Diseases of the Gallbladder and Bile Ducts - part 7 pdf

Should the extrahepatic bile duct be resected for locally advanced gallbladder cancer.. Over-all, 80% of patients will respond to conservative management but 20% may progress to suppurat

1997 Patients with a margin-negative (R0) resection

fol-lowed by adjuvant EBRT plus 5-FU had a favorable 5-year

survival rate of 64% However, similar to the findings of

Jar-nagin et al [58], 67% of the patients suffered distant failure,

emphasizing the need for more effective adjuvant

chemo-therapy for this disease

Intraoperative radiation therapy (IORT) has been

advoca-ted as a means to deliver high-dose, small-field therapy

di-rectly to the tumor bed without the dose limitations associated

with EBRT Todoroki et al [66] have reported the most

sub-stantial experience with IORT in 85 patients with AJCC stage

IV gallbladder cancer who underwent aggressive surgical

re-section with or without IORT at a mean dose of 21 Gy

Forty-seven patients in total received some form of radiation therapy

(EBRT and/or IORT) The local control rate was signifi cantly

higher after adjuvant radiotherapy (59%) than after

resec-tion alone (36%) Moreover, the 5-year survival rate was

sig-nifi cantly higher after adjuvant radiotherapy (9%) than after

resection alone (3%), with the most pronounced

improve-ment in 5-year survival rate (17%) in patients with only

microscopic residual disease (R1 resection)

The role of radiation therapy for the palliation of symptoms

such as jaundice, pain, and pruritus in patients with

unre-sectable disease is difficult to ascertain as published studies

consist of small numbers of patients with the signifi cant

con-founding variable that most patients also underwent a biliary

drainage procedure [59,67,68]

Chemotherapy

Most published studies concerning the role of chemotherapy

in patients with locally advanced or metastatic gallbladder carcinoma are limited by the small numbers of patients and

by the inclusion of patients with biliary tract cancers tunately, no single chemotherapeutic agent or combination

Unfor-of agents has been identified to be effective in the treatment

of this disease (Table 15.4) Though overall response rates range as high as 64%, complete responses are rare and median overall survival rates range from only 20 weeks to 15 months.5-fluoruracil (5-FU), administered either alone or in com-bination, is the most extensively studied chemotherapeutic agent for this disease In a prospective, randomized study of

53 patients with advanced gallbladder cancer treated with oral 5-FU alone or in combination with either streptozocin or methyl-CCNU, objective response rates ranged from 5 to 12% in the three treatment arms [69] 5-FU administered in combination with doxorubicin and mitomycin C (FAM) or in combination with cisplatin and epirubicin (CEF) has yielded response rates of 8% and 33%, respectively [70] Better re-sponse rates have been published in patients treated with combinations of 5-FU with hydroxyurea (30%) [71] or inter-feron alpha-2b (34%) [72]

Other chemotherapeutic agents have exhibited variable success in the treatment of advanced gallbladder cancer (Table 15.4) Cisplatin [73], mitomycin C [74], paclitaxel [75], and CPT-11 [76,77] have produced response rates of

Table 15.4 Systemic chemotherapy for advanced gallbladder carcinoma.

Falkson et al [69] 5-FU ± steptozocin or methyl-CCNU 53 9% (PR 5; CR 0) –

Taal et al (II) [74] MMC 30 a (13 GBCa) 10% (PR 3; CR 0) –

Okada et al (II) [73] Cisplatin 13 a (6 GBCa) 8% (PR 1; CR 0) –

Jones et al (II) [75] Paclitaxel 15 a (4 GBCa) 0% N/A

Gebbia et al (II) [71] 5-FU/LV/hydroxyurea 70 a (30 GBCa) 30% b (PR 9; CR 0) 8 months Patt et al (II) [72] 5-FU/IFN-alpha-2b 35 a (10 GBCa) 34% (PR 12; CR 0) 12 months Sanz-Altamira et al (II) [77] CPT-11 25 a (10 GBCa) 8% (PR 2; CR 0) 10 months Alberts et al (II) [76] CPT-11 36 a 8% (PR 2; CR 1) –

Kuhn et al [83] Gemcitabine/docetaxel 43 a (26 GBCa) 9% (PR 4; CR 0) 12 months Malik (II) et al [82] Gemcitabine/cisplatin 11 64% (PR 6; CR 1) 42 weeks Kim (II) et al [88] Cisplatin/xeloda 42 a (19 GBCa) 32% b (PR 5; CR 1) 9.1 months Malik et al [89] 5-FU/folinic acid 30 7% (PR 2; CR 0) 14.8 months Doval (II) et al [81] Gemcitabine/cisplatin 30 36% (PR 7; CR 4) 20 weeks Ishii et al [70] Cisplatin/epirubicin/5-FU 21 33% (PR 7; CR 0) –

5-FU/doxorubicin/MMC 25 8% (PR 2; CR 0) – Knox et al [85] Gemcitabine/5-FU 27 a (7 GBCa) 71% b (PR 5; CR 0) 5.3 months Patt et al [78] Xeloda 63 a (8 GBCa) 50% b (PR 2; CR 2) 9.9 months Alberts et al (II) [84] Gemcitabine/5-FU/leucovorin 42 a (14 GBCa) 21% b (PR 3; CR 0) 9.7 months

a These studies include patients with both extrahepatic biliary tract carcinoma as well as patients with gallbladder carcinoma (GBCa) The response rates are for all of the patients included in the study unless indicated by b , in which case the response rate is for the subset of patients with GBCa 5-FU = 5-fluorouracil; MMC = mitomycin-C; LV = leucovorin; IFN = interferon; PR = partial response; CR = complete response; N/A = not applicable.

10% or less as single agents In contrast, four of eight patients

with gallbladder carcinoma treated with single-agent oral

capecitabine had either a complete (n = 2) or partial (n = 2)

re-sponse [78] Several case reports have shown that

gemcita-bine is active in the treatment of patients with gallbladder

carcinoma [79,80] Accordingly, several phase II studies of

gemcitabine in combination with other agents have

subse-quently been reported Gemcitabine in combination with

cisplatin has yielded response rates of 36 to 64% [81,82]; in

combination with docetaxel yielded a response rate of only

9% [83]; and in combination with 5-FU has produced

response rates of 9 to 33% [84,85] (Table 15.3) Based on

these studies, it appears that gemcitabine is an important

component of the systemic therapy of gallbladder carcinoma,

but additional studies of gemcitabine in combination with

other agents are warranted, as the survival benefit with

ex-isting regimens is modest at best

Hepatic arterial infusion chemotherapy has been studied

in a few patients with locally unresectable gallbladder

can-cer Partial response rates of up to 60% have been reported,

but the median duration of response was only 3 months and

all patients developed progressive disease [86,87] The

medi-an overall survival rates of 12 to 14 months in these studies

is comparable to that achieved with intravenous

chemo-therapy, providing little impetus to recommend this more

complicated mode of drug delivery

Conclusions

Gallbladder carcinoma is an aggressive, rapidly fatal disease

unless discovered at an early stage Complete surgical

resec-tion offers the only chance for cure, but only 10 to 30% of

pa-tients have surgically resectable disease Radical resection is

indicated for early stage (T2) tumors and can result in

long-term survival even in patients with locally advanced (T3 or

T4) tumors Radical reresection should be offered to patients

who are incidentally discovered to have gallbladder

carcin-oma at the time of cholecystectomy Nonetheless, there is a

high incidence of recurrence, particularly distant recurrence,

in patients who undergo a complete surgical resection,

em-phasizing the need for effective adjuvant therapies Given the

rarity of this cancer, prospective, multi-institutional studies

will be necessary to accrue sufficient numbers of patients to

make meaningful progress in the treatment of this disease

Questions

1 Which of the following is NOT a risk factor for malignancy in a

gallbladder polyp?

a concurrent gallstones

b age less than 50 years

c polyp diameter greater than 10 mm

d solitary polyp

e symptomatic polyp

2 Which of the following is TRUE with respect to the incidence of

gallbladder carcinoma?

a it increases steadily with age

b it is decreasing in the United States

c women are affected three times as frequently as men

d american Indian natives are affected more frequently than African Americans

e all of the above

3 Which of the following is NOT a risk factor for gallbladder

carcinoma?

a concurrent gallstones

b gallstone size <1 cm

c anomalous pancreaticobiliary junction

d chronic typhoid infection

6 A wedge resection of the gallbladder fossa includes which

segments of the liver?

a I and IVb

b IVb and V

c V and VIII

d IVb and VIII

7 The term “extended cholecystectomy” may encompass a

resection of all of the following structures EXCEPT

a gallbladder

b common bile duct

c hepatoduodenal lymph nodes

d hepatic bisegments IVb and V

e all of the above

8 The most significant prognostic factor in gallbladder

9 Which is the most common pattern of failure after a potentially

curative surgical resection of gallbladder cancer?

a locoregional recurrence

b distant metastasis

10 Which of the following is TRUE concerning the adjuvant

treatment of gallbladder carcinoma?

a several large, randomized trials have established that

postoperative external beam radiation therapy prolongs

survival in patients after a margin-negative resection

b single-agent 5-FU has produced response rates of 50%

c hepatic arterial infusion chemotherapy yields a durable

response in patients with unresectable disease

d no single treatment regimen has been shown to be effective in

the treatment of this disease

11 What is the approximate median overall survival of patients

with advanced gallbladder carcinoma receiving

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S E C T ION 3.2

The intrahepatic and

extrahepatic bile ducts

Copyright © 2006 by Blackwell Publishing Ltd

• Describe common etiologies of acute cholangitis

• Understand the pathogenic mechanisms in the development of acute cholangitis

• Describe the bacteriology of bile and blood cultures in the setting of acute cholangitis

• Recognize clinical presentations and complications of acute cholangitis

• Understand the principles in the management of acute cholangitis and the different interventional strategies, in particular the endoscopic interventions

Introduction

Acute cholangitis is a common cause for emergency hospital

admissions It occurs as a result of bacterial contamination

and overgrowth within an obstructed biliary system, often

secondary to bile duct stones Over the past two decades,

nonsurgical therapy has evolved to become the mainstay in

the treatment of cholangitis with a signifi cant reduction in

overall morbidity and mortality compared to surgery With

the advances in therapeutic endoscopy and interventional

radiology, many patients can now be managed acutely

with-out surgery, with a better clinical with-outcome The acute

man-agement of cholangitis includes empiric broad-spectrum

antibiotic therapy, and urgent biliary decompression is

nec-essary for those who failed conservative management

Over-all, 80% of patients will respond to conservative management

but 20% may progress to suppurative cholangitis because of

complete bile duct obstruction and require urgent drainage

Etiology

The most common cause of acute cholangitis is stone

ob-structing the common bile duct, accounting for 80% of cases

seen in the Western world [1] Secondary common bile duct

(CBD) stones which originate from the gallbladder are more

likely to be cholesterol or mixed stones Primary CBD stones

are mostly brown pigment stones which form de novo within

the bile duct as a result of bacterial infection and biofilm

for-mation around a nidus, which may be a surgical clip or suture

or a small cholesterol gallstone In the East, patients with

hepatolithiasis or recurrent pyogenic cholangitis (Oriental

cholangiohepatitis) have stones that formed in the

intrahe-265

patic system and these can migrate into the CBD [2] These intrahepatic stones are often black in color, containing calci-

um bilirubinate and a relatively high cholesterol content [3]

In endemic areas, intrahepatic stones may form as a result of parasitic infestations, such as Ascariasis and Clonorchiasis, within the biliary system It is possible that the adult worms

of Ascaris lumbricoides [4] or Clonorchis sinensis [5] may cause

biliary obstruction and also serve as a nidus for bacterial infection and intrahepatic ductal stone formation This is supported by the presence of remains of adult worm and ova found in the center of these pigment stones [6]

Other causes of cholangitis include biliary obstruction associated with benign postoperative bile duct stricture, neoplasms, papillary stenosis, chronic pancreatitis, and scle-rosing cholangitis Infection is more common after nonsur-gical manipulation of the biliary system, such as percutaneous transhepatic cholangiogram (PTC) or endoscopic retrograde cholangiopancreatography (ERCP) in which drainage fails Foreign bodies, such as biliary stents or surgical sutures, may predispose to bacterial contamination and sludge/stone for-mation causing cholangitis Mirrizi’s syndrome due to ex-trinsic compression of the common hepatic duct caused by an impacted stone in the cystic duct can precipitate concomitant acute cholecystitis and cholangitis

Pathogenesis

As discussed above, bacterial contamination and biliary stasis are important factors in the pathogenesis of acute cholangitis [7] The biliary system is sterile under normal circumstances [8] except for transient bacterobilia The nat-ural defense mechanisms that protect the biliary system

Copyright © 2006 by Blackwell Publishing Ltd

against infection include: (1) an intact sphincter of Oddi

which guards against ascending infection from

duodenobili-ary refl ux, (2) the flushing effects of a unidirectional bile

flow, (3) the bacteriostatic effects of bile salts, (4)

immuno-globulin IgA secreted by the cholangiocytes, (5) phagocytic

activity of the Kupffer cells, and (6) mucinous coating and

tight intercellular junctions of the bile duct epithelium [9–

12] The last two mechanisms play a crucial role in

prevent-ing descendprevent-ing infection from the portal circulation

Animal (feline) studies demonstrated that bacteria could

gain entry to the bile duct via the portal venous system [10]

Bacterobilia can occur without bacteremia if there is no bile

duct obstruction, as seen after sphincterotomy or biliary

drainage with a patent stent [12] Chronic obstruction

renders the biliary system more susceptible to infection by

causing a raised intrabiliary pressure and bile stasis [10]

The nutrient-rich bile serves as a good culture medium for

bacterial multiplication The raised biliary pressure causes

refl ux of bacteria into the lymphatics and hepatic sinusoids

(cholangiovenous refl ux), leading to endotoxemia and

septicemia

The normal intrabiliary pressure ranges from 8 to

16 cmH2O Cholangiovenous refl ux was demonstrated in a

canine model when the intrabiliary pressure exceeded

25 cmH2O [13] In human studies, cholangitis can occur

when intrabiliary pressure exceeds 20 cmH2O Bile secretion

stops completely when the biliary pressure exceeds 30 cmH2O

[14] A continued elevation of bile duct pressure eventually

overwhelms the integrity of the biliary epithelium leading to

bacterial reflux into the systemic circulation The clinical

severity and mortality of acute cholangitis correlate well

with the intraductal pressure [15] In fact, forceful injection

of contrast during direct cholangiography was shown to

cause bacteremia [16]

Endotoxin, which is the breakdown product of the cell wall

of Gram-negative bacteria, is usually metabolized by the liver

and excreted in bile However, it may refl ux into the

sinusoi-dal spaces under high biliary pressure in the presence of bile

infection Relief of biliary obstruction allows endotoxin

ex-cretion to be resumed This is demonstrated by a study of 40

patients with calculous cholangitis There was a signifi cant

association between clinical acute cholangitis and the serum

and bile endotoxin levels Furthermore, signifi cant

reduc-tions in bile and serum endotoxin levels were achieved

with-in 24 hours after successful endoscopic drawith-inage [17] Biliary

decompression has also been shown to promote biliary

ex-cretion of antibiotics [18] and resumption of IgA seex-cretion in

bile [19] Hence, biliary decompression plays a crucial role in

the management of acute cholangitis

Bacteriological findings

Many clinical studies have reported the bacteriology of bile

and blood cultures in patients with acute cholangitis [20,21]

Leung et al analyzed the bile, biliary stones, and blood tures in 579 patients who presented over a 7-year period [21]

cul-Blood culture was positive in 121 patients (21%) and the

ma-jority yielded a single organism (Table 16.1) with Escherichia

coli being the predominant one In contrast, over two-thirds

of the bile cultures showed mixed infections with two or more bacteria Culture of bile duct stones always showed a mixed fl ora Two-thirds of the patients with bacteremia had similar organisms isolated from both blood and bile Analysis

of the cultures showed that E coli, Klebsiella sp., Enterobacter sp., Enterococcus sp., and Streptococcus sp were the most

commonly isolated bacteria (Table 16.2)

Anaerobic organisms, including Bacteroides sp and

Clostrid-ium sp., are found in CBD stones but occur more commonly

in intrahepatic bile duct stones [22] Pseudomonas sp may

be found in patients with prior instrumentation or surgery

Gram-positive organisms are isolated more often following

percutaneous drainage of the biliary system [23] Candida

albicans is the most common fungal cause of cholangitis, but

is usually associated with an immunocompromised state

Fever is the most common presentation, which occurs in over 90% of patients Abdominal pain ranges from mild to severe, often localized to the right upper quadrant Jaundice may

be absent in the early stages but a profound jaundice may suggest underlying malignant biliary obstruction [24]

Chills and rigor may complicate intermittent bacteremia [25] Elderly patient may present only with mental confusion and deterioration of general condition A combination of mental confusion, hypotension, and the Charcot’s triad constitutes the Reynolds’ pentad, which is invariably fatal

Table 16 1 Frequency (%) of polymicrobial infections in bile and

blood (Reproduced from Leung et al [21] with permission from the American Society for Gastrointestinal Endoscopy.)

Number of species Bile (n = 579) Blood (n = 121)

without urgent drainage of the biliary system The term toxic

cholangitis is an alternative term depicting this severe

condition

Recurrent pyogenic cholangitis presents with bouts of

Charcot’s triad A typical attack of cholangitis may last for

several hours or even days before subsiding spontaneously

Chronic bile duct obstruction may give rise to dilated

com-mon duct or segmental branch ducts Intrahepatic stones

may contribute to multiple liver abscesses and associated

liver atrophy with prolonged obstruction, and eventually

secondary biliary cirrhosis Patients with recurrent pyogenic

cholangitis typically have recurrent attacks of cholangitis

and may have undergone multiple operative interventions

However, the incidence of residual stones is over 70% and

recurrent stones may occur in 15% of patients after surgery

Silent cholangiocarcinoma is a major concern associated

with the intrahepatic strictures, even after complete stone

removal [26]

Multiple organ failure may develop in severe acute

cholangitis due to septicemia or endotoxemia Uncontrolled

infections can give rise to liver abscesses and secondary

scle-rosing cholangitis Spread of infection or infl ammation into

the portal circulation can lead to pyelophlebitis and portal

vein thrombosis [27] Cholecystitis and/or pancreatitis may occur secondary to biliary stones (Table 16.3)

Acute cholangitis carries signifi cant morbidity and an overall mortality rate ranging from 10 to 30% In a multivar-iate analysis [28], seven risk factors were identified which predict mortality in acute cholangitis: (1) age over 50 years, (2) female gender, (3) associated liver abscess, (4) underlying cirrhosis, (5) cholangitis due to a high-grade malignant stricture, (6) cholangitis after percutaneous transhepatic cholangiography, and (7) acute renal failure In addition, the following risk factors were found to account for therapeutic failure in acute cholangitis: (1) underlying malignancy, (2) bacteremia, (3) two or more bacteria isolated or a pan-resistant species recovered from bile, and (4) an elevated serum bilirubin higher than 2.2 mg/dL

Laboratory fi ndings

Complete blood counts often show a leukocytosis with a left shift Depending on the degree of biliary obstruction, liver function abnormalities could have a cholestatic or a hepato-cellular pattern Signifi cant elevation in the serum transam-inases can occur due to sudden acute biliary obstruction and infection within the first 24 to 48 hours Elevated serum alkaline phosphatase and direct hyperbilirubinemia are seen in over 80% of acute cholangitis cases [7] The presence

of a CBD stone can cause coexisting pancreatitis, often as a result of an impacted ampullary stone In this case, the serum amylase and lipase levels will be elevated However, mild hy-peramylasemia can occur in 40% of cholangitis patients without any concomitant pancreatitis

Radiologic imaging

Plain abdominal film is usually not helpful because most

Table 16.2 Species of bacteria isolated from bile, stones, and blood in

patients with bacterobilia-cholangitis (Reproduced from Leung et al

[21] with permission from the American Society for Gastrointestinal

a Isolated from 579 patients (1236 species).

b Isolated from 70 patients (152 species).

c Isolated from 121 patients with septicemia (128 species).

Table 16.3 Common complications of cholangitis (Reproduced from

Köksal and Lo Pyogenic cholangitis In: Brandt L, ed Clinical Practice of Gastroenterology Philadelphia: W.B Saunders, 1999: 1079–88, with permission from Elsevier.)

Cholecystitis Pancreatitis

gallstones are non radio-opaque However, the plain film can

sometimes reveal the presence of pneumobilia which

sug-gests a bilioenteric communication from prior

sphincteroto-my, surgical bypass, or spontaneous fistula due to stone

passage

Noninvasive imaging studies include abdominal

ultra-sound scan (US), computed tomography (CT), and magnetic

resonance cholangiography (MRC) Abdominal ultrasound

is quick and inexpensive but to some extent is operator

de-pendent It can demonstrate the presence of stones and

dilat-ed ducts It is especially useful to delineate the dilatdilat-ed

intrahepatic system with stones In addition, ultrasound may

reveal the presence of an abscess, evidence of acute

cholecys-titis, or pancreatitis

The technical limitation to abdominal ultrasound

exami-nation is an obese patient or interference from adjacent bowel

gas, which makes examination of the distal bile duct more

difficult It is also not a very sensitive test for the detection of

small common duct stones However, because it is readily

available and noninvasive, it should be considered the initial

imaging of choice for patients with suspected biliary sepsis

The CT scan is noninvasive and can detect the presence of

dilated intrahepatic or extrahepatic bile ducts However, it is

not very sensitive in the detection of small common duct

stones The pigment content of intrahepatic stones also makes

them less obvious on CT scans The CT scan produces good

images of the liver and pancreas and can define the extent of

underlying liver damage, such as segmental atrophy,

intra-hepatic abscess formation, or dilated intraintra-hepatic bile ducts

It can demonstrate isolated obstructed intrahepatic bile ducts

not seen on direct cholangiography, and is useful in

preoper-ative planning It also plays a role in the detection of silent

cholangiocarcinoma or metastatic cancer It may reveal

sple-nomegaly associated with portal hypertension secondary to

biliary cirrhosis

Magnetic resonance cholangiopancreatography (MRCP)

is a noninvasive imaging method of the pancreatobiliary

sys-tem An MRI of the abdomen is taken using a special protocol

and high-quality images of the bile duct and pancreatic duct

are produced without the injection of contrast It serves as a

good diagnostic tool in cases with failed ERCP, incomplete

delineation of the biliary anatomy, or bilioenteric

anastomo-sis Its sensitivity in defining stones and strictures is similar to

that of conventional direct cholangiography [29]

Further-more, it is less operator-dependent and its images are easily

reproducible It is especially useful to guide selective

drain-age of obstructed bile ducts In addition, it provides

informa-tion on adjacent soft tissue not obtained with ERCP or PTC

The major limitation of MRC is the lack of therapeutic options

Direct cholangiogram involves invasive procedures, that is

endoscopic retrograde cholangiography (ERC) or PTC in

which contrast is injected into the biliary system for imaging

Direct cholangiography serves to define the cause of bile duct

obstruction and has a potential for therapeutic applications

It is used as the gold standard for the diagnosis of acute angitis The choice between ERCP and PTC depends on the availability of local expertise and the nature and level of bili-ary obstruction Both imaging can define the extent of ductal involvement ERCP is relatively less invasive but the obstruct-

chol-ed ducts upstream may not be visualizchol-ed unless an occlusion cholangiogram is performed Upon inflating the occlusionballoon, contrast can be injected under pressure to fill the bile ducts proximal to the obstruction However, this rise in intrabiliary pressure may precipitate bacteremia by causing cholangiovenous refl ux and worsening of the pre-existing cholangitis Apart from diagnosing the obstructing patholo-

gy, therapeutic ERCP can be applied to remove bile duct stones or bypass the biliary obstruction in the same setting.PTC is useful to define the ductal anatomy and the extent and level of obstruction, especially in cases where ERCP has failed as in patients with a bilioenteric anastomosis PTC can

be performed under ultrasound guidance to define the structed ducts Once percutaneous access to the biliary sys-tem is established, transhepatic drainage of the bile ducts can

ob-be performed using an internal/external drainage catheter

or an indwelling stent PTC is more invasive and carries the risk and complications of hemobilia, hepatic arteriovenous shunting, and bile peritonitis

ManagementPrinciples of management for acute cholangitis

Untreated acute cholangitis is uniformly fatal Early tion of the underlying condition is crucial especially in eld-erly patients Empiric broad-spectrum antibiotics and prompt biliary decompression is the mainstay of therapy Approxi-mately 80% of patients will improve with conservative man-agement and antibiotic therapy [30] Twenty percent of patients may continue to deteriorate despite antibiotic ther-apy and will warrant urgent biliary drainage These patients continue to spike a temperature despite antibiotic treatment Mental confusion, hemodynamic instability, and multisys-tem involvement are predictors of poor clinical outcome Progressive tachycardia, dropping blood pressure, and oligu-ria are warning signs of impending sepsis The main objec-tive in emergency management of acute cholangitis is focused

recogni-on reducing the intrabiliary pressure and crecogni-ontrolling the underlying infection by biliary drainage

There are three major therapeutic options for urgent ary decompression Surgery has been the traditional treat-ment With the advances in technology over the past two decades, therapeutic ERCP has replaced surgical drainage as the treatment of choice for acute cholangitis A randomized controlled study showed that urgent ERCP and biliary drain-age is superior to emergency surgery in patients with acute cholangitis, with a signifi cantly lower morbidity and overall mortality [31] The choice between endoscopic decompres-sion and percutaneous transhepatic biliary drainage (PTBD)

bili-is determined by the biliary anatomy and availability of local

expertise In the following sections, we will discuss the

dif-ferent treatment modalities

Conservative management

An early diagnosis and resuscitative measures impact signifi

-cantly on the clinical outcome Medical management must

be initiated immediately once a presumptive diagnosis of

acute cholangitis is being entertained The general condition,

vital signs including blood pressure and pulse, and urine

output are closely monitored to detect any clinical

deteriora-tion Intravenous fl uid is given to maintain adequate

per-fusion of the vital organs, and broad-spectrum antibiotics

should be given after blood cultures are taken Patients are

kept ‘nil by month’ Coexisting coagulopathy should be

cor-rected with vitamin K and if necessary with fresh frozen

plasma Any patients who are clinically unstable or seriously

ill should be monitored in the intensive care unit Circulatory

support and mechanical ventilation may be required in cases

with septicemic shock

An ideal antibiotic regimen should cover both

Gram-nega-tive bacteria such as E Coli and Klebsiella, Gram-posiGram-nega-tive

bac-teria such as Streptococci sp., and anaerobes A combination of

a third-generation cephalosporin, ampicillin, and

metroni-dazole is commonly given An alternative choice is

ureidope-nicillins such as piperacillin [32] This monotherapy provides

similar antimicrobial coverage Other antibiotics given

included imipenem and the fluoroquinolones such as

ciprofloxacin

Any antibiotic given for cholangitis should ideally achieve

high levels in bile Unfortunately many antibiotics that are

normally excreted in bile fail to enter the biliary tree when

the system is completely obstructed [18,33] It has been

shown that biliary obstruction impairs both active and

pas-sive excretions of antibiotics into bile Although biliary

anti-biotic excretion resumes after successful relief of the

obstruction, the maximum achievable concentration of the

drug in bile may lag behind due to a delay in recovery of

the secretory function of the hepatocytes Thus, an antibiotic

may be effective against septicemia associated with

cholan-gitis, but it may not achieve a sufficient concentration in bile

for effective treatment of infection in bile unless the system is

drained

The biliary excretion profiles of five different antibiotics

were studied among patients with bile duct obstruction

[21,33] These included ceftazidime, cefoperazone,

imip-enem, netilmicin, and ciprofl oxacin With the sole exception

of ciprofloxacin, the bile obtained from over 90% of the

pa-tients at the time of endoscopic drainage contained no

detect-able level of antibiotic despite i.v infusion of the medication

The bile concentration of ciprofloxacin was only 20% of the

mean peak serum level, but it was still higher than the

neces-sary minimum inhibitory concentration for Gram-negative

bacteria

In a prospective randomized clinical trial of 100 patients with acute cholangitis, ciprofloxacin monotherapy was com-pared with the triple combination of ampicillin, ceftazidime, and metronidazole [34] Eighty-five percent of patients in the monotherapy group and 77% of those in the triple thera-

py group responded to antibiotic treatment The mean tions of fever, septicemic shock, and hospitalization were similar in the two treatment groups Similar proportions of patients in the two treatment groups required urgent endos-copy or surgery for uncontrolled infection The mortality rates were 4% in the ciprofloxacin group and 2% in the triple therapy group (Table 16.4)

dura-Traditionally, antibiotics are recommended to continue for

a week depending on the patient’s response A recent report suggested that prolonged antibiotic therapy is not necessary

if biliary drainage is established [35] Patients can also

be switched to oral antibiotics once the clinical condition

is stabilized Potential nephrotoxic drugs, such as the aminoglycosides, should be avoided in patients with obstructive jaundice [36], to minimize the risk of acute renal failure associated with sepsis and dehydration

Endoscopic drainage

Endoscopic drainage should be considered as the treatment

of choice for acute cholangitis when biliary sepsis fails to spond to conservative management and antibiotics Unstable patients may need urgent ERCP drainage even in the inten-sive care unit Any delay may be associated with a poor clini-

re-Table 16.4 Clinical responses of evaluable patients in the two

treatment groups (Reproduced from Sung et al., Journal of Antimicrobial Chemotherapy 1995;35:855–64.)

Treatment group Cipro Triple (n = 46) (n = 44)

No (%) of patients who responded to therapy 39 (85) 34 (77)

No (%) of patients who failed therapy 7 (15) 10 (23) Mean ( ±S.D.) duration of fever (days) 1.7 ± 1.4 2.4 ± 2.0 Duration of shock (number of patients)

Mean ( ±S.D.) hospital stay (days) 6.6 ± 4.3 7.7 ± 5.2 Need for emergency endoscopy/ surgery 6 (13) 7 (16) [no (%) patients]

Fever recurrence during hospitalization 1 (2) 3 (7) [no (%) patients]

Mortality attributable to infection 1 (2) 1 (2) [no (%) patients]

cal outcome Intravenous sedation should be kept to the

minimum during the ERCP procedure to avoid sedation

com-plications Close monitoring of vital signs (including oxygen

saturation) should be done throughout the entire procedure

Urgent ERCP is indicated in the presence of septicemic shock,

persistent abdominal pain, high fever, and altered mental

status A prospective study of 142 patients with acute

cholan-gitis assessed four parameters, that is: (1) heart rate greater

than 100/min, (2) albumin less than 30 g/L, (3) bilirubin

greater than 50 µmol/L, and (4) prothrombin time greater

than 14 seconds on admission, and concluded that the

pres-ence of one or more predictive risk factors is a strong

indica-tion for urgent ERCP [37]

An efficient and timely ERCP is crucial for a good clinical

outcome Once deep cannulation of the bile duct is achieved,

the purulent bile should be aspirated to decompress the

bili-ary system before further injection of contrast The amount

of contrast injected should be kept to a minimum to avoid

raising the intrahepatic pressure and precipitating

cholan-giovenous refl ux and septicemia Occlusion

cholangiogra-phy should be avoided Once the underlying ductal pathology

is delineated, the decision is to select the best method for

drainage based on the obstructing factor and the patient’s

condition The prime objective of an urgent ERCP is to

pro-vide effective drainage of the biliary system in a safe and

ex-peditious manner Prolonged instrumentation should be

avoided as these patients are often unstable An elective ERCP

can be performed to remove the obstructing stone after the

patient has improved clinically

Sphincterotomy with stone removal is reserved for stable

patients with single or small stones Although immediate

ex-traction of all ductal calculi to achieve CBD clearance was

widely practiced in a stable patient, such an aggressive

approach carried an increased morbidity of 28% among sick

patients even in experienced hands Complications such as

sphincterotomy bleeding and retroduodenal perforations

which require emergency surgery are highly undesirable in

the presence of severe cholangitis [38] Biliary manipulation

and stone extraction may delay effective drainage and

lengthen the procedure, putting the patient at an increased

risk of aggravated sepsis and prolonged sedation with

poten-tial circulatory and respiratory complications

Insertion of a nasobiliary drain provides urgent biliary

de-compression and allows more definitive procedures to be

performed later on an elective basis (Fig 16.1) It can be done

without a prior sphincterotomy and is preferred in unstable

patients or patients with difficult or multiple large stones In

a study of 105 patients with acute cholangitis who failed

con-servative management, urgent ERCP and biliary drainage

was successful in 102 patients with clinical improvement

achieved in 99 Fever responded within 3 days in the majority

of patients Despite the fact that 40% of patients were in

sep-tic shock prior to endoscopic drainage, the overall 30-day

mortality was only 4.7% and limited to the very sick patients

who presented initially with shock In this particular study,

23% of the patients had successful nasobiliary drain ment without a sphincterotomy [39]

place-Nasobiliary catheter drainage with or without otomy is a simple, safe, and effective treatment for acute chol-angitis The nasobiliary catheter with a straight tip can be used to directly cannulate the bile duct or be exchanged over

sphincter-a guide wire once deep csphincter-annulsphincter-ation is sphincter-achieved without sphincter-a sphincterotomy This avoids the risk of postsphincterotomy bleeding in the sick patients with underlying coagulopathy

In a retrospective study of 166 patients with acute tis, there were 120 patients with CBD stones, benign stric-tures in 10 and malignancy in 36 [40] Although not randomized, the demographics and clinical data were com-parable between the 93 patients in the nonsphincterotomy (Non-ES) group versus the 73 patients in the sphincterotomy (ES) group Effective drainage was established in 94% (Non-ES) and 92% (ES), respectively Procedure-related complica-tions occurred in two non-ES patients and eight ES patients

cholangi-No mortality was observed in this group of patients (Table 16.5)

Nasobiliary catheter drainage has several advantages and disadvantages It provides continuous external access to the

Figure 16.1 X-ray showing nasobiliary catheter drainage for acute

cholangitis secondary to multiple large common bile duct stones.

biliary system and allows: (1) bile collection, (2) intermittent

irrigation if indicated, (3) further cholangiographic study,

and (4) instillation of solvent for contact stone dissolution

However, it may cause local irritations and can be

cosmeti-cally unappealing since part of the catheter is taped to the

face, and is physically cumbersome due to an external

collec-tion bag It is a small-caliber catheter and kinks easily if not

handled properly The major concern, however, is the risk of

dislodgement, either accidentally or semi-intentionally by a

confused or unco-operative patient [41]

Insertion of an indwelling biliary stent is used as an

alter-native treatment for urgent biliary drainage and also as a

short-term temporizing measure for unstable patients with

large CBD stones (Fig 16.2) It can also be used in cases where

duct clearance cannot be achieved in a single session In a

prospective randomized trial, Lee et al showed that

endo-scopic drainage with a 6.5 French nasobiliary catheter or an

indwelling 10 French stent was equally effective in patients

with acute suppurative cholangitis caused by CBD stones

[42] The advantage is that the indwelling stent cannot be

dislodged by the patient and is therefore preferable to

naso-biliary catheter in a confused or combative patient Among

27 patients who presented with acute cholangitis [43], a 7

French biliary endoprosthesis placement was achieved in all

cases without sphincterotomy Early stent occlusion

oc-curred in one patient No mortality was observed Biliary

stent insertion is safe but the large channel therapeutic

duodenoscope is required for insertion of a 10 French stent A

sphincterotomy is not necessary for the placement of a single

biliary stent [44] but the presence of a sphincterotomy allows

better drainage with bile flowing through the stent as well as

alongside the stent The relative disadvantages of using a small (7 French) stent are: (1) a tendency for the stent to be blocked by viscous pus in the initial period, and (2) the need for a follow-up or repeat ERCP to remove the stent but this can be done at the time of subsequent stone extraction.During endoscopic stenting, a suitable length (defined as separation between the two flaps) stent should be chosen so that its proximal flap lies above the level of obstruction when the distal flap is placed at the papilla The stent position can be confirmed fluoroscopically and drainage of purulent bile verified endoscopically Even with a large 10 French stent, poststenting pancreatitis due to stent compression on the pancreatic orifice rarely occurs [45] However, a sphincterot-omy facilitates the manipulation of accessories if multiple stents are used and certainly helps to prevent post-ERCP pan-creatitis if bilateral plastic stents are placed for hilar obstruc-tion In a retrospective study of 444 patients with large or difficult CBD stones who underwent endoscopic stenting, a small but statistically signifi cant reduction in stone size was

Table 16.5 Outcomes of nasobiliary drainage (Reproduced from

Sugiyama et al., American Journal of Gastroenterology 1998;93:2065–

8, with permission from Blackwell Publishing.)

a Urgent drainage, performed within 72 hours of the onset of

cholangitis; early drainage, performed between 72 hours and 7 days.

b p < 0.05 vs ES group.

Figure 16.2 X-ray showing endoscopic stenting for large common bile

duct stones.

observed over a median follow-up period of 63 days [46] This

change in stone size was thought secondary to: (1)

mechani-cal friction of the stent against the stone, and (2) changes in

biochemistry of bile with improved bile fl ow thus facilitating

stone dissolution

In cases with difficult cannulation, alternative biliary

de-compression can be achieved by PTBD or surgical

explora-tion of the common bile duct In selected cases, precut

papillotomy using a needle-knife allows access into the

bili-ary system Precut papillotomy is relatively safe if done in the

presence of an impacted ampullary stone Subsequent

stan-dard sphincterotomy can be extended to facilitate stone

extraction and clearance of the biliary system Mild

post-sphincterotomy bleeding is a known complication which

re-sponds well to epinephrine injection A word of caution is

that, since precut sphincterotomy is performed with a free

wire, control over the wire is more difficult compared to a

standard sphincterotome and should be performed by an

ex-perienced endoscopist [47]

The overall result of successful endoscopic biliary drainage

is dramatic and gratifying The patients often report relief of

abdominal pain when the intrabiliary pressure is reduced

[30] Over the next 24 to 48 hours, fever responds with

ap-propriate antibiotic therapy, along with resolution of

deliri-um and bile clearance The patient is ambulatory a few hours

after the procedure and can resume oral diet very soon

there-after Several reports showed that outcome following

suc-cessful endoscopic drainage is superior to that of emergency

surgery In a prospective, randomized, controlled trial of

82 patients with severe acute cholangitis secondary to

cho-ledocholithiasis [31], the patients were randomized to

un-dergo either (1) sphincterotomy and nasobiliary drainage

under conscious sedation or (2) urgent diagnostic ERCP

fol-lowed by exploratory laparotomy under general anesthesia

Half of the patients presented initially with shock and

posi-tive blood cultures Both groups stabilized and defervesced

1 day after the procedure However, more patients in the

surgical group required ventilatory support and for a longer

duration The hospital mortality rates were 10 and 32%,

re-spectively Another retrospective study involving 27 patients

with acute cholangitis secondary to choledocholithiasis,

demonstrated similar mortality rates of 5 and 33%,

respec-tively [48]

After acute cholangitis is controlled, further definitive

therapy can be planned according to the general condition of

the patient and the underlying obstructing pathologies In a

patient with CBD stones, curative therapy can be achieved

with endoscopic sphincterotomy and stone extraction

Stones of diameter 1 cm or less can be easily removed with

basket or balloon catheter The major challenge to endoscopic

removal is the presence of large (greater than 2 cm) or

multi-ple stones in the CBD In such cases, mechanical lithotripsy

using a large, strong basket and a metal sheath is used to crush

the stones to aid in CBD clearance Mechanical lithotripsy is

the most commonly used method for stone fragmentation but it may fail in the presence of stone impaction when the basket fails to engage the stone [49,50] Other forms of intraductal lithotripsy include laser or electrohydraulic lithotri psy which requires the use of the mother–baby scope system to guide lithotripsy [51] Overall, the success with complete CBD clearance approaches 95% of cases For high-risk, debilitated patients who failed stone extraction during the initial urgent ERCP, long-term indwelling stent place-ment may be the only feasible option [52] For patients who have suffered from recurrent pyogenic cholangitis, the de-finitive treatment may involve a multidisciplinary approach with: endoscopic balloon dilatation of bile duct stricture, bili-ary stenting, and stone extraction; percutaneous transhe-patic cholangioscopy [53]; surgical choledochoscopy [54], postsurgical T-tube tract cholangioscopy [55]; and various forms of mechanical, extracorporeal shockwave [56], or laser lithotripsy [57] In patients with liver atrophy or multi-ple intrahepatic stones, hepatic resection [58] and creation

of a cutaneous hepaticojejunostomy may facilitate further stone removal

On the other hand, for patients who do not respond promptly to initial endoscopic drainage, the following possi-bilities should be entertained and excluded: (1) the presence

of undrained hepatic segments, especially in cases of nant hilar obstruction or recurrent pyogenic cholangitis with intrahepatic stones, (2) coexisting acute cholecystitis, and (3) cholangitic abscesses [24] In these scenarios, it is neces-sary to resort to PTBD and/or surgical drainage

malig-The timing of cholecystectomy is often debated in patients with CBD stones after the acute cholangitis is under control

In Western countries, most of the stones originate from the gallbladder and in a clinically stable patient; most surgeons would elect to perform a laparoscopic cholecystectomy to eliminate the source of further CBD stones However, in the absence of any gallbladder stones, many patients continue to

do well without any biliary symptoms For an elderly and clinically unstable patient, cholecystectomy may not be indi-cated because of the associated risks It is important to re-member that in Asian countries, hepatolithiasis may be the source of CBD stones and cholangitis, and the gallbladder is normal in up to one-third of the patients In the absence of gallbladder stones, cholecystectomy is not indicated and may not prevent recurrent cholangitis [59,60]

Percutaneous transhepatic biliary drainage

The percutaneous transhepatic access to the biliary tract is performed under local anesthesia by using a Chiba fine nee-dle Under ultrasound or fluoroscopic guidance, multiple passes are made until a dilated bile duct is entered A guide wire is then introduced and manipulated if possible into the duodenum After dilating the percutaneous tract, a pigtail biliary catheter is then advanced over the guide wire with the tip placed in the duodenum This provides the option for ex-

ternal or internal drainage Success rates of PTBD range from

80 to 100% [61] Similar to endoscopic decompression, PTBD

only offers temporary relief for the acute cholangitis When

the patient becomes stabilized, more definitive therapy is

necessary to correct the underlying obstructive lesion It is

indicated when endoscopic drainage fails because of difficult

cannulation, inability to drain an obstructed biliary system,

but more commonly as a result of prior gastric or biliary

sur-gery such as Billroth II gastrectomy or hepaticojejunostomy

that limit peroral access to the biliary system In patients with

intrahepatic stones, the percutaneous transhepatic approach

allows ready access into the diseased segment for removal

of the stones Percutaneous transhepatic cholangioscopy

(PTCS) can be performed to visualize and biopsy the

associ-ated bile duct stricture In selected cases with difficult bile

duct access, the combined peroral and transhepatic approach

has been used to allow endoscopic access into the biliary

sys-tem over a percutaneously placed guide wire

PTBD is associated with multiple adverse events, including

hemobilia, intra-abdominal bleeding, bile leak, biliary–

vascular fistula, and catheter-related sepsis Septic bile

peri-tonitis may occur as a result of puncturing an infected and

distended bile duct segment in the presence of cholangitis

Patients with underlying cirrhosis, coagulopathy, and ascites

are particularly susceptible to complications With the use

of fine needles, the mortality rate of PTBD is reduced to

below 5%

Surgical drainage

Surgical drainage for acute cholangitis is indicated when

ERCP and PTBD are unsuccessful or unavailable but is rarely

performed as an emergency today The procedure consists of

common bile duct exploration and placement of a

large-caliber T-tube In a stable patient, surgical drainage includes

sphincterotoplasty, bile duct resection, or bypass with a

bilio-enteric anastomosis Biliary decompression is the major

con-cern and any attempts to achieve ductal clearance at the

expense of prolonged surgery or instrumentation should be

avoided An elective follow-up choledochoscopy through an

established T-tube tract can be performed to remove any

residual stone

Historically, surgical drainage was the classic method for

biliary decompression However, it does carry formidable

postoperative morbidity and mortality Among 86 patients

with acute cholangitis who underwent emergent surgery,

five risk factors were identified [62]:

1 concomitant medical problems

2 arterial blood pH less than 7.4

3 total serum bilirubin level more than 90 µmol/L

4 platelet count less than 150 × 109/L

5 serum albumin concentration less than 30 g/L.

In the presence of three or more risk factors, postoperative

morbidity and mortality rates were 91 and 55%, respectively

In contrast, the corresponding rates were 34 and 6%,

re-spectively, in patients with two or fewer risk factors As cussed previously, endoscopic drainage is the treatment of choice because of better clinical outcome especially in the acute setting, with a signifi cantly reduced morbidity and mortality [31,47] PTBD, however, has not been care fully studied to compare its effi cacy against surgery Some institutions still prefer a surgical approach to PTBD once therapeutic endoscopy has failed [27]

dis-Conclusion

The management of acute cholangitis begins with early ognition of the condition, followed by aggressive resuscita-tion and antibiotic coverage Approximately 80% of patients will improve with conservative management For the re-maining 20% patients who continue to deteriorate despite antibiotics, urgent biliary drainage is required Emphasis

rec-is placed on reducing the biliary pressure effectively by a safe and expeditious method, rather than eliminating the underlying obstructive pathology With its signifi cant reduc-tions in morbidity and mortality in clinical trials, therapeutic endoscopy stands out as the treatment of choice for biliary decompression When endoscopic drainage is unavailable

or unsuccessful, then PTBD or surgery should be plated Emergent surgical drainage, with its formidable mortality and morbidity rates, is now considered the last resort PTBD, nevertheless, has not been carefully studied

contem-to compare its effi cacy against surgery Once acute gitis is stabilized, a detailed treatment plan can be carried out electively to remove or bypass the underlying obstruction

cholan-Questions

1 Which of the following are associated with acute cholangitis?

a common bile duct stone

b intrahepatic stone

c malignant biliary stricture

d sclerosing cholangitis

e all of the above

2 Both bacterobilia and biliary stasis are necessary in the

development of acute cholangitis.

a true

b false

3 Which of following are normal defense mechanisms against

infections of the biliary tree?

a intact sphincter of Oddi

b bacteriostatic effects of bile salts

c unidirectional bile flow

d phagocytic effects of Kupffer cells

e a, b, and c only

f all of the above

4 In the setting of acute cholangitis, bile cultures are

predominantly polymicrobial whereas blood cultures

frequently yield single organism.

a true

b false

5 Which of the following are typical for the “Charcot’s triad” of

acute cholangitis?

a fever and jaundice

b right upper quadrant abdominal pain

c hypotension

d altered mental status

e a and b only

f a and c only

g all of the above

6 A 65-year-old white male presented with 2 days of fever,

abdominal pain, and jaundice On examination, his

temperature was 39°C with a pulse of 110/min and blood

pressure 134/84 mmHg His abdomen was tender to palpation

in the right upper quadrant but no rebound or guarding

Murphy’s sign was negative His labs were significant for white

count of 16,000 with left shift His chemistry panel was

remarkable for aspartate aminotransferase of 290 units/L,

alanine aminotransferase 305 units/L, alkaline phosphatase

300 units/L, and total biliribin of 4 mg/dL An ultrasound of the

abdomen showed a dilated common bile duct with normal

gallbladder What is the next step in the management of this

patient?

a urgent ERCP and decompression

b administration of IV fluids and antibiotics

c MRCP

d percutaneous transphepatic biliary drain

7 The patient was started on ceftazidime, ampicillin, and flagyl;

12 hours later the patient remained febrile but became

somewhat more obtunded with blood pressure of

90/60 mmHg The next course of action is

8 At the time of ERCP, the cholangiogram showed a 10-mm

obstructing stone in the mid-CBD The distal CBD measured

6 mm The next step is

a sphincterotomy and stone removal

b biliary stent placement for drainage, followed by elective ERCP

with sphincterotomy and stone extraction

c prepare patient for surgery

9 Liver abcesses, pancreatitis, and portal vein thrombosis are

some of the complications of acute cholangitis.

a true

b false

10 An Asian male has history of recurrent episodes of cholangitis

Which of the following should be considered in the management of this patient?

a administration of ursodeoxycholic acid to prevent stone formation

b referral to surgeons for elective cholecystectomy

c close observation for signs or symptoms of cholangiocarcinoma

6 Maki T Pathogenesis of calcium bilirubinate gallstones: role of

E coli, β-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation Ann Surg 1966;164:90–100.

7 Hanau LH, Steigbigel NH Cholangitis: pathogenesis, diagnosis and treatment Curr Clin Infect Dis 1995;15:153–78.

8 Csendes A, Fernandez M, Uribe P Bacteriology of the der bile in normal subjects Am J Surg 1975;129:629–31.

gallblad-9 Sung JY, Leung JW, Olson ME, et al Demonstration of transient bacterobilia by foreign body implantation in the feline biliary tract Dig Dis Sci 1991;36:943–8.

10 Sung JY, Shaffer EA, Olson ME, et al Bacterial invasion of the biliary system by way of the portal-venous system Hepatol 1991;14:313–7.

11 Sung JY, Costerton JW, Shaffer EA Defense system in the ary tract against bacterial infection Dig Dis Sci 1992;37:6 89–96.

bili-12 Sung JY, Leung JW, Shaffer EA, et al Ascending infection of the biliary tract after surgical sphincterotomy and biliary stenting

15 Lygadakis NJ, Brummelkamp WH The signifi cance of ary pressure in acute cholangitis Surg Gyn Obst 1985;161: 465–9.

intrabili-16 Yoshimoto H, Ikeda S, Tanaka M, Matsumoto S Relationship of

biliary pressure to cholangiovenous reflux during endoscopic

retrograde balloon catheter cholangiography Dig Dis Sci

1989;34:16–20.

17 Lau JY, Ip SM, Chung SC, et al Endoscopic drainage aborts

en-dotoxemia in acute cholangitis Br J Surg 1996;83:181–4.

18 Leung JW, Chan RC, Cheung SW, et al The effect of obstruction

on the biliary excretion of cefoperazone and ceftazidime J

Antimicrob Chemo 1990;25:399–406.

19 Sung JY, Leung JC, Tsui CP, et al Biliary IgA secretion in

ob-structive jaundice: The effects of endoscopic drainage

Gastro-intest Endosc 1995;42:439–44.

20 Brook I Aerobic and anaerobic microbiology of biliary tract

dis-ease J Clin Microbiol 1989;27:2373–5.

21 Leung JW, Ling TK, Chan RC, et al Antibiotics, biliary sepsis,

and bile duct stones Gastrointest Endosc 1994;40:716–21.

22 Leung JW, Liu YL, Lau GCT, et al Bacteriologic analyses of bile

and brown pigment stones in patients with acute cholangitis

Gastrointest Endosc 2001;54:340–5.

23 Levine GJ, Botet J, Kurtz RC Microbiological analysis of sepsis

complicating non-surgical biliary drainage in malignant

ob-struction Gastrointest Endosc 1990;36:364–8.

24 Lee DW, Chung SC Biliary infection Baillieres Clin

Gastroen-terol 1997;11:707–24.

25 Sinanan MN Acute cholangitis Infect Dis Clin North Am

1992;6:571–99.

26 Chijiiwa K, Ichimiya H, Kuroki S, et al Late development of

cholangiocarcinoma after the treatment of hepatolithiasis Surg

Gyn Obs 1993;177:279–82.

27 Köksal R, Lo SK Pyogenic cholangitis In: Brandt L, ed Clinical

practice of gastroenterology Philadelphia: W.B Saunders,

1999:1079–88.

28 Gigot JF, Leese T, Dereme T, et al Acute cholangitis

Multivari-ate analysis of risk factors Ann Surg 1988;209:435–8.

29 Chan YL, Chan AC, Lam WW, et al Choledocholithiasis:

com-parison of MR cholangiography and endoscopic retrograde

cholangiography Radiology 1996;200:85–9.

30 Leung JW, Venezuela RR Cholangiosepsis: Endoscopic

drain-age and antibiotic therapy Endoscopy 1991;23:220–3.

31 Lai EC, Mok FP, Tan ES, et al Endoscopic biliary drainage for

severe acute cholangitis N Eng J Med 1993;326:1582–6.

32 Giron A, Meyers BR, Hirschmann SZ Biliary concentrations of

piperacillin in patients undergoing cholecystectomy

Antimi-crob Ag Chemo 1981;19:309–11.

33 Leung JW, Chan CY, Lai CW, et al Effect of biliary obstruction

on the hepatic excretion of imipenem-cilastatin Antimicrob Ag

Chemo 1992;36:2057–60.

34 Sung JY, Lyon DJ, Suen R, et al Intravenous ciprofloxacin as

treatment for patients with acute suppurative cholangitis: a

ran-domized, controlled clinical trial J Antimicrob Chemo 1995;35:

855–64.

35 van Lent AUG, Bartelsman JF, Tytgat GN, et al Duration of

anti-biotic therapy for cholangitis after successful endoscopic

drain-age of the biliary tract Gastrointest Endosc 2002;55:518–22.

36 Desai TK, Tsang TK Aminoglycosides nephrotoxicity in structive jaundice Am J Med 1988;85:47–50.

ob-37 Hui CK, Lai KC, Yuen MF, et al Acute cholangitis — predictive factors for emergency ERCP Alimen Pharmacol Ther 2001;15: 1633–7.

38 Lai EC, Chu KM, Ngan H Acute cholangitis In: Pitt HA, Locke DL, Ferrucci JT, eds Hepatobiliary and pancreatic dis- ease: the team approach to management Boston: Little Brown, 1995:229–38.

Carr-39 Leung JW, Chung SC, Sung JY, et al Urgent endoscopic age for acute suppurative cholangitis Lancet 1989;1:1037–9.

drain-40 Sugiyama M, Atomi Y The benefits of endoscopic nasobiliary drainage without sphincterotomy for acute cholangitis Am J Gastroenterol 1998;93:2065–8.

41 Leung JW, Cotton PB Endoscopic nasobiliary catheter drainage

in biliary and pancreatic disease Am J Gastroenterol 1991;86: 389–94.

42 Lee DWH, Chan ACW, Lam YH, et al Biliary decompression by nasobiliary catheter or biliary stent in acute suppurative chol- angitis: a prospective randomized trial Gastrointest Endosc 2002;56:361–5.

43 Misra SP, Dwivedi M Biliary endoprosthesis as an alternative to endoscopic nasobiliary drainage in patients with acute cholan- gitis Endoscopy 1996;28:746–9.

44 Hui CK, Lai KC, Yuen MF, et al Does the addition of endoscopic sphincterotomy to stent insertion improve drainage of the bile duct in acute suppurative cholangitis Gastrointest Endosc 2003;58:500–4.

45 Huibregtse K, Tytgat GNJ Palliative treatment of obstructive jaundice by transpapillary introduction of large bore bile duct endoprosthesis Gut 1982;23:371–5.

46 Chan AC, Ng EK, Chung SC, et al Common bile duct stones become smaller after endoscopic biliary stenting Endoscopy 1998;30:356–9.

47 Leung JW, Banez VP, Chung SC Precut (needle knife) omy for impacted common bile duct stone at the ampulla Am J Gastroenterol 1990;85:991–3.

papillot-48 Chijiiwa K, Kozaki N, Naito T, et al Treatment of choice for ledocholithiasis in patients with acute obstructive suppurative cholangitis and liver cirrhosis Am J Surg 1995;170:356–60.

cho-49 Chung SC, Leung JW, Leong HT, et al Mechanical lithotripsy of large common bile duct stones using a basket Br J Surg 1991;78:1448–50.

50 Tu R, Leung JW Mechanical lithotripsy for large bile duct stones Gastrointest Endosc 2004;59:688–90.

51 Leung JWC, Chung SCS Electrohydraulic lithotripsy with oral choledochoscopy BMJ 1989;299:595–8.

per-52 Cotton PB, Forbes A, Leung JW, et al Endoscopic stenting for long-term treatment of large bile duct stones: 2- to 5-year follow-up Gastrointest Endosc 1987;33:411–3.

53 Yeh YH, Huang MH, Yang JC, et al Percutaneous transhepatic cholangioscopy and lithotripsy in the treatment of intrahepatic stones: a study with 5 year follow-up Gastrointest Endo 1995;42:13–8.

54 Choi S, Choi TK, Wong J Intraoperative flexible

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55 Fan ST, Choi TK, Lo CM Treatment of hepatolithiasis:

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56 Binmoeller KF, Bruckner M, Thonke F, et al Treatment of

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57 Jakobs R, Maier M, Kohler B, et al Peroral laser lithotripsy

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58 Chijiiwa K, Kameoka N, Komura M, et al Hepatic resection for hepatolithiasis and long-term results J Am Coll Surg 1995;180: 43–8.

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pre-60 Lai KH, Lin LF, Lo GH, et al Does cholecystectomy after scopic sphincterotomy prevent the recurrence of biliary compli- cations? Gastrointest Endosc 1999;49:483–7.

endo-61 Chen MF, Jan YY, Lee TY Percutaneous transhepatic biliary drainage for acute cholangitis Internat Surg 1987;72:131–3.

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C H A P T E R 17

Cystic diseases of the biliary system

Robert J Porte and Pierre-Alain Clavien

17

O B J E C T I V E S

• List the differential diagnosis of cystic lesions in the liver

• Describe the diagnosis and management of polycystic liver disease

• Understand the various types of genetic background in polycystic liver disease

• Name the classification of cystic diseases of the biliary tract

• Understand the premalignant nature of cystic diseases of the biliary tract

• Understand the role of liver resection for biliary cystadenoma and cystadenocarcinoma

Introduction

Cystic lesions of the bile ducts and liver can result from a

vari-ety of pathologic processes They may be solitary or multiple

Cystic abnormalities occurring within the liver parenchyma,

which are not in continuity with the biliary tree, are referred

to as liver cysts Cystic lesions which are in direct continuity

with the intra- or extrahepatic bile ducts are considered as

biliary cysts The aim of this chapter is primarily to focus on

cystic lesions of the intra- and extrahepatic bile ducts

How-ever, because of the assumed role of the intrahepatic biliary

epithelium in the origin of the noncommunicating liver

cysts, this group of cystic liver diseases will be discussed here

as well Cystic lesions of the liver with an infectious origin

(e.g echinococcus or hydatid cysts, liver abscesses) and

pseu-docysts are outside the scope of this chapter and will not be

discussed

Cysts of the liver and bile ducts can occur as single entities,

but are frequently found in various combinations of intra- or

extrahepatic cystic abnormalities Although the exact

mech-anisms underlying the origin of liver cysts are unknown,

mutations in four distinct genes have been linked to various

types of polycystic liver disease [1] Cystic abnormalities of

the intra- and extrahepatic bile ducts have been historically

classified as acquired entities; however, it is likely that other

factors (i.e genetic factors) also play a role in the

pathogene-sis of cystic diseases of the bile duct, as will be discussed below

[2–4]

In general, true or epithelialized liver and biliary cysts can

be divided into two groups: a neoplastic and a non-neoplastic

group The neoplastic group primarily comprises biliary

Simple liver cysts

Simple hepatic cysts are also known as benign, nonparasitic,

or solitary cysts, the latter being a poor name, since they are multiple in 50% of the cases Although these cysts were tra-ditionally considered as rare lesions [5], by the wider applica-tion of imaging modalities, such as the computed tomography (CT) scan, we now know that these cysts can be found rather commonly in asymptomatic patients [6,7] The exact patho-genesis of simple hepatic cysts is unknown, but it has been suggested that they develop from biliary microhamartoma or aberrant bile ducts, which have lost contact with other parts

of the biliary system during the early embryological stages [8] Although simple hepatic cysts are not in direct continu-ity with the biliary tree, their presumed biliary origin, and the differential diagnosis with other types of hepatic and bili-ary cystic disorders, justifies a discussion of simple hepatic cysts in this chapter

Simple cysts can be found at all ages, although the lence increases with increasing age and women are more often affected than men Most cysts have a round or oval shape on cross-section and can vary in size from a few mm to more than 30 cm [8] They are usually asymptomatic and are found coincidentally during ultrasound or CT examination

preva-of the abdomen for unrelated symptoms or conditions sionally, large cysts cause vague upper abdominal complaints

Occa-Copyright © 2006 by Blackwell Publishing Ltd

or symptoms of partial bowel secondary to compression of

the gastrointestinal tract Large cysts located in the hepatic

hilum can cause obstructive jaundice or portal hypertension

due to compression of the hepatic duct or portal vein [6,7]

Compression of the inferior vena cava is a very rare

complica-tion, but it may lead to an inferior vena cava syndrome,

char-acterized by symptoms related to venous congestion of the

lower part of the body Acute abdominal pain may result from

rupture or bleeding into the cyst Depending on the size and

location within the liver, cysts can sometimes be found on

physical examination Serum values of the hepatic enzymes may be increased, but are usually within the normal range [8]

Histologically, the inner cystic lining is formed by a single layer of cuboidal or columnar epithelium that resembles bili-ary epithelium [8] The cystic fl uid is usually clear yellow and serous, but may appear bloody or purulent under given cir-cumstances The presence of numerous microhamartomas

in the surrounding liver, or the combination of multiple cysts should raise the possibility of autosomal dominant polycystic disease [3] Malignant degeneration, either to squamous cell carcinoma, adenocarcinoma, or a mixed type, is a rare but serious complication [9,10]

The diagnosis of simple cysts is usually made by nography or computed tomography [5] Differentiation with abscess, hematoma, and solid tumors is not difficult when using these radiological techniques (Fig 17.1) The differen-tiation between simple cysts and echinococcal (hydatid) cysts can be somewhat more difficult Depending on the local prevalence of echinococcal infections, hydatid liver cysts may be mistaken for a simple liver cyst in up to 5% of the cases [11] Although simple cysts are always unilocular and never have calcifi cations, echinococcal cysts are usually septated and frequently have calcifi cations in the wall [12] Serological studies will be helpful in discriminating the two conditions from each other Cysts with irregularities of the cystic wall or papillary projections into the cystic cavity should raise a very high suspicion for cystadenoma or cystad-enocarcinoma In these cases, carbohydrate antigen 19-9 (CA 19-9) or carcinoembryonic antigen (CEA) serum

ultraso-Table 17.1 Classification of hepatic and biliary cysts.

Non-neoplastic

Simple (solitary) liver cysts

Polycystic liver diseases

Autosomal recessive polycystic disease/ congenital hepatic fibrosis

Autosomal dominant polycystic diseases

Autosomal dominant polycystic kidney disease – type 1

Autosomal dominant polycystic kidney disease – type 2

Autosomal dominant polycystic liver disease

Cystic diseases of the biliary tract

Periductal hilar cysts

Caroli’s disease and Caroli’s syndrome

Choledochal cysts

Neoplastic

Biliary cystadenoma

Biliary cystadenocarcinoma

Figure 17.1 Computed tomography of the upper

abdomen showing a simple cyst in an otherwise normal liver.

concentrations are usually elevated, where as this is not the

case in simple cysts [13] Occasionally, metastasis from other

tumors can present as cystic lesions due to central necrosis

and cavity formation [5]

Treatment is not indicated in case of asymptomatic simple

cysts For symptomatic cysts different approaches have been

described Simple percutaneous puncture and aspiration of

the cystic content is not effective and is immediately followed

by refilling of the cysts [14] Percutaneous aspiration of the

cyst followed by the injection of a sclerosing agent (95%

alco-hol or minocycline) has a higher success rate of up to 70%

[15] However, for a long-term success, repeated procedures

are usually required, which carry the risk of infection or

scle-rosing cholangitis [15] The use of alcohol can be complicated

by pain, fever, or alcoholic intoxication Laparoscopic

un-roofing of the external part of the cyst, followed by

transposi-tion of an omental fl ap into the remaining cyst cavity, is

currently considered to be the treatment of choice for

symp-tomatic cysts [15,16] Open surgery is indicated when cysts

cannot be approached laparoscopically (e.g the posterior

segments VI and VII, and segment IVa), or when a potentially

malignant disease cannot be excluded [15,16] If aspiration

of the cystic contents, with precautions to avoid

contamina-tion of the abdominal cavity, provides evidence for a

malig-nancy, a partial liver resection is indicated [10,16] Also, the

incidental finding of a cystadenoma during or after

scopic fenestration of a liver cyst requires an open or

laparo-scopic enucleation of the cyst and in some cases hepatic

resection [17]

Polycystic diseases of the liver

Multiple liver cysts can be identified in three different types

of diseases: autosomal dominant polycystic kidney disease,

autosomal dominant liver disease, and autosomal recessive

polycystic liver disease (also known as congenital hepatic fi

-brosis) The hepatic abnormalities in the first two types of

polycystic liver disease are phenotypically similar, but

muta-tions in distinct genes have been linked to these disorders

Disease presentation in autosomal recessive polycystic liver

disease is highly variable and may vary from biliary

dysgene-sis, resulting in congenital hepatic fibrodysgene-sis, to intrahepatic

bile duct dilatations

Autosomal dominant polycystic diseases

The group of autosomal dominant polycystic diseases

con-sists of genetically heterogeneous disorders with identified

mutations in four distinct genes In the most common form,

cystic manifestations are most prominent in the kidneys, and

this disease is called autosomal dominant polycystic kidney

disease (AD-PKD) [18,19] Mutations in two different genes

have been linked to AD-PKD: PKD1 and PKD2 Mutations in

the PKD1 gene account for 85 to 90% of mutations in

AD-PKD families; the remaining 10 to 15% are due to mutations

in PKD2 [1] PKD1 and 2 encode for proteins called

polycys-tin-1 (PC-1) and polycystin-2 (PC-2), which have been acterized as membrane-bound proteins involved in cell–cell and cell–matrix interactions [1] Moreover, recent evidence demonstrates that PC-1 and PC-2 form the core of a mecha-notransduction signaling complex within ciliated epitheli-

char-um cells [20] How dysfunctional signaling from cilia may result in abnormal cell growth and differentiation remains to

be delineated Two other genes, protein kinase C substrate

80K-H (PRKCSH) and SEC63, have been linked to the

relatively rare, third form of isolated autosomal dominant polycystic liver disease that is not accompanied by renal

involvement [21,22] PRKCSH, located on chromosome

19p13, encodes for a protein called hepatocystin [21], and

SEC63 encodes for a component of the protein machinery in

the endoplasmic reticulum [22] The exact relationships tween these genes and the polycystic phenotype remain speculative

be-The three forms of polycystic liver disease are all ized by the development of multiple liver cysts and are phe-notypically indistinguishable The overall prevalence at autopsy studies is about 0.13% [1] The natural history of the autosomal dominant forms of polycystic liver disease is strik-ingly similar, despite the variations in molecular and genetic background [1,23] Hepatic cysts are rarely observed before puberty They tend to appear with increasing age, more com-monly in women, especially after multiple pregnancies or the use of drugs containing sex hormones [1,24] In addition

character-to liver and kidney cysts, patients with AD-PKD may also velop cysts in other organs, including the pancreas, spleen, ovaries, uterus, testes, thyroid, and mesenterium Other as-sociated disorders are colonic diverticula, vascular aneu-rysms, and inguinal hernias [24] Polycystic liver disease is considered to result from progressive dilatation of abnormal ducts in microhamartomas or von Meyenburg complexes, at the level of the small intrahepatic bile ducts [1,3] Apart from the initial gene mutation (“first hit”), a second loss-of-function mutation in the functional gene copy (“second hit”)

de-is believed to be responsible for initiation of cell proliferation and cyst formation Expanding cysts detach from the intra-hepatic bile duct, which explains the noncommunicating na-ture of the cysts in polycystic liver disease On histological examination the cysts are very similar to simple hepatic cysts The inner wall is formed by a single layer of more or less cuboidal epithelium, resembling biliary epithelium and they are surrounded by a thin fibrous wall [1]

Polycystic liver disease is usually asymptomatic and an incidental finding Symptoms occur in 10 to 20% of the patients and usually not before the third decade [18,19] Most symptoms center around the massive hepatomegaly and in-clude upper abdominal pain and discomfort, abdominal dis-tention, and dyspnea Hepatic function is well preserved in most cases and serum levels of liver enzymes are either nor-mal or only slightly elevated [1] In symptomatic patients the

liver can usually be felt on physical examination and may

extend downwards into the pelvis Complications may occur

from infection, compression, bleeding, or rupture of the

cysts Infection of hepatic cysts occurs in up to 3% of patients

with autosomal dominant polycystic disease who have

end-stage renal failure, but in less than 1% of such patients before

end-stage renal failure [25] Compression of the bile ducts

may result in jaundice Isolated cases with compression of the

inferior vena cava vein or portal vein, resulting in an inferior

vena cava syndrome or portal hypertension, have been

re-ported [1,19] Malignant degeneration is extremely rare and

has been described only in a few case reports [26]

Modern radiologic studies, such as ultrasonography,

com-puted tomography, or magnetic resonance imaging (MRI)

can be helpful in making the diagnosis or defining the cause

of complications Diagnostic puncture and aspiration of the

cyst content will facilitate in making the diagnosis when

in-fection of a cyst is suspected

Most patients with polycystic liver disease do not require

treatment When kidney disorders are present, the

abnor-malities in kidney function, rather than the liver disease,

de-fine the long-term prognosis [18] Treatment of liver cysts is

indicated in cases with serious complaints of pain or

conse-quences of compression and/or infection [1,19] There is

cur-rently no specific medical treatment for polycystic liver

disease As with simple liver cysts, decompressing puncture

alone does not provide long-term relief of symptoms

Chemi-cal ablation is only indicated when one or two dominant cysts

can be held responsible for the symptoms The indication for

surgical interventions is less evident than for simple cysts

Possible options are laparoscopic or open fenestration,

par-tial liver resection, and liver transplantation [1,16,27] Relief

of symptoms is often transient and the long-term effect of

most surgical interventions is disappointing Selected

pa-tients with severe symptomatic polycystic liver disease and

favorable anatomy benefit from liver resection and open or

laparoscopic fenestration with acceptable morbidity and

mortality The extent of hepatic resection and fenestration is

important for the long-term effectiveness of this procedure

[28] Some highly symptomatic patients with massive

poly-cystic liver disease may benefit from combined hepatic

resec-tion and fenestraresec-tion with acceptable risk [29] In general,

the indication for surgical interventions in polycystic liver

disease is limited and it should always be viewed in

relation-ship with the risk of postoperative complications, such as

in-fection or massive ascites production In selected cases with

diffuse bilobar polycystic disease and massive hepatomegaly,

liver transplantation with or without combined kidney

transplantation should be considered [27]

Autosomal recessive polycystic disease/congenital

hepatic fibrosis

Autosomal recessive polycystic disease, also known as

infan-tile polycystic disease, and congenital hepatic fibrosis are

often seen in combination, and it has debated whether these entities are a different expression of the same underlying de-velopmental disorder at the level of the intermediate or small intrahepatic bile ducts, rather than two distinct disorders [3,30] Both conditions are frequently associated with other liver malformations, such a Caroli’s disease and von Meyen-burg complexes, but also with renal dysgenesis, such as poly-cystic renal disease, renal dysplasia, or nephronophthisis [31] The exact prevalence of autosomal recessive polycystic disease is not known, but estimates have suggested a fre-quency of 1 : 20,000 live births [32] Liver abnormalities are characterized by fibrous enlargements of the portal tracts containing numerous abnormally shaped and ectatic bile ducts Macroscopically visible cysts are usually not present in the liver [3] Which term is used in an individual patient is mostly dependent on the amount of renal involvement, with the term autosomal recessive polycystic kidney disease pre-served for those cases with renal involvement as the most prominent feature Autosomal recessive polycystic kidney

disease has been linked to mutations in the PKHD1

(polycys-tic kidney and hepa(polycys-tic disease 1) gene, encoding for tin, and located on chromosome 6p [32] Fibrocystin is a large protein and may have a receptor function Recent evidence has linked the protein to the primary cilium of biliary epithe-lium cells This localization is in common with that of other proteins that have been associated with other types of poly-cystic diseases (see below) [32] Because cystic dilatations are not the main feature of these conditions, a further discus-sion would be outside the scope of this chapter However, high mortality rates associated with this disorder make it an important cause of pediatric death and a more detailed dis-cussion is given in Chapter 23

fibrocys-Cystic diseases of the biliary tract

Bile duct cysts may occur as solitary or multiple cystic tions throughout the entire biliary tree Originally, these abnormalities were termed choledochal cysts, based on the frequent occurrence of cysts in the common bile duct How-ever, cystic dilatations may occur throughout the entire bili-ary tree and “bile duct cysts” or “cystic diseases of the biliary tract” are considered as more appropriate terms for this con-dition [4] When confined to the intrahepatic bile ducts, the term Caroli’s disease is generally used, whereas the term cho-ledochal cyst is still frequently used for dilatations limited to the extrahepatic bile duct In addition to these types of bile duct cysts, a rarer condition, characterized by multiple peri-ductal cysts, has been identified

dilata-Multiple periductal cysts

Small cystic lesions of 1 to 2 mm are incidentally found

with-in Glisson’s capsule along the large with-intra- or extrahepatic bile ducts These rare cystic lesions have been referred to as muci-nous hamartoma or periductal cysts [33,34] They usually