as portal hypertension, focal lesions &
fatty liver.

Computerized Tomography (CT):

CT has a sensitivity of 63-96% & a specificity of
93-100% to detect biliary obstruction.
Non-calcified cholestrol gall stones can be easily
missed on CT because they may be isodense
with bile.

Endoscopic retrograde
ERCP not only permits direct visualization of the
biliary tree but also allows therapeutic
intervention e.g. removal of CBD stones or
biliary stenting. It is the gold standard test for
the evaluation of extrahepatic biliary disease
causing jaundice.

Percutaneous transhepatic
cholangiography: PTC
IN PTC, direct contrast visualization of the
biliary tree is obtained via a percutaneous
needle puncture of the liver. It is useful if
there is high biliary obstruction e.g. a tumour
at the bifurcation of the hepatic ducts.
It also permits therapeutic intervention such as
stent insertion to bypass a ductal malignancy.

Magnetic resonance
MRCP is superior to US & CT in detecting
biliary obstruction. It has a sensitivity of 82100% & a specificity of 92-98% to detect
biliary obstruction.

Liver Biopsy:
It has relatively low risk, it is needed in only
a minority of cases with hepatic
Major indications include chronic hepatitis,
cirrhosis, unexplained liver enzyme
abnormalities, hepatosplenomegaly of
unknown aetiology, suspected infiltrative
disorder, suspected granulomatous

Liver Biopsy:


Relative contraindications include a

tendency for clinical bleeding, INR>1.5 or
PT >3 sec above the control, severe
thrombocytopenia & marked ascites.
The risk of fatal haemorrhage in patients
undergoing LB is 0.4% if they have a
malignancy & 0.04% if they have nonmalignant disease.