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EXTRAHEPATIC BILIARY TRACT PATHOLOGY Darien Liew Daojuin

CHOLELITHIASIS, CHOLEDOCHOLITHIASIS
CHOLECYSTITIS AND CHOLANGITIS 12 May 2017
 Prepared by
CHOLELITHIASIS (GALLSTONES) Darien Liew Daojuin
12 May 2017
DEFINITION OF CHOLELITHIASIS

Cholelithiasis involves the presence of

gallstones, which are concretions that
form in the biliary tract, usually in the
gallbladder.

Characteristics
Develop insidiously
May remain asymptomatic for
decades
Biliary colic increase gallbladder
wall tension due to bile outflow
obstruction

Cystic duct obstruction persisting for > a

few hours can result in acute cholecystitis.
PATHOGENESIS
Risk Factor
PATHOGENESIS OF CHOLESTEROL STONES
1. Supersaturation
Increased biliary secretion of cholesterol
Associated with risk factors, e.g. obesity, metabolic syndrome, high caloric/cholesterol-
rich diets and genetic risk factors etc.
Genetic factors
Mutation in CYP7A1 results in deficiency of the enzyme cholesterol 7-hydroxylase, which
catalyzes the initial step in cholesterol catabolism and bile acid synthesis.
Mutations in the MDR3 (ABCB4) gene, which encodes the phospholipid export pump in the
canalicular membrane of the hepatocyte, may cause defective phospholipid secretion into bile,
resulting in cholesterol supersaturation of bile and formation of cholesterol gallstones
While supersaturation of bile with cholesterol is an important prerequisite for
gallstone formation, it is generally not sufficient by itself to produce cholesterol
precipitation in vivo. Most individuals with supersaturated bile do not develop stones
because the time required for cholesterol crystals to nucleate and grow is longer than
the time bile remains in the gallbladder.
PATHOGENESIS OF CHOLESTEROL STONES
2. Nucleation
Accelerated nucleation of cholesterol monohydrate in bile may be due to either an
excess of pronucleating factors or a deficiency of antinucleating factors.
Cholesterol monohydrate crystal nucleation and crystal growth probably occur within
the mucin gel layer.
Mucus hypersecretion resulting in trapping of the crystals and enhancing their
aggregation into stones.

3. Gallbladder hypomobility
If the gallbladder emptied all supersaturated or crystal-containing bile completely,
stones would not be able to grow. A high percentage of patients with gallstones
exhibit abnormalities of gallbladder emptying.

4. Biliary sludge
The presence of biliary sludge implies two abnormalities: (1) the normal balance
between gallbladder mucin secretion and elimination has become deranged, and (2)
nucleation of biliary solutes has occurred.
PATHOGENESIS (SUMMARY)
Cholesterol gallstone disease occurs
because of several defects, which include
1. bile supersaturation with cholesterol,
2. nucleation of cholesterol monohydrate
with subsequent crystal retention and
stone growth, and
3. hypomobility abnormal gallbladder
motor function with delayed emptying
and stasis.
TYPES OF GALLSTONES
Gallstones are formed because of abnormal bile composition. They
are divided into two major types:
1. Cholesterol stones
Account for >90% of all gallstones in Western industrialized countries.
Cholesterol gallstones usually contain >50% cholesterol monohydrate plus an
admixture of calcium salts, bile pigments, proteins, and fatty acids.

2. Pigment stones
Composed primarily of calcium bilirubinate; they contain <20% cholesterol and
are classified into black and brown types, the latter forming secondary to
chronic biliary infection.
TYPES OF GALLSTONES
1. CHOLESTEROL STONE

Cholesterol stones arise exclusively in the gallbladder

Consist of 50% to 100% cholesterol.
Pure cholesterol stones are pale yellow; increasing proportions of
calcium carbonate, phosphates, and bilirubin impart gray-white to
black discoloration.
They are ovoid and firm; they can occur singly, but most often there
are several, with faceted surfaces resulting from their apposition.
Most cholesterol stones are radiolucent, although as many as 20%
may have sufficient calcium carbonate to be radiopaque.
TYPES OF GALLSTONES
2. PIGMENT STONE

May arise anywhere in the biliary tree and are classified into black
and brown stones.
Black pigment stones are found in sterile gallbladder bile.
Black stones are usually small in size, fragile to the touch, and numerous
Because of calcium carbonates and phosphates, 50% to 75% of black stones are
radiopaque.

Brown stones are found in infected intrahepatic or extrahepatic

ducts.
Brown stones tend to be single or few in number and to have a soft, greasy, soaplike
consistency that results from the presence of retained fatty acid salts released by
the action of bacterial phospholipases on biliary lecithins.
Brown stones, which contain calcium soaps, are radiolucent.

The stones contain calcium salts of unconjugated bilirubin and lesser

amounts of other calcium salts, mucin glycoproteins, and cholesterol.
 TYPES OF GALLSTONES

Cholesterol Gallstones Pigmented Gallstones

TYPES OF GALLSTONES
3. MIXED STONE

Cholesterol gallstones may become colonized with bacteria and can

elicit gallbladder mucosal inflammation.
Lytic enzymes from the bacteria and leukocytes hydrolyze bilirubin
conjugates and fatty acids.
As a result, over time, cholesterol stones may accumulate a substantial
proportion of calcium bilirubinate and other calcium salts, producing
mixed gallstones.
CLINICAL MANIFESTATION
Only 10% of individuals with gallstones develop clinical evidence.
Symptomatic gallbladder stones will manifest as biliary pain of
cholecystitis.
Sudden onset and persists for 2 hours, if it continues for >6 hours, a complication such
as cholecystitis or pancreatitis may be present.
Often excruciating, which typically localizes to the right upper quadrant or epigastric
region and can be constant or, less commonly, spasmodic.
Such biliary pain is caused by gallbladder or biliary tree obstruction, or by
inflammation of the gallbladder itself.
The pain is constant in nature and is not relieved by emesis, antacids, defecation,
flatus, or positional changes. It may be accompanied by diaphoresis, nausea, and
vomiting.
BILIARY COLIC
Characteristics of Biliary Colic
Sporadic and unpredictable episodes
Pain that is localized to the epigastrium or right upper quadrant, sometimes
radiating to the right scapular tip
Pain that begins postprandially, is often described as intense and dull,
typically lasts 1-5 hours, increases steadily over 10-20 minutes, and then
gradually wanes
Pain that is constant; not relieved by emesis, antacids, defecation, flatus, or
positional changes; and sometimes accompanied by diaphoresis, nausea,
and vomiting
Nonspecific symptoms (eg, indigestion, dyspepsia, belching, or bloating)
HISTORY
Gallstone disease may be thought of as having the following 4 stages:
1. The lithogenic state, in which conditions favor gallstone formation
2. Asymptomatic gallstones
3. Symptomatic gallstones, characterized by episodes of biliary colic
4. Complicated cholelithiasis
HISTORY
Distinguishing uncomplicated
biliary colic from acute
cholecystitis or other
complications is important. Key
findings that may be noted
include the following:
Uncomplicated biliary colic
Pain that is poorly localized and
visceral; an essentially benign
abdominal examination without
rebound or guarding; absence of
fever
Acute cholecystitis Well-
localized pain in the right upper
quadrant, usually with rebound
and guarding; positive Murphy
sign (nonspecific); frequent
presence of fever; absence of
peritoneal signs; frequent
presence of tachycardia and
diaphoresis; in severe cases,
absent or hypoactive bowel
sounds
INVESTIGATION
Ultrasound investigation of choice
CT and MRCP for detecting
complications of gallstones
TREATMENT
SURGICAL

Once gallstones become symptomatic, definitive surgical intervention

with cholecystectomy is usually indicated (typically, laparoscopic
cholecystectomy is first-line therapy at centers with experience in this
procedure).
Careful selection of patients is warranted and should fulfill the
following criteria:
Small stone size (<0.5 to 1 cm)
Good gallbladder function (e.g, normal filling and emptying)
Minimal or no calcification
REFERENCES
1. http://emedicine.medscape.com/article/175667-overview
2. Harrisons Principles of Internal Medicine, 19th Edition
3. Davidsons Principles and Practice of Medicine, 22nd Edition
4. Robbins Basic Pathology, 9th Edition
 Prepared by
CHOLEDOCHOLITHIASIS Darien Liew Daojuin
12 May 2017
DEFINITION
Choledocholithiasis refers to the presence of 1 or more gallstones
in the common bile duct (CBD).
This occurs when a gallstone passes from the gallbladder into the CBD.
A gallstone in the common bile duct may impact distally in the ampulla
of Vater, causing abdominal pain and jaundice.
Stagnant bile often becomes infected, and bacteria can spread
rapidly back up the ductal system into the liver to produce a life-
threatening infection called ascending cholangitis.
Obstruction of the pancreatic duct by a gallstone in the ampulla of
Vater can trigger activation of pancreatic digestive enzymes within
the pancreas itself, leading to acute pancreatitis.
PATHOPHYSIOLOGY
Passage of gallstones into the CBD occurs in 1015% of patients with
cholelithiasis. The incidence of common duct stones increases with
increasing age of the patient, so that up to 25% of elderly patients may
have calculi in the common duct at the time of cholecystectomy.
Undetected duct stones are left behind in 15% of cholecystectomy
patients.
The overwhelming majority of bile duct stones are cholesterol stones
formed in the gallbladder, which then migrate into the extrahepatic
biliary tree through the cystic duct.
PATHOPHYSIOLOGY
Primary calculi arising de novo in the ducts are usually brown
pigment stones developing in patients with
1. hepatobiliary parasitism or chronic, recurrent cholangitis;
2. congenital anomalies of the bile ducts (especially Carolis disease);
3. dilated, sclerosed, or strictured ducts; or
4. an MDR3 (ABCB4) gene defect leading to impaired biliary
phospholipids secretion (low phospholipidassociated cholesterol
cholelithiasis).
Common duct stones may remain asymptomatic for years, may pass
spontaneously into the duodenum, or (most often) may present with
biliary colic or a complication.
PARASITISM
Parasites residing in the biliary tree include
1. Clonorchis sinensis,
2. Opisthorchis viverrini,
3. Opisthorchis felineus, and
4. Fasciola hepatica.
They are willowy, leaf-like, flat flukes dwelling in the bile ducts and
gallbladder. Human ascarides, Ascaris lumbricoides, dwelling in the
small intestine, inadvertently migrate into the bile ducts and cause
biliary obstruction.

Reference : https://www.ncbi.nlm.nih.gov/pubmed/17515382
CLINICAL FEATURES
May be asymptomatic
May be found incidentally by operative cholangiography at
cholecystectomy
May manifest as recurrent abdominal pain with or without jaundice.
RUQ pain
Fever, pruritus and dark urine
 Prepared by
CHOLECYSTITIS Darien Liew Daojuin
12 May 2017
ACUTE CHOLECYSTITIS
Acute inflammation of the gallbladder wall usually follows obstruction of
the cystic duct by a stone. Inflammatory response can be evoked by three
factors:
1. mechanical inflammation produced by increased intraluminal
pressure and distention with resulting ischemia of the gallbladder
mucosa and wall
2. chemical inflammation caused by the release of lysolecithin (due to
the action of phospholipase on lecithin in bile) and other local tissue
factors; this will disrupt the normal mucosal epithelium to the direct
detergent action of bile salts. Prostaglandin released will contribute
to mucosal and mural inflammation.
3. bacterial inflammation, which may play a role in 5085% of
patients with acute cholecystitis. The organisms most frequently
isolated by culture of gallbladder bile in these patients include
Escherichia coli, Klebsiella spp., Streptococcus spp., and Clostridium
spp.
PATHOPHYSIOLOGY
Cause Mechanism of injury Type of Injury
Obstruction of the Distention of the Ischemic necrosis
outflow tract and/or gallbladder
compression of the cystic
artery by a gallstone
Mechanical and Formation of Mucosal injury or
inflammatory injury to inflammatory mediators necrosis and
biliary cells and chemical injury by inflammation
detergents
Secondary bacterial Inflammatory response Mucosal injury or
infection necrosis and
inflammation
ACUTE CHOLECYSTITIS
Acute calculous cholecystitis Acute inflammation of a gallbladder
that contains stones. Precipitated by obstruction of the gallbladder
neck or cystic duct.
MORPHOLOGY
In acute cholecystitis, the gallbladder usually is
enlarged and tense,
bright red or blotchy, violaceous color, the latter imparted by subserosal hemorrhages.

The serosa frequently is covered by a fibrinous, or in severe cases,

fibrinopurulent exudate.
In 90% of cases, stones are present, often obstructing the neck of the
gallbladder or the cystic duct. The gallbladder lumen is filled with cloudy
or turbid bile that may contain fibrin, blood, and frank pus.
When the contained exudate is mostly pus, the condition is referred to as
empyema of the gallbladder.
In mild cases the gallbladder wall is thickened, edematous, and
hyperemic.
In more severe cases the gallbladder is transformed into a green-black
necrotic organa condition termed gangrenous cholecystitis.
MORPHOLOGY
On histologic examination, the inflammatory reactions are not
distinctive and consist of the usual patterns of acute inflammation (i.e.,
edema, leukocytic infiltration, vascular congestion, frank abscess
formation, or gangrenous necrosis).
The morphologic changes in chronic cholecystitis are extremely
variable and sometimes subtle.
The gallbladder may be contracted, of normal size, or enlarged.
Mucosal ulcerations are infrequent; the submucosa and subserosa
often are thickened from fibrosis.
In the absence of superimposed acute cholecystitis, mural lymphocytes
are the only signs of inflammation.
CLINICAL PRESENTATION
Biliary pain that progressively worsens.
Approximately 6070% of patients report having experienced prior attacks that resolved
spontaneously.
Generalized in the right upper abdomen.
Radiate to the interscapular area, right scapula, or shoulder.

A low-grade fever is characteristically present,

RUQ tender on palpation.
Murphys Sign - Deep inspiration or cough during subcostal palpation of the RUQ usually
produces increased pain and inspiratory arrest .

Localized rebound tenderness in the RUQ is common, as are abdominal distention

and hypoactive bowel sounds from paralytic ileus, but generalized peritoneal
signs and abdominal rigidity are usually lacking, in the absence of perforation.
The patient is anorectic and often nauseated. Vomiting is relatively common and
may produce symptoms and signs of vascular and extracellular volume depletion.
Jaundice is unusual early in the course of acute cholecystitis but may occur when
edematous inflammatory changes involve the bile ducts and surrounding lymph
nodes.
ACUTE ACALCULOUS CHOLECYSTITIS
The main cause of this illness is thought to be bile stasis and increased
lithogenicity of bile.
Critically ill patients are more predisposed because of increased bile
viscosity due to fever and dehydration and because of prolonged
absence of oral feeding resulting in a decrease or absence of
cholecystokinin-induced gallbladder contraction.
Gallbladder wall ischemia that occurs because of a low-flow state due to
fever, dehydration, or heart failure may also play a role in the
pathogenesis of acalculous cholecystitis.
Acute acalculous cholecystitis; predisposing factors
Major nonbiliary surgery
Severe trauma
Severe burns
Sepsis
CHRONIC CHOLECYSTITIS
Chronic cholecystitis may be the sequel to repeated bouts of acute
cholecystitis, but in most instances it develops without any history of
acute attacks. It is almost always associated with gallstones.
Symptoms and morphologic alterations are similar to acute calculous
cholecystitis but milder in form.

Presentation
Recurrent attacks of steady epigastric or RUQ pain
Nausea, vomiting and intolerance for fatty foods

Diagnosis is pathological, based on the examination of resected

gallbladder.
PATHOPHYSIOLOGY
In chronic cholecystitis, the varied appearance of the gallbladder
reflects the degree of inflammation and fibrosis.
The gallbladder may be distended or shrunken and appear atrophic.
Fibrous serosal adhesions suggest previous episodes of acute
cholecystitis.
On gross examination, the wall is usually thickened, but it may be thin
in some cases. The mucosa may be intact with preservation or
accentuation of its folds, or it may be flattened with outflow
obstruction. Mucosal erosions or ulcers are frequently associated with
impacted stones
The diagnosis is based on three histologic characteristics:
A predominantly mononuclear inflammatory infiltrate in the lamina propria, with or
without extension into the muscularis and pericholecystic tissues
Fibrosis
Metaplastic changes.
INVESTIGATION
 ENDOSCOPIC RETROGRADE
CHOLANGIOPANCREATOGRAPHY (ERCP)
This technique remains widely used as both a
diagnostic and therapeutic modality. Using a
side-viewing endoscope the ampulla of Vater
can be identified and cannulated.
Injection of water-soluble contrast directly
into the bile duct provides excellent images
of the ductal anatomy and can identify
causes of obstruction, such as calculi or
malignant strictures.
While the widespread availability of
ultrasound and MRCP has reduced its
diagnostic use, ERCP still has a real role in the
assessment of the patient with obstructive
jaundice. In this group of patients, it is
especially useful in determining the cause
and level of obstruction.
MAGNETIC RESONANCE
CHOLANGIOPANCREATOGRAPHY (MRCP)
MRCP is an imaging technique based on the principles of nuclear
magnetic resonance used to image the gall bladder and biliary
system. It is non-invasive and can provide either cross-sectional or
projection images. E
xcellent images can be obtained of the biliary tree demonstrating
ductal obstruction, strictures or other intraductal abnormalities.
Images comparable to those obtained at ERCP or percutaneous
transhepatic cholangiography (PTC) can be achieved non-invasively
without the potential complications of either technique.
MRCP
MANAGEMENT
In acute cholecystitis, the initial treatment includes bowel rest,
intravenous hydration, correction of electrolyte abnormalities,
analgesia, and intravenous antibiotics.
Laparoscopic cholecystectomy is the standard of care for the surgical
treatment of cholecystitis.
Percutaneous Drainage For patients at high surgical risk, placement
of a sonographically guided, percutaneous, transhepatic
cholecystostomy drainage tube coupled with the administration of
antibiotics may provide definitive therapy.
 COMPLICATIONS
1. Empyema of the gallbladder
2. Gangrene of the gallbladder and perforation
3. Fistula formation
Fistula formation into an adjacent organ adherent to the gallbladder wall may result from inflammation
and adhesion formation.
Fistulas into the duodenum are most common, followed by, the hepatic flexure of the colon, stomach or
jejunum, abdominal wall, and renal pelvis.

4. Gallstone ileus
Mechanical intestinal obstruction resulting from the passage of a large gallstone into the bowel lumen.
The site of obstruction by the impacted gallstone is usually at the ileocecal valve, provided that the
more proximal small bowel is of normal caliber.

5. Porcelain gallbladder
Calcium salt deposition within the wall of a chronically inflamed gallbladder may be detected on the
plain abdominal film.
Cholecystectomy is advised in all patients with porcelain gallbladder because in a high percentage of
cases this finding appears to be associated with the development of carcinoma of the gallbladder.
ACUTE GANGRENOUS CHOLECYSTITIS
REFERENCES
1. https://clinicalgate.com/infectious-and-inflammatory-disorders-of-
the-gallbladder-and-extrahepatic-biliary-tract/
2. Harrisons Principles of Internal Medicine, 19th Edition
3. Davidsons Principles and Practice of Medicine, 22nd Edition
4. Robbins Basic Pathology, 9th Edition
5. Bailey and Loves Short Practice of Surgery, 26th Edition
 Prepared by
CHOLANGITIS Darien Liew Daojuin
12 May 2017
CHOLANGITIS
Cholangitis acute inflammation of the wall of bile ducts, almost always
caused by bacterial infection of the normally sterile lumen.
It can result from any lesion obstructing bile flow, most commonly
choledocholithiasis, and also from surgery involving the biliary tree. Other
causes include tumors, indwelling stents or catheters, acute pancreatitis,
and benign strictures.
Bacteria most likely enter the biliary tract through the sphincter of Oddi,
rather than by the hematogenous route.
CHOLANGITIS
Ascending cholangitis refers to the propensity of bacteria, once within the
biliary tree, to infect intrahepatic biliary ducts.
The usual pathogens are E. coli, Klebsiella, Enterococci, Clostridium, and
Bacteroides. Two or more organisms are found in half of the cases.
Bacterial cholangitis usually produces fever, chills, abdominal pain, and
jaundice.

In some world populations, parasitic cholangitis is a significant problem.

Causative organisms include
Fasciola hepatica or schistosomiasis in Latin America and the Near East,
Clonorchis sinensis or Opisthorchis viverrini in the Far East
cryptosporidiosis in persons with acquired immunodeficiency syndrome.
CHOLANGITIS
Suppurative cholangitis purulent bile fills and distends bile ducts,
with an attendant risk of liver abscess formation.
Because sepsis rather than cholestasis is the predominant risk in
cholangitic patients, prompt diagnosis and intervention are imperative.
RISK FACTOR
CLINICAL PRESENTATION
Charcots Triad Fever is present in approximately
Fever 90% of cases, with chills and rigors.
Jaundice
RUQ Pain Abdominal pain and jaundice is
thought to occur in 70% and 60%
of patients, respectively.
Reynolds Pentad
Charcots Triad Patients present with altered mental
Mental status change status 10-20% of the time and
Sepsis hypotension approximately 30% of
the time.
DIAGNOSIS
The diagnosis of the cause of cholangitis can be made on magnetic
resonance cholangiography (MRC) as it is non-invasive and involves no
exposure to radiation, but diagnostic and therapeutic (drainage of the
biliary system) modalities include endoscopic retrograde
cholangiopancreatography (ERCP) and percutaneous transhepatic
cholangiography (PTC).
MRC is preferred before ERC or PTC, as it indicates the level of the
block (eg, high or low) and the patency of the biliary ductal
confluence; this helps in the selection of the therapeutic procedure for
drainage of the biliary system (ie, ERC for low blocks and PTC for
high blocks with confluence but not patency).
REFERENCES
1. http://emedicine.medscape.com/article/774245-overview
2. Davidsons Principles and Practice of Medicine, 22nd Edition
3. Robbins Basic Pathology, 9th Edition
EXTRAHEPATIC BILIARY Last Reviewed

PATHOLOGY 19 May 2017