Diseases of the Gallbladder and Bile Ducts - part 6 pptx

• Understand the pathogenesis of gallstone formation• List the different risk factors of gallstone formation • Understand the natural history of asymptomatic and symptomatic gallstones •

as erlotinib (OSI-774, Tarceva) have been evaluated in biliary

cancers [71] In a phase II study that included biliary cancer

or hepatocellular cancer (although patients were not selected

on the basis of EGFR expression), erlotinib was given

contin-uously at a dose of 150 mg/day orally Of the 36 evaluable

pa-tients with biliary tumors, two had a partial response and

seven (25%) were progression-free at 6 months

Conclusions

Currently available medical approaches to the treatment

of biliary malignancy are primarily palliative in intent

Chemotherapy appears to have a palliative benefit compared

with the best supportive care in advanced gallbladder and

bile duct cancers When used as a radiosensitizer,

5-fluorouracil may also give palliative benefit for locally

ad-vanced neoplasia The role of chemotherapy in the adjuvant

setting after surgical resection remains to be defined

Never-theless, we have typically combined adjuvant chemotherapy

with radiation in patients with positive margins or regional

lymph node involvement For patients with locally advanced

disease who would be surgical candidates if they attained

tumor regression, we use systemic chemotherapy as part of a

neoadjuvant multimodality approach As immune, gene,

an-tiangiogenic, and apoptotic strategies undergo further

devel-opment, they will likely be applied to biliary cancers

Questions

1 Gallbladder cancer is more likely than hilar cholangiocarcinoma

to recur with distant disease.

a true

b false

2 Gemcitabine-containing chemotherapy regimens have among

the highest response rates in gallbladder cancer.

a true

b false

3 There is a trend for better survival in patients with unresectable

biliary malignancies who receive systemic chemotherapy

compared with best supportive care.

a true

b false

c may be true, but did not reach statistical significance

4 Pathways that may be involved in biliary malignancies include:

ErbB-2, hepatocyte growth factor/Met, interleukin-6/

glycoprotein130, cyclooxygenase-2 (COX-2), vascular

endothelial growth factor (VEGF), transforming growth

factor-beta (TGF-β), MUC1 and MUC4, factor-beta-catenin, telomerase, and

chemo-2 Heimbach JK, Haddock MG, Alberts SR, et al Transplantation for hilar cholangiocarcinoma Liver Transpl 2004;10(Suppl 2): S65–8.

3 Mambrini A, Fiorentini G, Pennucci C, et al Intra-arterial patic chemotherapy combined with systemic infusion of 5-FU

he-in patients with advanced biliary tract cancers Proc Am Soc Clin Oncol 2004;22:4197.

4 Jarnagin WR, Ruo L, Little SA, et al Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies Cancer 2003;98:1689–700.

5 Amano H, Takada T, Kato H, et al Five year results of a ized study of post-operative adjuvant chemotherapy in resected pancreatic-biliary carcinomas Proc Am Soc Clin Oncol 1999;18:273a (abstr 1049).

random-6 Treadwell TA, Hardin WJ Primary carcinoma of the der The role of adjunctive therapy in its treatment Am J Surg 1976;132:703–6.

gallblad-7 Gonzalez Gonzalez D, Gerard JP, Maners AW, et al Results of diation therapy in carcinoma of the proximal bile duct (Klatskin tumor) Semin Liver Dis 1990;10:131–41.

ra-8 Pitt HA, Nakeeb A, Abrams RA, et al Perihilar noma Postoperative radiotherapy does not improve survival Ann Surg 1995;221:788–98.

cholangiocarci-9 Schoenthaler R, Phillips TL, Castro J, et al Carcinoma of the trahepatic bile ducts The University of California at San Fran- cisco experience Ann Surg 1994;219:267–74.

ex-10 Serafini FM, Sachs D, Bloomston M, et al Location, not staging,

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12 Urego M, Flickinger JC, Carr BI Radiotherapy and ity management of cholangiocarcinoma Int J Radiat Oncol Biol Phys 1999;44:121–6.

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35 Patt YZ, Hassan MM, Lozano RD, et al Phase II trial of cisplatin (P), Intron A (I), Adriamycin (A), and 5-fl uorouracil (F) (PIAF) for biliary tree cancer (BTC) Proc Am Soc Clin Oncol 1999; 18:297a (abstr 1139).

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doxo-37 Doval DC, Sekhon JS, Gupta SK, et al A phase II study of citabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer Br J Cancer 2004;90:1516–20.

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39 Tan BR, Smukler A, Majerus E, et al Gemcitabine and tin in the treatment of metastatic cholangiocarcinoma and gall- bladder cancer Proc Am Soc Clin Oncol GI San Francisco 2004;abst 175.

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41 Bhargava P, Jani CR, Savarese DM, et al Gemcitabine and tecan in locally advanced or metastatic biliary cancer: prelimi- nary report Oncology (Huntington) 2003;17(9 Suppl 8): 23–6.

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S E C T ION 3

Specific conditions

Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition

Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd

S E C T ION 3.1

The gallbladder

Copyright © 2006 by Blackwell Publishing Ltd

• Understand the pathogenesis of gallstone formation

• List the different risk factors of gallstone formation

• Understand the natural history of asymptomatic and symptomatic gallstones

• Describe the current medical treatment options for patients with symptomatic gallstone disease

Introduction

Gallstones are highly prevalent in industrialized countries,

affecting 10 to 15% of men and up to 25% of women [1]

Al-though the majority of individuals with gallstones remain

asymptomatic, symptomatic gallstone disease is considered

the most common and costly digestive disease in the United

States [2] Studies in the 1960s reported cholecystectomy

rates of 500,000 per year for the United States [3]; with the

development of laparoscopic cholecystectomy in the late

1980s, this fi gure has risen further to an estimated 700,000

operations per year [4] Over the past several decades, there

have been major advances in our understanding of gallstone

pathogenesis; with the improvements in, and wide

availabil-ity of, imaging modalities such as ultrasound and computed

tomography, the epidemiology and natural history of

chole-lithiasis has been studied extensively In this chapter, we

discuss these developments, with special emphasis on their

implications for the treatment of gallstone disease

Types of gallstones

Gallstones are characterized by their chemical composition

They are classifi ed, somewhat arbitrarily, into cholesterol

stones (>50% cholesterol content), mixed stones (20 to 50%

cholesterol content), and pigment stones (<20% cholesterol

content), the latter being composed primarily of calcium

bili-rubinate Early epidemiologic studies have suggested that 80

to 90% of all stones in Western countries were of the

choles-terol or mixed type and only 10 to 20% were pigment stones

219

[5], but others have found pigment stones in up to 30% of individuals with cholelithiasis In Asia, up to 70% of all gallstones are pigment stones Due to the predominance

of cholesterol gallstones in the United States, much of the research effort has focused on this type of stone and less is known about the pathogenesis of pigment stones

Pathogenesis of gallstone formation

Components of normal bile

The main components of bile are water, electrolytes, and ganic solutes, the latter consisting predominantly of bile salts, cholesterol, and phospholipids [6] Bile salts are classified as either primary or secondary The primary bile acids, cholic and chenodeoxycholic acid, are synthesized in the liver from cholesterol and then conjugated with either glycine or tau-rine After excretion with bile fl uid into the duodenum, most

or-of the bile acid pool is reabsorbed in the distal small bowel and recirculated via the enterohepatic circulation A small amount (less than 5%) of bile salts enters the colon, where

it undergoes deconjugation by bacteria, resulting in the formation of secondary bile acids (deoxycholic and litho-cholic acid) [7]

Most of the cholesterol found in bile is synthesized de novo

in the liver Cholesterol is insoluble in water and is therefore dependent on some other vehicle for its solubilization in bile Understanding the mechanisms responsible for the solubili-zation of cholesterol has facilitated analysis of the biochemi-cal events occurring during the formation of cholesterol stones [8,9]

Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition

Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd

Pathogenesis of cholesterol stones

The formation of cholesterol gallstones has been separated

into three stages: (1) cholesterol solubilization and

satura-tion, (2) nucleasatura-tion, and (3) stone growth [8]

Cholesterol is virtually insoluble in bile and therefore

re-quires interaction with other molecules to be solubilized [8]

For many years, it was thought that cholesterol was

main-tained in solution almost entirely by the formation of

so-called micelles, composed of bile acids, phospholipids, and

cholesterol Bile acids are amphipathic compounds,

contain-ing both hydrophilic and hydrophobic groups When the bile

acid concentration reaches a certain level (termed critical

mi-cellar level), individual bile acid molecules aggregate into

small clusters with their polar ends oriented outwardly and

the hydrophobic portions oriented towards the inside of the

cluster Phospholipids enter this aggregate, leading to

swell-ing of the micelle which in turn facilitates incorporation of

cholesterol Cholesterol molecules are ultimately

transport-ed within the matrix of this structure The concentration of

bile acids and phospholipids relative to cholesterol has been

thought to be the critical factor in determining cholesterol

solubilization, and the relationship between these three

sub-stances has commonly been depicted in form of a “cholesterol

triangle” [9] (see also Chapter 1, Fig 1.9) (Fig 12.1)

The concept of mixed micelle formation and its role in

for-mation of cholesterol gallstones has recently been challenged

by the demonstration that much of the biliary cholesterol

exists in a somewhat different structure, termed a vesicle [9] Vesicles are made up of phospholipid bilayers, similar to cell membranes, with interspersed bile acids [10] Cholesterol is solubilized within the hydrophobic portion of the bilayer The relative importance of micelles and vesicles in cholest-erol stone formation remains the subject of intensive research.The process by which cholesterol monohydrate crystals form and aggregate has been termed nucleation The obser-vation that many normal individuals without gallstones secrete cholesterol-supersaturated bile suggests that factors other than the hepatic secretion of cholesterol-saturated bile are important for the formation of gallstones [11] It has been shown that nucleation occurs more rapidly in the gallbladder bile of patients with cholesterol gallstones than in individu-als with saturated bile without stones [12] This finding initi-ated efforts to identify the nature of either pronucleating or antinucleating factors A heat-labile glycoprotein has been identifi ed in patients with cholesterol gallstones and has been shown to reduce nucleation time signifi cantly [13] Increased gallbladder mucus secretion has also been reported to be a potent pronucleating factor [14] Mucin secretion is stimu-lated by prostaglandins Aspirin, an inhibitor of prostaglan-din synthesis, both significantly inhibits mucus secretion and reduces the incidence of experimentally induced choles-terol gallstones in an animal model [15] This finding gener-ated considerable enthusiasm as it appeared feasible to prevent gallstone formation through prophylactic usage of

Figure 12.1 Phase-equilibrium diagram of a model

bile system consisting of sodium taurocholate, egg yolk lecithin, cholesterol, and water (10 g/dL total lipid concentration, 0.15 mol/L NaCl, pH 7.0, 37°C) Adapted from Donovan and Carey [9].

Chapter 12: Natural history and pathogenesis of gallstones 221

prostaglandin inhibitors However, studies in humans have

not found an effect of aspirin usage on gallstone formation

[16] and this concept has been abandoned Recently, a

bacte-rial lipopolysaccharide has been shown to induce mucin

hypersecretion suggesting that — contrary to the commonly

accepted assumption — bacteria may play a role not only in

the development of pigment gallstones but also in cholesterol

stone formation [17]

In summary, although cholesterol supersaturation is

commonly viewed as a prerequisite for cholesterol gallstone

formation, the impact of pronucleating factors in vivo

re-mains incompletely understood [18] Efforts continue to

un-derstand the role of cholesterol supersaturation and the

balance between pronucleating and antinucleating factors in

the formation of cholesterol stones

The role of the gallbladder

Gallbladder contraction is induced by meals and mediated by

the hormone cholecystokinin When the gallbladder

con-tracts, 70 to 80% of the fasting volume is released into the

duodenum Stasis of bile within the gallbladder has been

im-plicated in the increased frequency of gallstone formation in

patients after truncal vagotomy and during pregnancy [19]

Radioisotope and manometric studies have confirmed that

gallbladder stasis and decreased gallbladder emptying occur

during the early stages of formation of experimentally

in-duced cholesterol gallstones [20] High progesterone levels

have also been shown to reduce gallbladder contractility in

an animal model [21], a mechanism that may contribute to

the increased risk for gallstone formation during pregnancy

Further evidence implicating gallbladder stasis as an

etiol-ogic factor in cholesterol gallstone formation comes from

bil-iary scintigraphic studies of human patients with gallstones,

in whom a decreased motor response to cholecystokinin

stimulation has been noted Decreased gallbladder emptying

has been demonstrated in patients with cholesterol gallstones

[22] as well as, in the absence of stones, in individuals with

biliary cholesterol crystals

The mechanism by which stasis of bile within the

gallblad-der promotes cholesterol gallstone formation remains poorly

defined Conceivably, stone growth from cholesterol crystals

is a slow process Even with enough time for microcrystals to

nucleate, in subjects with normal gallbladder function these

small cholesterol aggregates are likely to be ejected into the

duodenum before growing into macroscopic gallstones

Fur-thermore, gallbladder stasis may be associated with

altera-tions in gallbladder absorptive or secretory function or with

sequestration of bile acids in the gallbladder, reducing the

amount of bile salts available for cholesterol solubilization

[23]

Pathogenesis of pigment stones

Pigment stones are characterized by their low cholesterol

content and their high concentration of bilirubin, which is

usually in excess of 40% Bilirubin is secreted by the liver into the bile mostly in its diglucuronide form with only small amounts of the monoglucuronide and unconjugated forms

As for cholesterol, bile salts facilitate solubilization of the monoglucuronide and unconjugated forms of bilirubin The unconjugated form is hydrophobic and may precipitate from solution as calcium salts or bilirubin polymers [24] It is believed that pigment stones occur when the bile is super-saturated with unconjugated bilirubin Pigment stones are associated with diverse clinical conditions and can be conve-niently divided into “black stones” and “brown stones.”Black pigment stones occur in patients with chronic hemo-lysis, liver cirrhosis, or compromised ileal function, as with Crohn’s disease or ileal resection In patients with hemolysis, secretion of bilirubin into bile may be increased more than 10-fold, with a shift from diconjugates to monoconjugates Bilirubin monoconjugates are more sensitive to hydrolysis by endogenous beta-glucuronidase, leading to accumulation of unconjugated bilirubin which subsequently precipitates with calcium The pathogenesis of gallstone formation in pa-tients with cirrhosis is less well understood, but mild hemoly-sis and bile salt hyposecretion leading to reduced solubility of unconjugated bilirubin may play a role Patients with Crohn’s disease and extensive ileitis have higher levels of bilirubin

fl ux through the liver and higher biliary bilirubin tions Results from animal experiments suggest that this may

concentra-be due to bile salt malabsorption in the ileum resulting in high amounts of intracolonic bile salts This leads to solubili-zation of intracolonic unconjugated bilirubin, which is then free to be reabsorbed, transported back to the liver, and ex-creted into the bile, thereby leading to increased concentra-tion of biliary bilirubin [25]

Similar to cholesterol stone formation, a variety of other factors may contribute to pigment stone formation, including secretion by the gallbladder of mucous glycoproteins, biliary stasis, biliary calcium concentration, and bile acidifi cation[23]; the exact contribution of each of these factors remains

to be elucidated The role of bacterial infection in the genesis of black pigment stones has long been discussed; there are some indications that bacteria may play a role, but find-ings have been inconclusive to date [26]

patho-Brown pigment stones can be located throughout the intrahepatic and/or extrahepatic biliary tract and are the typical type of gallstone associated with bacterial infection and biliary stasis [27] Bacterial enzymes hydrolyze biliary lipids, conjugated bilirubin, and bile salts The resultant free bile acids, free fatty acids, and unconjugated bilirubin precip-itate as such or form insoluble calcium salts Mucin glycopro-teins and bacterial debris may contribute to the growing gallstone

Common duct stones

Gallstones located in parts of the biliary tree other than the gallbladder may be classifi ed as either primary, those that are

formed in the bile duct, or secondary, those that are formed in

the gallbladder and passed through the cystic duct into the

common duct or the intrahepatic bile ducts Epidemiologic

evidence suggests that most common duct stones arise in the

gallbladder [28] Most patients with cholesterol stones in the

common duct also have gallbladder stones of identical

com-position In contrast, patients with pigment stones in the

common duct often do not have corresponding stones in the

gallbladder Pigment stones, particularly those of the brown

pigment type, are therefore thought to form anywhere in the

biliary tree, very often in the intrahepatic portion of the

bili-ary tree; they probably constitute the majority of primbili-ary

common duct stones Although the main factors

contribut-ing to the formation of primary common duct stones appear

to be biliary bacterial infections and stasis of bile in the

com-mon duct, abnormal sphincter of Oddi activity has also been

discussed as a contributing factor Wong and colleagues

re-ported elevated common bile duct pressures at operation in

patients with common duct stones [29] However, two other

groups could not confirm this finding [30,31] Whether the

increased prevalence of gallstones in patients with

juxtapap-illary duodenal diverticula is due to a motor abnormality of

the sphincter of Oddi has also been controversial It has been

suggested that sphincter insufficiency causes higher rates of

bacterial contamination of the biliary tree which in turn

leads to higher frequencies of brown pigment stone

forma-tion [32] Addiforma-tional studies are needed to clarify the role of

motor abnormalities of the sphincter of Oddi in the

patho-genesis of primary common duct stones

In the Far East and Japan, intrahepatic stones or

hepatico-lithiasis are very prevalent, whereas in the West they are

extremely rare [33] Most intrahepatic stones are also brown

pigment stones (calcium bilirubinate stones) where bacterial infection and bile stasis are also thought to be of pathogenetic importance (see above) However, intrahepatic brown pig-ment stones include more cholesterol and less calcium biliru-binate and bile acid compared to brown pigment stones in the extrahepatic bile ducts [34] In addition, recently an in-creased number of primary cholesterol stones in the intrahe-patic bile ducts have also been identified [35] The formation

of cholesterol-rich brown pigment stones and cholesterol stones in the intrahepatic bile ducts suggests the possibility that there might be an underlying metabolic defect There is recent evidence that the formation of these stones may be due

to decreased secretion of phospholipids as a consequence of such a metabolic defect leading to the formation of intrahe-patic stones [36]

Biliary sludge

Biliary sludge was first described with the advances of dominal ultrasonography as an echogenic material in the gallbladder that shifts slowly with positioning of the patient [37] (Fig 12.2) Similar pathogenetic mechanisms as in gall-stone disease are assumed to apply to the formation of biliary sludge, and the role of biliary sludge as a precursor of choles-terol and pigment gallstones has been proposed by Lee and colleagues [38] Gallbladder sludge, as determined ultraso-nographically, has been presumed to be a manifestation of biliary stasis It has been demonstrated that sludge is com-posed, in part, of calcium bilirubinate crystals, cholesterol monohydrate crystals, and gallbladder mucus [39] In a study

ab-of patients receiving total parenteral nutrition (TPN), sludge could be detected in all patients after 6 weeks of TPN [40] With continuation of TPN, stones developed in almost half of

Figure 12.2 Transabdominal ultrasound of a

gallbladder containing large amounts of sludge and multiple gallstones generating characteristic acoustic shadowing.

Chapter 12: Natural history and pathogenesis of gallstones 223

these patients during follow-up On the other hand, the

rein-stitution of oral feedings led to disappearance of sludge

within 4 weeks

Risk factors for gallstone formation

A large number of diverse factors predispose individuals to

the development of gallstones (Table 12.1) The prevalence of

gallstones varies greatly among different ethnic groups

sug-gesting that genetic factors may play an important role

Gall-stone prevalence in certain Asian countries is 3 to 5%, but

populations in Europe and North America have an overall

prevalence of 10 to 20%; in certain ethnic subgroups such as

the North American Pima Indians and Chippewa, gallstones

rates reach 60% In a recent study from Mexico, it was shown

that the development of gallstones in the Mexican

popula-tion was associated with characteristics of the Amerindian

population [41] Further evidence in favor of genetic

influ-ence for the development of symptomatic gallstone disease

was provided by a Swedish study of over 43,000 twin pairs

[42] In their study, they found that heritability was the major

susceptibility factor for symptomatic gallstones There is also

considerable temporal variation in gallstone prevalence,

sup-porting an influence of dietary factors and lifestyle It has

been argued that the ancient Greeks knew renal colic but did

not know gallstone disease, and this has been attributed to

their diet and style of living Several studies in more recent times have also shown increases in the prevalence of gall-stones over time

Gallstones are twice as common in women as in men, and the prevalence increases with age The family history also seems to be of importance: first-degree relatives of gallstone patients have a 4.5-fold risk of having gallstones compared to matched controls [43] Obesity has long been identified as an important risk factor One study reported a six-fold increased risk for gallstone formation in very obese women compared

to lean women [44] Whether hypertriglyceridemia sents an additional independent risk factor remains contro-versial Rapid weight loss, either due to dietary measures

repre-or bariatric surgery, is associated with a high incidence ofgallstones [45] There is some evidence that this risk can

be reduced by the administration of ursodeocycholic acid [46]

A peculiar form of cholelithiasis was recently described by Rosmorduc [47] All patients described in this study shared the following features: at least one episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of chronic cholestatis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by ursodeoxycholic acid thera-

py In all these patients a mutation in the ABCB4 gene could

be identified The ABCB4 gene, formerly called MDR3 gene is

the phosphatidylcholine translocator across the canalicular membrane of the hepatocyte Accordingly, the phospholip-ids concentration is low leading to a high cholesterol/phospholid ratio and cholesterol crystals in the bile of these patients Therefore, this clinical syndrome is referred to as low phospholipids-associated cholelithiasis In a second

study, mutations in the ABCB4 gene were found in 56% of

pa-tients presenting the symptoms mentioned above and three independent clinical features were strongly associated with

ABCB4 mutations: recurrence of symptoms after

cholecys-tectomy; intrahepatic hyperechoic foci; intrahepatic sludge

or microlithiasis and age less than 40 years at the onset of

symptoms [48] Therefore ABCB4 gene mutations might

represent a major genetic risk factor for a symptomatic and recurring form of cholelithiasis occurring in young adults.Pregnancy predisposes women to gallstones, probably due

to a combination of the effects of estrogens causing an crease in biliary cholesterol saturation and progesterones causing atony of the gallbladder In a study by Coelho and colleagues performed in Brazil, 4% of nulliparous women had gallstones compared to 35% of women with six or more pregnancies [49] As mentioned above, biliary sludge com-monly develops during pregnancy and may evolve into gallstones or may resolve after the birth [50]

in-Patients with Down syndrome have an increased lence of gallstones and, in a recent study, it was demonstrated that adults with Down syndrome also have a higher risk for symptomatic gallstone disease [51]

preva-Table 12.1 Risk factors for gallstone formation.

Fasting, total parenteral nutrition

Drugs (octreotide, ceftriaxone, clofibrate)

Noninsulin-dependent diabetes mellitus

ABCB4 gene mutations

Black pigment gallstones

Medications such as estrogen-containing contraceptives

and estrogen given to postmenopausal women raise the risk

of gallstones [52], as do lipidlowering agents, such as clofi

-brate and gemfibrozil, which promote biliary cholesterol

excretion

Conditions leading to gallbladder stasis (TPN, diabetes,

spinal cord injury, and possibly autonomic dysfunction) are

associated with an increased risk of gallstone formation

Some good news for many of us: the consumption of at least

two cups of coffee per day has recently been reported to be

associated with a 40% reduction in the rate of gallstone

formation [53]

Natural history of gallstones

Gallstones are common and are frequently discovered

inci-dentally in asymptomatic patients Although their

sponta-neous disappearance is a rare event — with the exception of

stones that formed during pregnancy or weight reduction

[54] — gallstones will remain “silent” in more than

two-thirds of individuals [55] They can, however, cause

symp-toms and complications, including biliary colic, acute

cholecystitis, and obstructive jaundice with or without

bili-ary pancreatitis

Asymptomatic gallstones

The management of asymptomatic stones has generated

considerable controversy At one time, cholecystectomy for

asymptomatic stones was recommended because

prophylac-tic surgery was assumed to prevent excess morbidity from

subsequent symptomatic gallstone disease [56] However,

subsequent studies suggested that the cumulative risk for the

development of symptoms or complications from

asymptom-atic gallstones is relatively low, in the range of 1 to 2% per

year [57] One study found a risk of approximately 10% at 5

years, 15% at 10 years, and 18% at 15 years [58] Patients

re-maining asymptomatic for 15 years were unlikely to develop

symptoms later Moreover, most patients who did develop

complications from their gallstones experienced prior

warn-ing symptoms Decision analysis has suggested that the

cu-mulative risk of death due to asymptomatic gallstone disease

with an expectant approach is small, and therefore

prophy-lactic cholecystectomy is not warranted for this patient

population [54]

Some reports have suggested that patients with diabetes

mellitus and gallstones may be more susceptible to septic

complications [59] and may have an increased risk of

periop-erative morbidity and mortality [60] This has led some

authorities to advise prophylactic cholecystectomy for all

di-abetic patients with cholelithiasis, irrespective of whether

they have developed symptoms However, when focusing on

diabetic patients with asymptomatic gallstones, other

inves-tigators found that the course of their disease is as benign as it

is in nondiabetic patients [61] Based on these findings and the decision analysis by Friedman and colleagues [62], pro-phylactic cholecystectomy in diabetic patients with asymp-tomatic gallstones does not seem to be warranted

Gallstones have long been suspected to be a risk factor for the development of carcinoma of the gallbladder The inci-dence of gallbladder cancer in patients with cholecystolithia-sis is approximately 1 in 10,000, compared to 1 in 30,000 in individuals without gallstones [55] This risk is felt to be too low, however, to justify prophylactic cholecystectomy in every individual with cholelithiasis [49]

Symptomatic gallstones

Biliary colic is the most common presentation of

symptomat-ic gallstone disease [54] and is felt to be due to tonsymptomat-ic spasm around the cystic duct secondary to temporal obstruction by

a gallstone Biliary colic is defined as recurrent episodes of severe steady pain located in the epigastrium and right upper quadrant, lasting 30 minutes or more, often associated with nausea and vomiting [63]

Because pain in the upper abdomen is a common plaint and may be due to a large variety of diseases in patients who also have (asymptomatic) gallstones, identifying those patients with true symptomatic gallstone disease remains a clinical dilemma The onset of a biliary colic may be provoked

com-by food, but this is a weak discriminator of gallstone disease Intolerance to fried and fatty food is associated with gallstone disease, but is very common in general and lacks specificity Dyspeptic symptoms are common in the general population

as well as in individuals with gallstones, and a causal tionship remains to be established In a considerable propor-tion of patients with gallstones, dyspeptic symptoms are relieved after cholecystectomy but these patients cannot be clearly identifi ed preoperatively [64] Identifying patients with symptomatic gallstone disease is important because the annual risk of recurrent pain attacks after an episode of biliary colic ranges from 6 to 40% [65,66] Still, it has been estimated that 30% of patients who experience biliary pain will not have subsequent episodes in the future [54]

rela-Fortunately, serious gallstone-related complications are less common, and occur at an annual rate of 3 to 8% [57] Cholecystitis accounts for the majority of severe gallstone complications occurring in approximately 10% of patients with symptomatic cholelithiasis [57] Obstructive jaundice, cholangitis, and biliary pancreatitis are comparably rare; 20

to 50% of patients with symptomatic gallstone disease will not experience serious complications over the subsequent 20 years [57] Complications are almost always preceded by bili-ary pain, which may be considered a warning symptom [54] After having experienced a complication, patients have a high risk for recurrence of a symptomatic episode, which occurs in roughly 30% over 3 months in those who do not undergo cholecystectomy [54]

Chapter 12: Natural history and pathogenesis of gallstones 225

Treatment of gallstones

Treatment is generally recommended for symptomatic

gall-stones In the absence of contraindications to surgery,

elec-tive laparoscopic cholecystectomy will be the treatment of

choice in most patients Common duct stones can be removed

endoscopically; however, to avoid recurrence of

symptomat-ic gallstone disease, cholecystectomy will still need to be

con-sidered in patients with secondary common duct stones and

stones remaining in the gallbladder A sphincterotomy after

endoscopic stone extraction will prevent recurrence of

biliary pancreatitis (but not cholecystitis) in patients unfit to

undergo gallbladder surgery

Oral gallstone dissolution therapy with bile acids may be

appropriate in highly selected, mildly symptomatic patients

who refuse cholecystectomy or who are felt to be at signifi

-cant risk for surgery The treatment is only successful for

small stones (less than 0.5 to 1.5 cm) that are noncalcified (as

evidenced by plain abdominal X-ray film or abdominal CT

scan) Ursodeoxycholic acid (UDCA) is generally considered

the agent of choice A meta-analysis suggests that success

rates are higher for UDCA treatment than for

chenodeoxy-cholic acid treatment (CDCA) [67]; the latter is associated

with considerable dose-related side-effects, such as elevation

of liver enzymes, hypercholesterolemia, and watery

diar-rhea [68] UDCA therapy given at a dose of 8 to 12 mg/kg per

day for at least 6 months results in complete gallstone

dissolu-tion in only 40% of patients [67] The success rate is inversely

correlated with gallstone diameter It approaches 90% in

highly selected patients with small (<5 mm) floating stones

and is considerably lower for larger stones [67,68] The

disso-lution rate (if stones dissolve) is generally slow and can be

ex-pected to be around 0.5 to 1.0 mm per month Stones recur

after dissolution in about 50% of patients at an annual rate of

about 10% during the first 3 to 5 years [68]

Extracorporeal shockwave lithotripsy (ESWL) with or

without adjuvant UDCA treatment has not generated much

enthusiasm in the United States but is available in several

countries outside the United States It is most successful in

patients with solitary radiolucent stones with a diameter of

less than 2 cm

Topical dissolution therapy of noncalcified stones involves

the perfusion of the gallbladder with organic solvents such

as methyl tert-butyl ether (MTBE) The solvent is instilled

via a catheter introduced into the gallbladder either

per-cutaneously or endoscopically (i.e., via a nasobiliary tube)

Gallstones can generally be dissolved within a few hours,

regardless of size and number Unfortunately, stone

recur-rence is high: 40% for solitary stones and 70% for multiple

stones over 5 years [69] Signifi cant complications may occur

and are mainly due to the invasive approach Bile leakage

occurs in up to 5% of patients after percutaneous gallbladder

puncture Pancreatitis and cystic duct perforation may

complicate endoscopic retrograde cannulation [68] As long as MTBE is contained within the gallbladder, it is well tolerated Attempts to use MTBE to deal with common bile duct stones, however, have failed due to signifi cant side-effects [70] MTBE leaking from the bile duct into the duodenum may result in severe duodenitis, and if enough ether is absorbed, it causes profound sedation and other systemic effects (e.g., hemolysis or renal insufficiency) [70]

With the advent of minimal invasive surgical techniques, such as laparoscopic cholecystectomy and the advances in endoscopic retrograde techniques of stone removal, dissolu-tion therapy and ESWL are rarely needed

d high progesterone levels

e gallbladder mucus secretion

2 Which of the following conditions is associated with the

formation of black pigment stones?

3 Brown pigment stones can be located throughout the intra- or

extrahepatic biliary tract and they are typical gallstones associated with bacterial infection and biliary stasis.

a only 1 is correct

b only 2 is correct

c 1 and 2 are correct and connection is correct

d 1 and 2 are correct, connection is incorrect

4 Undisputed risk factors for gallstone formation are all, except the

a asymptomatic gallstones should always be operated

b patients with asymptomatic gallstones for more than 15 years are unlikely to develop symptoms

c most patients experience warning symptoms before developing

a cholecystitis is the most common complication of gallstones

b 20 to 50% of patients with symptomatic gallstone disease will

not experience serious complications over the next 20 years

c complications are almost never preceded by biliary pain

d after having experienced a gallstone complication, the risk for

recurrence is low

7 Biliary pain is characterized by the following symptoms, except:

a epigastric pain lasting less than 5 minutes

b concomitant symptoms very often are nausea and vomiting

c biliary pain can be provoked by food

d dyspeptic symptoms are common in individuals with gallstones

e the risk for recurrent pain after cholecystectomy ranges from 6 to

40%

8 Which is the best answer regarding oral gallstone dissolution

therapy with bile acids?

a chenodeoxycholic acid is the drug of choice

b treatment is only successful for small stones

c ursodeoxycholic acid therapy results in complete gallstone

dissolution in 90% of patients

d the success rate correlates with the gallstone diameter

e stones almost never recur after successful dissolution

9 Which of the following statements regarding topical dissolution

therapy with methyl tert-butyl ether is true?

a stone recurrence after successful dissolution is low

b common bile duct stones can also be dissolved

c leakage of the solvent into the duodenum rarely causes

side-effects

d topical dissolution usually takes several days

e bile leakage occurs in up to 5% of patients after percutaneous

gallbladder puncture

References

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40 Messing B, Bories C, Kunstlinger F, Bernier JJ Does total

par-enteral nutrition induce gallbladder sludge formation and

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44 Maclure KM, Hayes KC, Colditz GA, et al Weight, diet, and the risk of symptomatic gallstones in middle-aged women N Engl J Med 1989;321:563–9.

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dissolu-C H A P T E R 13

Acute and chronic cholecystitis

Stefan Breitenstein, Armin Kraus and Pierre-Alain Clavien

13

O B J E C T I V E S

• Describe the pathogenesis of acute and chronic cholecystitis

• Recognize the clinical presentation

• List different diagnostic investigations

• Recognize complications of acute and chronic cholecystitis

• Distinguish surgical and nonsurgical treatment options

• Define the time for cholecystectomy of acute cholecystitis

History

As long ago as 2000 BC, the anatomy of the gallbladder and

bile ducts was known, as is proven by clay models [1] The

first description of gallstones was in the 5th century by the

Greek physician Trallianus, who wrote of calculi within

the bile ducts The first known successful

cholecystolithoto-my was performed by Dr Joenisius in 1676, when he noted an

abdominal wall abscess that had ruptured, with the discharge

of pus and bile

The 19th century brought the development of anesthesia

and more detailed knowledge of biliary colic and

intermit-tent fever from obstructive biliary disease, Courvoisier’s law

(gallbladder dilatation when there is biliary obstruction

below the level of the cystic duct) The first cholecystectomy

was carried out by Langenbuch, a surgeon from Berlin, in

1882 [2] The surgical treatment of gallbladder disease

re-mained largely unchanged until the first laparoscopic

chole-cystectomy was performed by Muhe in 1985 Laparoscopic

surgery has added a new dimension to the treatment of

cho-lecystitis by providing a minimally invasive surgical option

with decreased patient discomfort and length of hospital

stay

Acute calculous cholecystitis

In developed countries, at least 10% of white adults have

gallstones, with women having twice the risk and age further

increasing the prevalence in both men and women [3] Most

patients are asymptomatic However, patients with

asymp-tomatic gallstones develop acute cholecystitis with an

inci-229

dence of 1 to 2% per year [4] Epidemiology of diseases of the gallbladder is described in detail in Chapter 3 and Chapter 12 further describes the pathogenesis of stone formation

Pathophysiology and histological features

In the majority of cases, acute cholecystitis originates from cystic duct obstruction, which in industrialized countries is predominantly caused by gallstones In developing coun-

tries, helminthic infection, such as Ascariasis, mainly

ac-counts for cystic duct obstruction Consecutive distention of the gallbladder induces the release of mediators, such as pros-taglandin E2and I2, which cause an infl ammatory response within the gallbladder [5] Infection of the accumulated bile

fl uid is secondary (Fig 13.1)

Positive bile cultures are found in 40 to 60% of patients and include common enteric organisms These are Gram-positive

and Gram-negative aerobes and anaerobes: Escherichia coli, Klebsiella, Streptococcus faecalis, Clostridium tetani, Proteus, En- terobacter, and anaerobic streptococci In a study undertaken

to define the bacteriology of gallstone disease, control jects without symptomatic gallstone disease had sterile bile cultures while 22% of patients with symptomatic gallstones and 46% of patients with acute cholecystitis had positive bile

sub-cultures The most common bacteria were E coli, Streptococcus

D, Klebsiella, and Enterobacter [6] With cystic duct

obstruc-tion as a precondiobstruc-tion for infl ammaobstruc-tion and infecobstruc-tion, the subsequent route of the pathogen into the gallbladder has not yet been clarified

Stone-induced damage to the mucosa and mucosal edema leads to lymphatic and venous obstruction, and possibly lo-calized areas of ischemia Bile salts become concentrated in

Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition

Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd

the gallbladder and cause further mucosal damage This

damage can further progress to abscess or perforation

Histological findings in the early phase show an acute

in-fl ammatory reaction characterized by edema, vascular

con-gestion, hemorrhage, neutrophilic infiltration, and mucosal

necrosis In a later phase, transmural infl ammation,

second-ary acute vasculitis, and mural necrosis follow [7]

Presentation

Acute cholecystitis is more common in the middle aged and

the elderly It occurs at a ratio of 1 : 3.5 in patients under the

age of 40 compared to those over 40 [8] Of all affected

pa-tients, 60 to 80% have had previous biliary tract symptoms,

while the remaining patients present with acute cholecystitis

as the first indication of biliary tract disease

The clinical presentation of acute cholecystitis consists

of the triad: (1) constant right upper abdominal pain, (2)

elevated infl ammatory parameters such as leukocytosis

and elevated C-reactive protein, and (3) tenderness on

palpation in the right upper abdominal quadrant (Murphy’s

sign)

Nausea and vomiting are often described in acute

chole-cystitis However, there is no supportive data for these signs,

and the results of recent studies are inconsistent In 1996, a

retrospective study of patients with acute, nongangrenous

cholecystitis found fever in only 29% and leukocytosis

(greater than 11,000 µL) in 68% of the patients, with 28% of

the patients lacking either sign [9] Electrolyte abnormalities

depend on the degree of sepsis and/or dehydration

Associated complications of common bile duct

obstruc-tion (choledocholithiasis) or gallstone-induced pancreatitis

will lead to elevation of cholestasis parameters and liver

enzymes (bilirubine, alkaline phosphatase, and

trans-aminases) or pancreatic enzymes (amylase and lipase),

respectively

Intraoperatively, the surgeon identifies acute cholecystitis through signs of acute infl ammation, such as omental adhe-sions to the gallbladder wall, edema, fragility, pericholecystic fluid, and gangrene The gallbladder wall is usually thickened

by edema, vascular congestion and hemorrhage, or it may pear necrotic The serosa is dull and may be covered with patches of fibrinopurulent exudates A gallstone is frequently found obstructing the outflow pathway

ap-Acute cholecystitis should be clinically differentiated from biliary colic by the presence of constant pain instead of col-icky pain and the presence of Murphy’s sign Bacterial infec-tion in the gallbladder may lead to septicemia, which is associated with increased morbidity and mortality Patients with severe acute cholecystitis may have mild jaundice (serum concentrations of bilirubin <60 mmol/L) caused by infl ammation and edema around the biliary tract and direct pressure on the common bile duct from the distended gall-bladder [10] This special constellation has to be distin-guished from Mirizzi’s syndrome (Chapter 14)

Complications

Predictive parameters specific to the course of acute cystitis have been described by Schafer et al [11] Patients with a severe infl ammation are signifi cantly older (>70 years), predominantly male, with a prolonged duration

chole-of symptoms (>3.5 days), as well as increased C-reactive protein levels (>150 mg/L) and white blood cell counts (>14,000/µL)

Gangrenous cholecystitis occurs in up to 30% of patients admitted with acute cholecystitis The gangrene occurs most commonly at the gallbladder fundus, because of the limited vascular supply in this area If the infl ammation inside the gallbladder persists, it may cause perforation of the gallblad-der wall This usually occurs in patients with delayed admis-sion to hospital or who do not respond to medical therapy After the gallbladder has perforated, patients usually experi-ence temporary relief of symptoms, as gallbladder distention decreases, but peritonitis develops soon after Free perfora-tion presents with generalized biliary peritonitis and is asso-ciated with a considerable mortality Perforation with the formation of localized pericholecystic abscesses is more com-mon, because the adherent viscera adjacent to the perfora-tion tend to localize spillage of the contents of the gallbladder

A mass in the right upper abdominal quadrant may be ble under these circumstances

palpa-A perforation of a gallstone into another part of the intestinal tract may cause a cholecystoenteric fistula The most common locations of these fistulas are the duodenum and the hepatic flexure of the colon Air in the biliary tree (pneumobilia) can be seen on abdominal radiographs Pass-ing of a gallstone from the biliary tract to the intestinal tract through a fistula may cause gallstone ileus, with a mortality

Chapter 13: Acute and chronic cholecystitis 231

Imaging

Ultrasound

Ultrasound is the imaging modality of choice for acute

chole-cystitis as it is cost effective, widely available, and offers a

high diagnostic accuracy It can reveal gallstones, gallbladder

wall thickening (more than 4 mm), pericholecystic fl uid,

biliary ductal dilatation, and a sonographic Murphy’s sign

(maximal pain with probe pressure directly over the

gall-bladder) The most sensitive ultrasonographic finding, with a

positive predictive value of 92%, is the presence of

cholecys-tolithiasis with a gallstone impacted in the gallbladder neck

in combination with a sonographic Murphy’s sign [12]

Gall-stones are visualized in ultrasound as echogenic foci with a

hypoechoic shadow (Fig 13.2)

Computed tomography(CT)

If the cause of the abdominal symptoms is not clear or if

ultra-sound is not conclusive, a CT may be performed The

detec-tion abilities of CT for gallstones is limited to 75% Bennett et

al have defined gallstones, thickened gallbladder wall,

peri-cholecystic fl uid, and subserosal edema as major criteria and

gallbladder distention and sludge as minor diagnostic criteria

(Fig 13.3) With the presence of one major and two minor

criteria, the authors reported a sensitivity, specificity, and

ac-curacy of CT for the diagnosis of acute cholecystitis to be 91.7,

99.1, and 94.3%, respectively [13]

Magnetic resonance imaging(MRI)/ magnetic

resonance cholangiopancreatography (MRCP)

MRI is not recommended as an investigation for acute

chole-cystitis although it can be indicated in patients with a

suspi-cion of common bile duct stones or an unclear clinical

presentation The sole presence of pericholecystic fl uid on

T2-weighted images without contrast agent has a sensitivity

of 91%, a specificity of 79%, a positive predictive value of 87%, and a negative predictive value of 85% for acute chole-cystitis compared with the diagnosis made from clinical, so-nographic, and surgical findings [14] The ability to diagnose gallbladder stones is similar to that of ultrasound because of the potential to visualize fl uid in the biliary tree

Common bile duct stones are detected with a sensitivity of 93% by MRI and the level of biliary obstruction can be deter-mined in up to 97% of the patients [15] (Fig 13.4) More de-tailed information about imaging of the biliary system is given in Chapter 4

Radioisotope cholescintigraphy

Radioisotope cholescintigraphy, often called a HIDA scan (hepatobiliary iminodiacetic acid), is a nuclear imaging study used to diagnose cystic duct obstruction A radioactive technetium-labeled iminodiacetic acid derivative (99 m tech-netium iminodiacetic analogue) is injected intravenously and will normally be taken up by the liver and then the gall-bladder Uptake by the liver and excretion into the duode-num without filling of the gallbladder is indicative for occlusion of the cystic duct This test has a sensitivity of up

to 86% in the correct clinical setting [16] Although a normal HIDA scan can exclude acute cholecystitis, it provides

no information about other abdominal structures and may not reveal the cause of a patient’s abdominal pain The HIDA scan is advocated in the United States due to its high diagnos-tic accuracy On the other hand, this modality is not wide-spread in Europe where ultrasound is the preferred method of imaging

Figure 13.2 Ultrasound of acute calculous cholecystitis with thickened

gallbladder wall and gallstone.

Figure 13.3 Computed tomography of acute cholecystitis with

thickened gallbladder wall and impacted gallstone.

Nonsurgical treatment

Nonsurgical management of acute cholecystitis consists of

fasting, intravenous fl uids, analgesia, and antibiotics It is

postulated that under this treatment the gallstone disimpacts

and falls back into the gallbladder, which allows emptying of

the gallbladder, resulting in reduction of the infl ammation

The theoretical aim of fasting is to rest the gallbladder, to

re-duce bile secretion, and therefore to decrease gallbladder

dis-tention and infl ammatory response However, there are no

randomized, prospective studies which prove the effi cacy of

fasting Indometacin in a dosage of 75 mg suppositories once

per day over 3 days has been reported to signifi cantly reduce

temperature, pain, white blood cell count, bilirubine, and

hospitalization time (5.4 versus 8.5 days) compared to a

pla-cebo group [17] The use of meperidine instead of morphine

for pain control in acute cholecystitis has often been

recom-mended as it is assumed that morphine increases the

sphinc-ter of Oddi pressure to a greasphinc-ter extent than meperidine It

has been shown that both opiates do increase the sphincter

of Oddi pressure [18], similar clinical results have been

re-ported for meperidine and morphine [19]

As 40 to 60% of patients with acute calculous cholecystitis

have positive bile cultures with common enteric organisms,

the administration of antibiotics is an essential element of

medical therapy Most common bacteria isolated from bile

fl uid are E coli, Enterococci, Klebisiella (30 to 80%) or

anaer-obes such as Bacteroides and Clostridium (15 to 30%) [6,20]

Requirements for antibiotics suitable for the treatment of acute cholecystitis are biliary excretion, no inactivation by bile fl uid, and efficiency against Gram-positive and Gram-negative bacteria Options are amoxicilline with clavolanic acid, second generation cephalosporine with metronidazole, piperacillin with tazobactam, or ciprofloxacin Antibiotic therapy should be continued over a period of 7 to 10 days, de-pendent on the clinical findings [6] In 15 to 35% of cases, the conservative management fails resulting in the need for emergency surgery Surgery is indicated in the presence of peritonitis or deterioration of the clinical condition of the patient

Surgical treatment

Cholecystectomy is the definitive treatment for patients with acute cholecystitis In the 1970s, it was common practice to admit patients to hospital initially for medical management with the intention of “cooling down” the infl ammation and

to perform elective open cholecystectomy several weeks later At the end of the 1970s, the concept changed to “early” open cholecystectomy, meaning within the first 36 to 72 hours from the onset of symptoms

With the introduction of laparoscopic cholecystectomy at the beginning of the 1990s the question of timing arose again

At the beginning of the decade, acute cholecystitis was garded as a contraindication for laparoscopic cholecystecto-

re-my, as there was a conversion rate of up to 75%, no shorter length of hospital stay, and a signifi cantly longer operation time, especially in severe acute cholecystitis compared to the open approach [21]

With increasing experience of laparascopic tomy, these problems were surmounted A randomized trial published by Kiviluoto et al in 1998 showed laparoscopic cholecystectomy within 4 days after the onset of symptoms

cholecystec-to be at least as safe and effective as the open procedure [22]

A prospective, randomized trial by Johansson et al revealed

a signifi cantly shorter postoperative stay for the laparoscopic group and a similar complication rate and similar cost com-pared to the open group [23] Today, the laparoscopic ap-proach is widely accepted as the first choice for most cases ofacute calculous cholecystitis Currently, there is no consen-sus for the optimal time-point of cholecystectomy for acute cholecystitis “Early” versus “delayed” operations are distin-guished in the literature without standardization of these time-points [24]

For open cholecystectomy, nine prospective, randomized trials comparing early and delayed operation have been ana-lyzed “Early” operation ranged from 1 to 7 days after the beginning of symptoms, while “delayed” operation ranged from 6 to 12 weeks after the onset of symptoms The pooled rate of overall mortality was 0.2% in the early and 1.6% in the delayed group At least one perioperative complication was observed in 17.7% of patients in the early group and in

Figure 13.4 Magnetic resonance cholangiopancreatography (MRCP)

of a Mirizzi’s syndrome — compression of the common bile duct by

gallstone impacted in the cystic duct.

Chapter 13: Acute and chronic cholecystitis 233

17.9% of patients in the delayed group Hospitalization time

was shorter in patients with the “early” operation

Three prospective, randomized trials have evaluated early

versus delayed laparoscopic cholecystectomy “Early”

opera-tion ranged from 1 to 3 days after the beginning of symptoms

“Delayed” operations were carried out 5 days after admission

in one study and 6 to 8 weeks and 8 to 12 weeks in the other

two trials Conversion rates were similar for early and

de-layed laparoscopic cholecystectomy, with a shorter

hospital-ization time for early laparoscopic surgery in all three studies;

10.9% of the patients suffered from at least one perioperative

complication in the “early” group and 15.6% in the “delayed”

group

Some prospective studies showed an increasing

conver-sion rate if laparoscopic cholecystectomy was performed later

than 48 to 72 hours after the beginning of symptoms [11,25],

but there are still no recommendations beyond this early

pe-riod of approximately 5 days It is unclear whether an

“inter-mediate” operation (between the early and the delayed time

point), has any advantage compared to late operation

Cam-eron et al [26] recommend elective cholecystectomy after an

episode of acute cholecystitis not later than 2 months after

the onset of symptoms

Although in clinical practice, many surgeons still prefer

initial conservative management routinely for patients with

acute cholecystitis, the conclusion to be drawn from the data

at present is that early cholecystectomy with a laparoscopic

approach is the treatment of choice for acute calculous

cholecystitis

Tube cholecystostomy

With the implementation of the laparoscopic

cholecystec-tomy, the indication for a tube cholecystostomy dropped

rapidly Tube cholecystostomy is only taken into

consider-ation today in critically ill patients with acute calculous or

acalculous cholecystitis unable to tolerate general

anesthe-sia The documented average mortality is less than 0.8% in

the average population, versus 14 to 30% in severely ill

pa-tients [27] Percutaneous cholecystostomy involves the

placement of a small drainage catheter directly into the

gall-bladder, commonly with ultrasound guidance and under

local anesthesia This can provide an easy, minimally

inva-sive approach for the interim management of acute

cholecys-titis in patients that do not tolerate surgery [28]

Cholecystitis in pregnancy

Cholecystitis during pregnancy presents special challenges

Fortunately, ultrasound can be safely performed for

diagno-sis during pregnancy In addition, a recent study reviewing

open and laparoscopic cholecystectomies performed during

pregnancy revealed that laparoscopic surgery is safer than

the open approach, with lower occurrence of premature

labor and equally low fetal mortality [29] The second

tri-mester has been considered the best time to perform

opera-tive procedures during pregnancy because organogenesis is complete and spontaneous abortions are less frequent than

in the first trimester Procedures performed in the third mester have been associated with more occurrences of pre-mature labor Nevertheless, several studies demonstrated that both open and laparoscopic surgery can be performed safely in all trimesters [30]

tri-Conservative medical management of symptomatic lithiasis in pregnant women often leads to suboptimal clini-cal outcomes and maternal illness may pose a greater threat

chole-to the fetus than surgery Three studies have shown the mission rate for pregnant patients with biliary tract disease to

read-be greater than 50% in patients with conservative ment, and 16% of the patients had either spontaneous abortions or preterm births [31] An aggressive surgical man-agement of biliary tract diseases in pregnancy should there-fore be favored

manage-Common bile duct stones

The presence of common bile duct stones is presumable

in cases of elevation in liver enzymes (particularly glutamyltransferase and bilirubine) and dilation of the ex-trahepatic and intrahepatic bile ducts in ultrasound Patients with high suspicion of common bile duct obstruction are candidates for a preoperative endoscopic retrograde cholan-giopancreatography (ERCP) with papillotomy (refer to Chapter 5) If the preoperative situation is not conclusive, in-traoperative cholangiography should be performed

γ-In the case of intraoperatively detected stones, in general, laparoscopic or open common bile duct exploration are op-tions However, the presence of cholecystitis leads to higher fragility of the cystic duct, increased tendency of bleeding, and distorted anatomy Therefore, postoperative ERCP is preferable due to its success rate, which surpasses 90%

Acute acalculous cholecystitis

Approximately 5 to 10% of cases of acute cholecystitis are not associated with gallstones This process is therefore termed acalculous cholecystitis

Pathogenesis and histological features

The pathophysiology of acalculous cholecystitis is torial Risk factors include severe trauma or burns, major sur-gery (such as cardiopulmonary bypass), long-term fasting, total parenteral nutrition, sepsis, diabetes mellitus, athero-sclerotic disease, systemic vasculitis, and acute renal failure [32] According to current knowledge, disruption of micro-circulation and gallbladder mucosal ischemia are assumed

multifac-to play a central role [33] Increased bile viscosity from stasis with subsequent obstruction of the cystic duct has been suggested as another contributing factor Gangrene and necrosis of the gallbladder are observed in 45 to 60% of cases [34], but in general no specific histologic differences

have been noted between acute calculous and acalculous

cholecystitis [7]

Presentation

Acalculous cholecystitis is a life-threatening condition and

tends to occur in intensive care patients with multiple

trauma or acute nonbiliary illness Scientific criteria for the

diagnosis of acute acalculous cholecystitis is lacking It is

a part of multiple organ failure and associated with a

con-siderable mortality rate of up to 50% This is signifi cantly

higher than the overall mortality of all intensive care

pa-tients Over 70% of patients have atherosclerotic disease,

which might be associated with the high prevalence of the

condition in elderly men [35] Immunocompromized

pa-tients more often develop primary infections caused by

opportunistic organisms that result in primary infective

cholecystitis [36]

The diagnosis of acute acalculous cholecystitis is a

challenge and mostly based on a combination of clinical,

laboratory, and radiological criteria Clinical findings are

not very specific and might be difficult to identify because

of patient sedation and analgesia Only half of the patients

present with pain and tenderness in the right upper quadrant

[37]

Imaging

Radiologic imaging techniques are unreliable in cases of

crit-ically ill patients [38,39] It has been demonstrated that a

great proportion of intensive care patients present with

ultra-sonographic abnormalities resembling cholecystitis without

having acute acalculous cholecystitis [40] Furthermore, CT

is often not conclusive for the diagnosis of acute cholecystitis

[41]

Therapy

Conservative management for acalculous cholecystitis

includes pain control and broad-spectrum antibiotics

While positive bile cultures with enteric organisms have

been found in acute calculous cholecystitis, they have been

reported less frequently in acute acalculous cholecystitis (6

to 28%) [37]

There are currently no controlled studies available

com-paring percutaneous cholecystostomy with cholecystectomy

in a patient population with acute acalculous cholecystitis

Since conservative treatment of severe acute acalculous

cho-lecystitis involves a high risk of gangrene and perforation,

and modern anesthetic techniques allow safe operations for

even severely ill patients, cholecystectomy is the best

man-agement of these patients [42] In patients unable to tolerate

general anesthesia, percutaneous cholecystostomy can

alle-viate the symptoms at a lower risk Interval cholecystectomy

is usually not indicated if the patient survives the acute

acal-culous cholecystitis

Chronic calculous cholecystitis

Chronic cholecystitis is almost always associated with stones Chronic calculous cholecystitis has also been used as

gall-a synonym of symptomgall-atic cholecystolithigall-asis The correlgall-a-tion between clinical history, the histological severity of chronic cholecystitis, and the intraoperative technical diffi -culties caused by infl ammation is poor Cholecystolithiasis is

correla-a well-estcorrela-ablished risk fcorrela-actor for gcorrela-allblcorrela-adder ccorrela-ancer correla-and the risk seems to correlate with stone size [43]

Pathogenesis and pathological features

The pathogenesis of this common disorder is not fully stood It has been suggested that recurrent attacks of mild acute cholecystitis, caused by transient obstruction of the cystic duct by stones, lead to the development of a chronic in-flammation of the wall of the gallbladder Besides the repara-tive infl ammatory changes, the repetitive mucosal trauma produced by the gallstones could play a pathogenetic role as well Because of the poor correlation between the severity of the infl ammation and the number and volume of stones, it has been postulated that the intensity of infl ammatory re-sponse of the mucosa caused by gallstones is genetically de-termined, which has been demonstrated in other digestive organs [44]

under-Mucosal erosions or ulcers are frequently found with pacted stones The histologic diagnosis of chronic cholecysti-tis is based on the following three characteristics: (1) a predominantly mononuclear infl ammatory infiltrate in the lamina propria with or without extension to the muscularis and pericholecystic tissues, (2) fibrosis, and (3) metaplastic changes [7] Dystrophic calcifi cations are often associated with fibrous tissue, which can progress to porcelain gallblad-der For unknown reasons, carcinoma of the gallbladder is more frequently associated with this condition (Chapter 15)

im-A rare entity of chronic cholecystitis is the matous cholecystitis, which occurs in 1 to 2 % of the chole-cystectomies [45] Histologically, it is usually associated with plasma cells and occasionally with giant cells or ceroid-containing histiocytes These cells may form tumor-like ag-gregates that are sometimes confused with neoplasms [7] The principal intraoperative characteristic is the thickening

xanthogranulo-of the gallbladder wall with a tendency to adhere to other organs The findings on the imaging studies may be mis-taken for cancer The important consequence is that chole-cystitis is often associated with a technically demanding cholecystectomy

Presentation

The typical symptom of chronic calculous cholcystitis or symptomatic cholecystolithiasis is intermittent, subacute right upper quadrant pain which may radiate to the

Chapter 13: Acute and chronic cholecystitis 235

back These typical biliary colics result from transient

obstruction of the cystic duct by stones The pain lasts

from minutes to hours and is often preceded by a fatty

meal, which precipitates gallbladder contraction against the

stones No fever or other signs of infl ammation are present,

although nausea and vomiting are common Between the

attacks, the patients are asymptomatic Only few patients

present with a clinical history of recurrent attacks of acute

cholecystitis

Intraoperatively, the gallbladder can be distended or

shrunken The degree of infl ammatory reaction is variable

and the wall of the gallbladder can be thickened or thin

Imaging and therapy

If the symptoms are classic, patients with chronic calculous

cholecystitis only require ultrasound for diagnosis Since its

introduction in 1985, laparoscopic cholecystectomy has

rapidly replaced open cholecystectomy for the treatment of

symptomatic gallstones [46] This surgical revolution was

initiated by the benefits of the minimally invasive approach,

patients’ demand for this new technology, and a strong

economic interest of the involved industry Today, elective

laparoscopic cholecystectomy is the treatment of choice for

chronic symptomatic cholecystolithiasis

Laparoscopic and open cholecystectomies have similar

morbidity and mortality rates However, the rate of bile duct

injuries and leaks is higher in laparoscopic (0.3 to 0.5%) [47]

than in open procedures (0 to 0.2%) Infl ammation of the

gallbladder and the surgeon’s experience are risk factors for

bile duct injury [48]

Chronic acalculous cholecystitis

Pathogenesis

Chronic acalculous cholecystitis remains a controversial

en-tity that accounts for 5 to 20% of cholecystectomies [49] The

clinical entity of chronic acalculous cholecystitis represents a

number of pathophysiological processes of the gallbladder,

including infl ammation, dyskinesia, outflow obstruction,

and impaired intrinsic gallbladder motility There is still a

controversy regarding the diagnosis and treatment of this

disease

Histologically, an infl ammation in chronic acalculous

cholecystitis can be verified in 80 to 100% of the cases

[50] The correlation between severity of infl ammatory

changes and clinical findings is unknown However, autopsy

series and histologic studies of gallbladders removed

inciden-tally during surgery show comparable pathologic changes

[51]

Presentation

Biliary dyskinesia is a quite common term, used as a

syn-onym of chronic acalculous cholecystitis It describes a group

of complex, functional biliary conditions in patients with typical symptoms of biliary tract disease without distinct structural abnormalities and in absence of stones in the gallbladder Barnes [52] postulated that biliary dyskinesia emanates from either the gallbladder or the cystic duct or the sphincter of Oddi On clinical presentation, patients often show other nonspecific symptoms, including epiga-stric pain, nausea, vomiting, bloating, and altered bowel habits

Imaging and therapy

On ultrasound examination, in case of chronic acalculous cholecystitis the gallbladder is free of stones Cholecy-stokinin cholescintigraphy (CCK-HIDA scan) is common

in the United States This usually shows a decreased ejection fraction of isotopes and biliary colic pain is induced

by injection of cholecystokinin An ejection fraction of less than 35% is considered as indicative for gallbladder dysmotility

A number of studies, however, have shown that results of CCK-HIDA studies do not predict clinical outcome after cho-lecystectomy [53] As a consequence of this, many surgeons, mainly in Europe, indicate laparoscopic cholecystectomy for chronic acalculous cholecystitis on the basis of symptoms of biliary colic, careful medical history and physical examina-tion, regardless of additional tests

Outcome

The laparoscopic cholecystectomy, with less pain and a

short-er length of hospital stay, has resulted in an increased use of cholecystectomy for the treatment of chronic acalculous cho-lecystitis A number of retrospective studies have determined the effi cacy of laparoscopic cholecystectomy in acalculous gallbladder disease Resolution of symptoms after cholecys-tectomy following chronic acalculous cholecystitis was re-ported in 78 to 96% of patients [49]

Questions

1 Which is not a clinical feature of acute cholecystitis?

a right upper quadrant colic (<6 hours)

b fever

c tenderness in the right upper quadrant

d elevated leukocyte count

e nausea and vomiting

2 Which of the following statements is not true? Acute acalculous

cholecystitis

a is diagnosed by specific ultrasonic findings

b is a condition with considerable mortality

c is appropriately treated by emergency cholecystectomy

d is found in critically-ill patients

e has a high risk of gangrene and perforation