HEPATOBILIARY SURGERY
Jaundice: applying lessons
from physiology
Vidyasagar Ramappa
Guruprasad P Aithal
Abstract
Jaundice is a common presentation in medical and surgical gastroenter-
ology practice. Knowledge of the physiology of bilirubin metabolism
will help the clinician to understand the mechanisms of development of
jaundice. This along with clinical evaluation, laboratory investigation
and non-invasive imaging will help when making a firm diagnosis. Further
management may require advanced imaging and/or invasive techniques,
which should be chosen in the light of the given clinical scenario based
on the risk-benefit ratio, local availability and expertise.
Keywords Bilirubin; diagnosis; hyperbilirubinemia; jaundice
Introduction
Jaundice is derived from the French word jaune meaning yel-
low discolouration. It is the most common sign of liver disease. It
is characterised by yellow discolouration of the skin and mucous
membranes due to abnormal increase in the serum bilirubin
concentration. Tissue deposition of bilirubin occurs only in the
presence of serum hyperbilirubinemia and is usually a sign of
liver disease or less commonly haemolytic disorder. Clinical ex-
amination usually reveals the degree of hyperbilirubinemia. The
earliest place to manifest jaundice is the sclera due to the high
elastin in the scleral tissue and the affinity of bilirubin to it. The
presence of scleral icterus indicates a serum bilirubin of at least
50 mmol/L. Greenish tinge to icterus indicates longstanding
jaundice and is due to oxidation of bilirubin to biliverdin.
The other causes for yellowing of the skin are carotenoderma,
which is due to excess consumption of carotene-containing foods
such as carrots and leafy vegetables, wherein the sclera is spared
and the yellow pigmentation is concentrated over the palms,
soles, forehead, and nasolabial creases. Drugs such as quinacrine
and exposure to phenols also cause yellow discolouration.
Another indicator of jaundice is dark urine or tea or cola coloured
urine, which the patients commonly describe. Jaundice has
various causes and attempts to classify jaundice dates back to the
time of Hippocrates. By the time of William Osler, distinctions
were made between obstructive and non-obstructive jaundice. In
the latter part of the 20th century with a better understanding of
Vidyasagar Ramappa MD MRCP is a Specialist Registrar at the
Nottingham Digestive Disease Centre: Biomedical Research Unit,
Nottingham University Hospital NHS Trust, Nottingham, UK. Conflicts of
interest: none declared.
Guruprasad P Aithal MD PhD FRCP is a Consultant Physician at the
Nottingham Digestive Disease Centre: Biomedical Research Unit,
Nottingham University Hospital NHS Trust, Nottingham, UK. Conflicts of
interest: none declared.
SURGERY 32:12
the bilirubin metabolism, progress in imaging technology and
sophisticated biochemical methods, the exact cause of jaundice
could be elucidated. Hyperbilirubinemia occurs when the bal-
ance between production and clearance is altered and thus a
logical evaluation of a jaundiced patient requires the under-
standing of bilirubin production and metabolism.
Bilirubin metabolism (Figure 1)
Sources of bilirubin
Bilirubin, a tetrapyrrole pigment moiety, is a breakdown product of
haem (Ferriprotoporphyrin IX). In a normal healthy person daily
bilirubin production averages about 0.5 mmol (250e300 mg).
About 80% of this bilirubin is derived from breakdown of haemo-
globin from senescent red blood cells (RBCs) in the reticuloendo-
thelial system, 15% from ineffective erythropoiesis in the marrow
and 5% from turnover of haemoproteins such as myoglobin, cat-
alases and cytochromes enzyme system elsewhere in the body.
Production of bilirubin
The production of bilirubin takes place in the reticuloendothelial
system in a two-step process. First is oxidation of the haem by
haem oxygenase involving breaking open of the alpha bridge
resulting in the formation of biliverdin. Second step is reduction
of this green pigment by biliverdin reductase to colourless
bilirubin.
Plasma transport
The bilirubin so formed in the reticuloendothelial cells is virtu-
ally insoluble in water and potentially toxic. To be transported in
blood the bilirubin binds reversibly and non-covalently with
albumin.
Hepatic uptake
Unconjugated bilirubin tightly bound to albumin is transported
to the liver where the bilirubin but not the albumin is taken up
across the basolateral membrane of the hepatocytes by a carrier
mediated transport process possibly via a member of the organic
anion transporter (OATP) family.1 Within the cytosol, two
cytosolic binding proteins ligandins Y and Z transport the bili-
rubin to the smooth endoplasmic reticulum of the hepatocyte for
conjugation with glucuronic acid and also to prevents efflux of
bilirubin back in to plasma.
Hepatic conjugation
In the presence of the co-substrate uridine diphosphate (UDP),
the enzyme uridine diphosphoglucoronyl transferase (UDP-GT)
medicates conjugation of the hydrophobic bilirubin to hydro-
philic bilirubin monoglucuronide and diglucuronide conjugates
that are suitable for excretion. This enzyme is encoded by the
UDP-GT gene on chromosome 2. Mutations in the gene form the
basis of the congenital unconjugated hyperbilirubinemias. The
UDP-GT activity is well maintained in both acute and chronic
hepatocellular damage and even increased in cholestasis by gene
up regulation.2
Biliary excretion
These then diffuse from the endoplasmic reticulum towards the
apical cell membrane or the canalicular membrane to be excreted
into bile canaliculi by an ATP dependent export pump belonging
627 2014 Elsevier Ltd. All rights reserved.
 HEPATOBILIARY SURGERY
Figure 1
to the multidrug resistance protein 2 (MRP2).3 This forms the rate-
limiting step in the synthesis in bilirubin metabolism. This step is
affected in both acute and chronic hepatocellular injury thus
explaining the rise in predominantly conjugated bilirubin in such
cases. Small amounts of conjugated bilirubin are secreted across
the sinusoidal membrane by MRP3 directly into blood stream,
which undergoes renal excretion. Normally 80e85% of the bile is
made of bilirubin diglucuronide and 15e19% of bilirubin mono-
glucuronide and remaining made of traces of unconjugated bili-
rubin. The conjugated bilirubin excreted into bile drains into
duodenum and passes unchanged in the proximal small bowel
until it reaches the distal small bowel and colon wherein it is
hydrolysed by the intestinal bacterial betaglucuronidase to un-
conjugated bilirubin. This is then further reduced by the gut flora
to colourless urobilinogen. Between 80% and 90% of this is
excreted in the faeces either unchanged or oxidized to urobilin or
stercobilin, which imparts the natural colour to the stools. The
remaining 10e20% of the urobilinogen is passively absorbed and
circulated in the enterohepatic circulation for re-conjugation and
to be excreted in bile. A trace of this absorbed in the enterohepatic
circulation escapes hepatic uptake into the systemic circulation
and filtered across the glomerulus to be excreted in the urine.
Measurement of bilirubin
Serum bilirubin is measured using a variation of the original Van
den Bergh colorimetric reaction. The indirect and direct refers to
the total and conjugated bilirubin levels respectively. With the
Van den Bergh method the normal total serum bilirubin con-
centration is 17 mmol/L (<1 mg/dl). Up to 30% (i.e. 5.1 mol/L
[0.3 mg/dl]) is in the conjugated form. Increased understanding
of the bilirubin metabolism and sophisticated methods of
SURGERY 32:12
measurements of bilirubin have led to the belief that in jaundiced
patients with hepatobiliary disease, the bilirubin monoglucur-
onide fraction is higher. Unconjugated bilirubin is bound to al-
bumin and hence not filtered in the glomerulus but conjugated
bilirubin is, and almost all of it is reabsorbed by the proximal
tubules and very small traces are excreted in urine. Thus pres-
ence of bilirubinuria is a suggestion of liver disease. However in
prolonged cholestatic jaundice the conjugated bilirubin fraction
in serum covalently binds to albumin, which explains the reason
why the bilirubin levels declines more slowly than clinical re-
covery due to longer half-life of albumin.
Disorders of bilirubin metabolism
Hyperbilirubinemias can result from any defects in the steps of
bilirubin metabolism mentioned earlier:

overproduction

impaired uptake and conjugation lead to unconjugated/
indirect hyperbilirubinemia and

impaired excretion of bilirubin from damaged hepatocytes
or bile ducts leads to direct/conjugated
hyperbilirubinemia.
Overproduction of bilirubin
Haemolytic disorders either inherited or acquired leading to
excessive haem production cause hyperbilirubinemia. In these
conditions, the serum bilirubin rarely exceeds 86 mmol/L
(5 mg/dL). Generally these groups of patients have elevated
serum haptoglobulin and reticulocyte counts and there is no
alteration in liver enzymes (Table 1). Accelerated haemolysis
especially in inherited conditions is associated with formation of
pigment gallstones that may obstruct biliary tree and lead to
conjugated hyperbilirubinemia with elevated liver enzymes.
Impaired uptake and conjugation
Certain drugs like rifampicin, probenecid and protease inhibitors
like indinavir cause unconjugated hyperbilirubinemia by
reducing the hepatic uptake.4 Rare inherited syndromes such as
Crigler Najjar syndromes I and II and Gilberts syndrome are
caused by dysfunctional or absence of UDPG enzyme activity.
Crigler Najjar I is very rare and is characterized by complete
absence of the enzyme UDPG leading to neonatal kernicterus and
death. Crigler Najjar II is more common and there is reduced
activity of the enzyme and patients live to adulthood. Gilberts
syndrome is quite common and is due to reduced enzyme ac-
tivity and manifests clinically as very mild jaundice especially in
times of physiological stress characterized by isolated rise in
serum bilirubin (unconjugated fraction) and normal enzymes.
Impaired excretion
Elevated conjugated hyperbilirubinemias occur in two rare syn-
dromes namely Rotors syndrome, which is due to defective
storage of bilirubin in the hepatocytes, and Dubin Johnsons
syndrome, which is due to defect in the MRP2 gene.4 Both these
cause asymptomatic jaundice and run a benign course.
When a clinician encounters a patient with jaundice, the basic
liver function test can indicate the pattern jaundice (i.e. whether
hepatocellular or cholestatic). In hepatocellular conditions
(Table 2) there is a disproportionate rise in the cellular enzyme
concentration namely the alanine aminotransferase (ALT) and
628 2014 Elsevier Ltd. All rights reserved.
 HEPATOBILIARY SURGERY

aspartate aminotransferase (AST) compared to the alkaline

Causes of isolated hyperbilirubinemia phosphatase (ALP). However in cholestatic conditions (Table 3)
A. Increased production there is a significant rise in the ALP rather than the ALT. This,
i. Haemolysis however, is not a strict criterion, but can be used as a general
1. Congenital guide to direct the investigations appropriately. Bilirubin is,
a. Membrane defects, however, raised in both conditions and cannot be used to
e.g. spherocytosis, elliptocytosis differentiate between the pathologic processes. Prolonged pro-
b. Enzyme defects, thrombin time can occur with both hepatocellular and long-
e.g. glucose 6 phosphate dehydrogenase and pyruvate kinase standing cholestatic jaundice. Correction of the prothrombin time
deficiency after administering vitamin K is suggestive of cholestasis which
c. Haemoglobinopathies, would have resulted due to malabsorption of vitamin K. Failure
e.g. sickle cell disorder of correction of prothrombin time indicates inability to synthe-
2. Acquired sise clotting factors from vitamin K, hence, significant hepato-
a. Immune haemolysis cellular injury. Thus the pattern of liver enzymes, albumin and
b. Microangiopathic haemolytic anaemia prothrombin time will usually indicate whether a jaundiced pa-
c. Paroxysmal nocturnal haemoglobinuria tient has a hepatocellular or a cholestatic disease.
ii. Ineffective erythropoiesis
1. B12, folate deficiency, thalassaemia and severe iron
deficiency anaemia
Cholestatic condition causing jaundice
B. Impaired uptake
i. Drugs, e.g. protease inhibitors 1. Non-obstructive
ii. Inherited conditions a. Viral hepatitis
1. Crigler Najjar type I e phenobarbitone unresponsive i. Fibrosing cholestatic hepatitis e hepatitis B and C
2. Crigler Najjar type II e phenobarbitone responsive ii. Cholestasis with hepatitis e hepatitis A and E,
3. Gilberts syndrome cytomegalovirus, EpsteineBarr virus
C. Impaired excretion b. Alcoholic hepatitis
i. Inherited conditions c. Drugs
1. Dubin Johnson syndrome i. Pure cholestasis e anabolic steroids, pill
2. Rotors syndrome ii. Cholestatic hepatitis e co-amoxiclav, flucloxacillin,
erythromycin esteolate
Table 1 iii. Chronic cholestasis e chlorpromazine
d. Primary biliary cirrhosis
e. Primary sclerosing cholangitis
f. Vanishing bile duct syndrome
i Chronic rejection
Hepatocellular conditions causing jaundice
ii. Drugs: chlorpromazine
1. Viral hepatitis g. Inherited
a. Hepatitis A, B, C and E i. Progressive familial intrahepatic cholestasis
b. EpsteineBarr virus h. Miscellaneous
c. Cytomegalovirus i. Cholestasis of pregnancy
d. Herpes simplex ii. Sepsis
2. Alcohol iii. TPN
3. Autoimmune hepatitis/overlap syndromes iv. Paraneoplastic syndrome
4. Medications/drugs v. GVHD
a. Dose dependent, e.g. paracetamol overdose vi. Benign postoperative cholestasis
b. Idiosyncratic, e.g. isoniazid 2. Obstructive
5. Environmental toxins a. Malignant
Vinyl chloride, carbon tetrachloride, bush tea, kava kava, i. Cholangiocarcinoma
mushroom ii. Pancreatic cancer
6. Metabolic causes iii. Gall bladder cancer
a. Wilsons disease iv. Periampullary cancer
b. Haemochromatosis v. Malignant involvement of the porta hepatis lymph nodes
c. Non-alcoholic fatty liver disease (NAFLD) b. Benign
d. a1 antitrypsin deficiency i. Choledocholithiasis
7. Vascular causes ii. Primary sclerosing cholangitis
a. BuddeChiari syndrome iii. Chronic pancreatitis
b. Ischaemic hepatitis iv. AIDS cholangiopathy

Table 2 Table 3

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 HEPATOBILIARY SURGERY
Hepatocellular conditions that cause jaundice most commonly
include viral hepatitis, alcohol, drugs and cirrhosis from any
cause. Wilsons disease should be considered in patients who are
young (<40 years of age) and mimic acute viral hepatitis with
disproportionate hyperbilirubinemia (which is due to Coombs
negative haemolytic anaemia) and a particularly low alkaline
phosphatase with an alkaline phosphatase to bilirubin ratio of
<4.4 Middle-aged women presenting with jaundice, malaise, ar-
thralgias and fever should raise the suspicion of autoimmune
hepatitis. Alcohol-related liver diseases are associated with a
minimal or no elevation of ALT (usually <250 U/L) and an AST:
ALT ratio of at least 2:1 or greater5 though this ratio is not specific
for alcohol related liver disease alone. Raised mean cell volume
and gamma-glutamyl transferase are other markers suggestive of
alcohol aetiology. However in patients with acute viral hepatitis,
toxin, and drug-mediated or even ischaemic hepatitis the ALT can
reach very high values of typically greater than 500 U/L in the
acute setting. Drug induced jaundice is either dose related as with
paracetamol overdose or idiosyncratic occurring in a minority of
the people with a great number of drugs such as such as diclofe-
nac, phenytoin, co-amoxiclav and anti-tuberculosis drugs.6 In
patients with jaundice due to cirrhosis, there is a modest elevation
of bilirubin with modest elevation of liver enzymes as it represents
end stage of chronic hepatocellular injury. Chronic viral hepatitis
should always be a consideration especially in patients with risk
factors (previous infusion of blood products, surgical in-
terventions, and intravenous drug abuse). Clues to diagnosis of
haemochromatosis are the presence of diabetes, arthritis and
greyish complexion of the skin although patients are increasingly
diagnosed at an early stage. Cirrhosis due to alpha-1-antitrypsin
deficiency may not coexist with lung disease and can only be
identified by specific investigations.
When pattern of liver injury is cholestatic, the next step is to
investigate whether or not the cholestasis is due to biliary
obstruction using a variety of imaging modalities. In patients
with apparent non-obstructive cholestatic jaundice diagnosis is
often made by serologic testing and/or liver biopsy. A number of
conditions that cause hepatocellular jaundice can also present as
a cholestatic picture such as acute alcoholic hepatitis,7 hepatitis B
and C8 and ductopenic rejection after liver transplantation. A
variety of drugs also cause cholestatic jaundice including esteo-
late salt of erythromycin, ampicillin, flucloxacillin, clavulanic
acid,6,9 imipramine, chlorpromazine and oral contraceptive pills
wherein the jaundice has a temporal relationship with drug
usage. Drug induced cholestatic jaundice usually resolves after
withdrawal of the offending drugs seldom leads to chronic
cholestasis and progressive fibrosis. Primary biliary cirrhosis
should be suspected in middle-aged women presenting with
pruritis, jaundice and excessive fatigue. Primary sclerosing
cholangitis is characterized by intrahepatic and extrahepatic
stricturing and 75% of these patients have inflammatory bowel
disease. Cholestasis of pregnancy occurs in third trimester of
pregnancy and tends to recur in subsequent pregnancy.10 Other
causes of non-obstructive intrahepatic cholestatic jaundice
include those patients on total parenteral nutrition11 and people
with sepsis12 which occurs due to down regulation of the
transporters such as MRP2 by the proinflammatory cytokines.
Obstructive jaundice implies obstruction of biliary system
either within the liver or outside of the liver. Generally jaundice
SURGERY 32:12
only develops when majority of the biliary drainage is impaired,
hence obstruction from truly intrahepatic cholangiocarcinoma
may not cause clinical jaundice. Both benign (chol-
edocholithiasis) and malignant conditions (pancreatic, bile duct
and gall bladder cancers) present with jaundice. Chronic
pancreatitis can cause distal bile duct stricturing where the duct
traverses the head of pancreas. AIDS cholangiopathy is due to
opportunistic infection of the biliary epithelium resulting in
stricturing mimicking primary sclerosing cholangitis.13 Biliary
strictures causing jaundice also can occur after hepatic arterial
infusion of chemotherapeutic agents or result from surgical
injury to the bile duct or the hepatic artery.14
Diagnostic approach to the patient with jaundice
The key steps for the evaluation of a patient with jaundice
involve:

history taking and clinical examination.

screening lab tests and formulation of a working differen-
tial diagnosis.

specialized tests to further narrow the diagnosis.
History and clinical examination
Carefully elicited history and physical examination in the light of
the routine laboratory screening tests can correctly differentiate
between hepatocellular and cholestatic jaundice in up to 75% of
the cases. Physical examination provides important clues in a
patient with jaundice. Fever and abdominal tenderness, espe-
cially in the right upper quadrant suggests cholangitis and biliary
sepsis. Palpable gall bladder has been considered a sign sug-
gestive of pancreatic neoplasm and against choledocholithiasis
(Courvoisiers law) though this finding is neither sensitive nor
specific. Ascites, spider naevi and gynaecomastia are suggestive
of chronic parenchymal liver disease. Xanthomas are suggestive
of primary biliary cirrhosis, skin hyperpigmentation in haemo-
chromatosis and KaysereFleischer rings in Wilsons disease.
Initial laboratory evaluation
A battery of tests is helpful in the initial workup of a jaundiced
patient. These include bilirubin, liver enzymes (ALT, AST and
ALP), and prothrombin time. The activity of ALP significantly
rises in the setting of biliary obstruction and intrahepatic chole-
stasis. However increase in alkaline phosphatase may reflect
release of isoenzymes from extrahepatic tissues especially from
bones. Thus more specific markers of biliary canalicular enzymes
such as gamma glutamyl transferase, 50 nucleotidase are esti-
mated to confirm the hepatic origin of the elevated alkaline
phosphatise. Aminotransferases (ASTefound in cytosol and
mitochondria of hepatocytes and other extrahepatic tissues such
as cardiac and skeletal muscle) and ALT (predominantly seen in
cytosol of the hepatocytes) are elevated in liver cell damage
caused by drugs, toxins, ischaemia and viral infection most
commonly hepatitis E in the developed world, a significant pro-
portion of which are often misdiagnosed.15 Predominant amino-
transferase (ALT, AST) elevation compared to ALP suggests
hepatocellular disease. However, chronic alcohol excess leads to a
deficiency of 5 pyridoxal phosphate enzyme, a necessary co-
substrate for aminotransferases.16 Deficiency of co-substrate re-
sults in little or no elevation of ALT (and a corresponding serum
concentration of AST to ALT ratio of >2) that has been considered
630 2014 Elsevier Ltd. All rights reserved.
 HEPATOBILIARY SURGERY

characteristic of alcoholic liver disease. Acute Wilsons disease
can also present with a similar biochemical picture. Measurement
of the markers of copper metabolism such as ceruloplasmin and
serum copper in the setting of acute Wilsons is of little utility.17
Haemolysis leads to AST release from erythrocytes and causes
excess elevation of AST with an AST:ALT ratio of >2.2. A com-
bination of high bilirubin (due to coexistent haemolysis) and a
low ALP is also a characteristic feature of acute liver failure due to
Wilsons disease. A combination of a ratio of ALP (IU/L) to total
bilirubin (mg/dl) of <4 and AST to ALT ratio of >2.2 has a very
high sensitivity and specificity for the diagnosis of Wilsons dis-
ease in subjects presenting with acute liver failure.
There are, however, exceptions to the rule wherein a rise in
ALT up to ten times upper limit of normal can occur with chol-
edocholitiasis with cholangitis.18 In addition, the levels of liver
enzyme elevation do not reflect the severity of liver injury nor
the prognosis of the patient.
Prothrombin time is a measure of the activity of the clotting
factors I, II, V, VII and X that are synthesized in the liver. Pro-
longation of the prothrombin time reflects hepatocellular injury
or a deficiency of vitamin K that is involved in the synthesis of
clotting factors II, VII, IX and X. Correction of prothrombin time
after parenteral vitamin K reflects cholestasis/biliary obstruction
causing vitamin K malabsorption.
Thus, integrating the history, physical examination and initial
laboratory tests helps to distinguish pre-hepatic from hepatocel-
lular or cholestatic causes of jaundice. Further selection of
appropriate special investigations, imaging in particular for
biliary obstruction is based on this initial information.
Imaging studies (Table 4)
Abdominal ultrasonography
This is the initial imaging of choice to obtain information about
the hepatic parenchyma and the intra and extrahepatic biliary
tree. It is non-invasive and reproducible.19,20 However, there is
an element of interobserver variation in real-time ultrasonogra-
phy and the major disadvantages are that interpretation can be
difficult in obese patients and periampullary lesion and distal
common bile duct pathology cannot be easily made out due to
obscuring bowel gas. The sensitivity and specificity of detecting
biliary obstruction in jaundiced patient varies between 55e91%
and 82e95% respectively depending on the site of obstruction
and radiographers experience.
CT scan of the abdomen
This is an alternative means of obtaining information about
obstructed biliary tree and gives more accurate measurement of
the calibre of the dilated biliary tree and the level of obstruc-
tion.19e21 It is also good for imaging the pancreas and peri-
ampullary region. It has the ability to detect subcentimeter
lesions. The sensitivity rates are in the range of 63e96% and
specificity up to 100% for detecting the calibre of the dilated
biliary tree and locating the mass lesions.
Magnetic resonance cholangiopancreatography
This modality of imaging permits clear cut and rapid delineation
of the biliary tree and is superior to ultrasonography or CT.22 The
usage is growing in clinical practice with increasing availability.
It has a sensitivity of 90e100% and specificity of 94e98% in
detecting lesions of the biliary tree. It is advantageous by the fact
that it does not involve any contrast to be administered and has
running costs comparable to that of a diagnostic ERCP.
Endoscopic retrograde cholangiopancreatogram (ERCP)
ERCP has been considered as the gold standard for the investi-
gation of biliary tree pathology in majority of the cases. It in-
volves passage of an endoscope into the duodenum and
catheterization of the ampulla of Vater and injection of contrast
medium into the biliary tree and/or pancreatic tree for direct

Comparison of performance characteristics of imaging modalities

Imaging modality Sensitivity Specificity Morbidity Mortality Comments

Abdominal ultrasound 55e91 82e95 e e Non-invasive, portable, operator dependent,

Abdominal CT
Magnetic resonance
cholangiopancreatography
Endoscopic retrograde
cholangiopancreatogram
THC
Endoscopic ultrasonography
difficult interpretation in obese patients and
bowel gas may obscure distal biliary tree
63e96 93e100 Non-invasive, better resolution than USG,
exposure to radiation and contrast induced
renal toxicity
84e100 94e98 e e Non-invasive, superior to USG and CT for
biliary tree imaging. Claustrophobia, patient
compliance, may miss small calibre duct
disease
89e98 89e100 3 0.2 Direct imaging, permits sampling, therapeutic
intervention, associated complications
98e100 89e100 3 0.2 Similar to ERCP, but more useful for lesions
proximal to the common hepatic duct, difficult
if intrahepatic ducts not dilated
89e97 67e98 e Superior to USG and CT, ability to obtain
histology

Table 4

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 HEPATOBILIARY SURGERY

visualisation of the pancreatobiliary tree. It is invasive involving

the use of sedation, analgesia and contrast medium. It is highly
accurate in diagnosing obstruction of the biliary tree and permits
acquisition of biopsy or brushings for cytology and permits
therapeutic procedures such as sphincterotomy, stone extraction,
and dilatation of stricture and stent insertion. ERCP is highly
accurate in diagnosis of biliary tree pathology with sensitivity
rates of 89e98% and specificity of 89e100%.20 The overall
technical success rate is above 90%. It however, also is associ-
ated with risks of pancreatitis (2% in low risk individuals and
overall mean rate of around 5%) and other complications such as
bleeding, perforation. respiratory complications (3%) being
higher when interventional procedures are performed.23 The
overall cost of ERCP is much higher than all other non-invasive
imaging.24

Percutaneous transhepatic cholangiography (PTC)

This involves passage of a fine needle catheter through the skin
into the liver to cannulate a peripheral bile duct till aspiration of
bile and obtaining images of the biliary tree with injection of
contrast medium. This procedure is used in cases wherein ERCP
has been unsuccessful or considered not feasible due to altered
anatomy following surgery. In patients with known hilar stric-
tures, PTC has been recommended by some as a preferred initial
investigation because of a modest success rate for decompression
using ERCP in such clinical scenario. The procedure has sensi-
tivity and specificity of 89e100% and 98e100%, respectively.
The morbidity and mortality is similar to that of ERCP.25

Endoscopic ultrasonography (EUS)

This modality obtains images of the biliary tree with sensitivity
and specificity comparable to that of MRCP26 and has advantage
of permitting sampling of the pancreatic lesions and more ac-
curate staging of neoplasms comparable to that of CT. In
selected cases of low probability of obstruction of the biliary tree,
the choice of directly proceeding to therapeutic ERCP following
EUS is an added advantage and this initial EUS strategy has the
greatest cost utility by avoiding unnecessary ERCP procedures.24 Figure 2
The risks involved in EUS is similar to that of any diagnostic
upper GI endoscopy with mortality and morbidity rate of <0.1%
when biopsy is involved.27 EUS is useful in situations in wherein the next step in the management would be direct visualization
the patient is felt to be a high-risk candidate for ERCP or PTC. with ERCP or PTC and appropriate treatment instituted at the
same sitting if permissible. However if the biliary tree is not
Nuclear imaging studies
dilated on the initial screening ultrasound or CT then further
Though a non-invasive test useful in investigating biliary disease
investigations are based on the clinical likelihood of biliary
such as cholecystitis and biliary dyskinesias it has limited use-
obstruction. If the likelihood of biliary obstruction is low then
fulness in the investigation of a jaundiced patient.
investigations should be directed towards workup of intrinsic
liver disease. In cases of intermediate suspicion of biliary
Diagnostic strategies for imaging
obstruction then MRCP or EUS is the investigation of choice prior
The choice and order of imaging modalities depend on the clin- to investigation of hepatic disorder In this patient population
ical probability of biliary obstruction causing jaundice (Figure 2). with a low disease prevalence, EUS is superior to MRCP in
Based on a clinical decision analysis model of obstructive jaun- detecting bile duct stones <5 mm that would have been missed
dice several diagnostic imaging modalities have been on a abdominal US or CT. EUS is most useful for confirming a
compared.28 The implication of these studies is that if the sus- normal biliary tree.29 In patients whom ERCP or PTC is the
picion of biliary obstruction is high and initial ultrasound does investigation of choice the default choice would be in favour of
not reveal a dilated biliary system then further studies to visu- ERCP as it offers a broader range of interventional options than
alise the biliary system should be pursued. Thus in a jaundiced PTC. Clinical strategies depend heavily on the local expertise and
patient the initial approach to investigate the biliary tree would availability of a particular specialist procedure such as MRCP and
be either an ultrasound or CT scan. If the bile ducts are dilated endoscopic ultrasound.

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 HEPATOBILIARY SURGERY
In a patient with biliary obstruction, therapy is directed at
relieving the obstruction. The available options are interven-
tional endoscopic and radiologic modalities which include
sphincterotomy, balloon dilatation of focal strictures, and
placement of drains or stents. The investigatory and therapeutic
strategy choice will depend on the location the obstruction and
the likely cause of obstruction. Focal intrahepatic strictures are
generally amenable to radiologic approach for balloon dilatation.
Lesions distal to the bifurcation of the hepatic ducts are generally
amenable to ERCP.
Serology
When imaging studies do not reveal biliary obstruction, jaun-
diced patients with biochemical evidence of cholestasis and or
hepatocellular dysfunction should be evaluated for evidence of
underlying liver disease. Based on the initial clinical history and
presentation in the light of clinical suspicion various laboratory
tests need to be performed. They include hepatitis viral serology
for hepatitis B and C in chronic cases and hepatitis A and E,
EBV, CMV for acute presentations, iron studies which include
serum iron level, ferritin, transferrin saturation for haemo-
chromatosis, serum copper and cerruloplasmin for Wilsons
disease, autoantibody profile (i.e. antinuclear antibodies [ANA],
liver kidney microsomal antibody [LKMA] and smooth muscle
antibody [SMA] with serum immune electrophoresis or immu-
noglobulin estimation for autoimmune hepatitis, anti-
mitochondrial and M2 antibodies for primary biliary cirrhosis
and a1-antitrypsin for a1-antitrypsin deficiency. If none of these
serologic investigations reveal the cause of jaundice, liver bi-
opsy is suggested as the investigatory modality that provides
precise details of the hepatic lobular architecture and special
histological stains will elucidate the cause in majority of undi-
agnosed persistent jaundice.
In summary, the key to investigation to the diagnosis and
management of patients with jaundice is to distinguish initially
as to whether pattern of liver injury is hepatocellular or chole-
static. In cholestatic conditions, it is important to consider non-
obstructive causes, confirm biliary obstruction with less inva-
sive imaging modalities followed by appropriate techniques to
establish the diagnosis as well as institute prompt treatment. The
choice of test and technique in an individual patient depends on
combination of clinical decision making, access and expertise in
particular techniques. A Pirinen AE. A comparison of ultrasound, computed tomography and
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