Review Article

Gallstones in Chronic Liver Disease

1\IlichaelAnthuny Silva, M.B.B.S., M.S., FR.CS.Ed, Terence Wong, M.B.B..','., Ph.D., 1H.R.C.P.

Gallstones oeeur more eommonly in patients with eirrhosis. The ineidenee inereases with severity ofliver discase, and the majority remain a~ymptomatie. \Vhen symptoms do oeeur, morbidity and mortalityare mueh higher than in noneirrhotie patients. A~)'mptomatie gallstones in eirrhotie patients are bestmanaged eonservatively with dose follow-up and surgery if ~ymptoms oeeur. The management ofasymptomatie gallstones found ineidentally at abdominal surgery for another indieation is controversial.Laparoseopie eholeeysteetomy is the treatment of ehoiee for symptomatie eholelithiasis in patients withwell-eompensated liver disease, whereas patients with eholedoeholithiasis are best managed endo-seopieally. Symptomatie eholclithiasis in the deeompensated patient remains a ehallenge, and thesepatients are best managed in speeialized hepatobiliary ecnters. This review examines the evidenee eurrentlyavailable on gallstones in ehronie liver disease and the factors that influence its management.(J G\STROI"'.I'FSTSURG2005;9:739-746) @ 2005 The Society for Surgery of the Alimentary Tract

KEy \VORDS:Cholelithiasis, eholcdoeholithiasis, cirrhosis, ehoic<.ystectomy, cholecystostomy

Gallstones (GS) are common in the general popu-lation, and it is estimated that about 10-20% of theadult population in developed countries have GS.I-3The prevalence is higher in women, the obese, andolder patients.I-3 The reported frequencies of GS inchronic liver disease (CLD), in comparison, tends tobe higher.l-6 In autopsy studies, the frequency of GSin patients with CLD ranges from 3.6% to 46%, witha 1.2- to 3-fold increasc comparcd with the generalpopulation.I-3,7 Studies using ultrasonography report

urevalence GS ranging between 22% and 54%.1.2,. ,8-11Oespite this high prevalence, the managementof GS in patients with CLD remains controversial, 1-4and the aim of this review was to examine the evidence

for current treatment strategies.

THE EPIDEMIOLOGY OF GALLSTONESIN PATIENTS WITH CHRONICLIVER DISEASE

GS are found in 10-20% of the general adult popu-lation.I-3,12 In comparison, autopsy studies haveshown up to a threefold increase in GS among cir-

rhotic ~atients compared with noncirrhotic con-trolS.7,1 ,13,14Similarly, ultrasonographic studies have

a.lso co~firmed t~e hig~er prevalence of GS in pa-nents Wlth CLD,,6,8-IO:L.16(fable 1).

These studies report the prevalence of asymptom-atic GS. The prevalence of c\inically manifest GS inpatients with CLO is largely unknown.17 A reeemretrospective review of medical records of 38,459 in-patients with various forms of liver disease foundthe prevalence of symptomatic GS to be 7.5%,18although the possibility of occasional detection biascannot be exc\uded. In a longitudinal cohort studyof a group of 34 patients with asymptomatic GS andCLO, 18% developed symptoms over 6 years.191\1-though the number of patients in the study wassmall and the duration of follow-up was short, thisfigure is comparable to that of asymptomatic GS innoncirrhotic patients.1 In noncirrhotic patient~,thereis a mean delay of about 8 years between stone forma-tion and the onset of symptoms.20 Ir is not clc.irwhether this holds true for GS in CLO.

There exists a 3:I female predominanec for theincidence of GS in the population without CLD.!.!,12This pattem is similar in patients with CLD,II,!I!'although some early reports indica.ted that the inei-dence of GS was higher in males.) GS oceur morefrequently in patients with cirrhosis than in paticllts

From The Livcr Unit, QlIccn Elizabcth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham, Unitcd kingdom.Reprim reqllests: Michael A. Silva, M.S., F.R.C.S.Ed.. c/o Liver SlIrgical Secretaries, 3rd Floor, Nuftield House, Queen Elizaberh !lospir.]I,

Univcrsity Hospital Birmingham NIIS Trust, Edgbaston. Birmingham BIS 2TII, United Kingdom. e-mail: MASilva@bham.ac.uk

@ 2005 The Society tor Surgcry of the Alimemary TractPublished by Elsevier lnc.

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doi: 10.10 16/j.gassur.2004.09.041

740 Silvaand Wong

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Gastrointestinal Surgery

Table 1. Prevalence of gallstones in chronic liver disease (CLO)

with chronic hepatitis,9 and pigment stones occurmore frequently in GS of patients with CLD, whileits incidence also increases with age.8,15.24,25

GALLSTONES IN RELATION TOETIOLOGY AND SEVERITY OF LIVERDISEASE

The risk of GS appears to be indep.endent of theunderlying etiology of liver disease.4. 5,26ln a studylooking at the etiology of CLD, in 313 cirrhotic pa-tiems, its cause did not seem to be importam as a riskfactor for GS formation.26 In another study of theprevalence of GS in CLO in relation to the etiologyof disease, 356 cirrhotic patients were compared with247 cases of chronic hepatitis B and C without cirrho-sisj a multivariate analysis showed that the durationand severity of cirrhosis were the only factors inde-pendently related to the development of GS in CLD,

whereas hepatitis B surface anti~en (HBsAg) positi-vity behaved as a negative factor. Several other stud-ies have confirmed that the risk of developing GS iscorrelated with severity of CLD as graded by theChilds-Pugh classification, rather than the etiologyof the disease.5.6.8.9.18.21

The etioloR of symptoms in patients with GSis unknown.2 It may be partly due to chance, de-pending on the movement of stones and their im-paction in Hartmann's pouch 01' in the cystic duct.1It follows that the relative size of the calculi and

the caliber of various parts of the biliary tree may beimportam. 1 It is, however, cIear that other factorsplay a role. Stasis may precipitate symptoms andis considered particularly relevam in tlle etiology ofpostoperative cholecystitis.28-30 Stasis to bile flow isincreased in CLD and may be a cause for the in-creased incidence of GS in these patients.31-35 Ad-vanced age, female gender, vira I etiology of cirrhosis,family history of GS, and duration of GS disease are,however, factors that are associated witll symptomatic

gallbladder disease. 17Male gender and alcoholic cir-rhosis have interestingly been found to have an in-verse relationship to the presence of symptoms.17

MECHANISMS OF GALLSTONEFORMATION IN CHRONIC LIVERDISEASE

The mechanisms leading to the increased inci-dence ofGS in CLD are notwell understood.18 About

80% of GS in patients with CLD are pigmemstones compared with 20% in noncirrhotic pa-tients.17,18.21;25.36Patiems with liver cirrhosis may alsohave increased hemolysis secondary to hypersplen-ism, resulting in a higher incidence of pigmemstones.4.10 Studies have shown that however effi-

ciem, the liver does not convert ali the unconjugatedbilirubin into bilirubin monoglucuronides and diglu-curonides: a small fraction of the unconjugatedmoiety escapes conjugation and 'spills' imobile.37 InCLO, the fraction of bilirubin escaping conjuga-tion increases. The resultam excess unconjugated bi-lirubin in bile is vulnerable to polymerization and/01' to co-precipitation with free ionized calcium.37.38Deconjugation may also be catalyzed by glucuroni-dases of bacterial 01'mucosal origin,39 and bilirubinmonoglucuronide may also undergo nonenzymatichydrolysis to form unconjugated bilirubin. Even innormal bile, therefore, tlle low concentration ofunconjugated bilirubin still exceeds its aqueous 5011.1-bility by 100- to 1000-fold.39.4oThis unconjugatedbilirubin has been identified as a component ofbiliarysludge, which is believed to precede GS, especiallypigmem stones.39 Additionally, decreased apolipo-protein A-I and A-II levels in advanced CLO havealso been implicated as cause for a higher incidence ofGS in these patients.zz

Pigment GS could be either black 01'brown. Blackpigment stones, which commonly occur in the gall-bladder only, are small (approximately 3 mm) andoccur witll increased frequency in patiems with CLD

107

Author (first) Year Type of study No. of subjects Prevalence of gallstones (%)

Bouchier IAD7 1969 Autopsy Patients with CLD (n = 235) 29.4Contrais (n = 4460) 12.8

Iber FLIO 1977 Autopsy Paticnts with CLD (n = 460) 33Contrais (n = 316) 13

Iber FUo 1990 Autopsy Patients with CLD (n = 299) 46Contrais (n = 178) 21

Fornari F5 1990 Ultrasound Patients with CLD (n = 410) 31.9ContraIs (n = 414) 20

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and in those with hemolytic disease.9,11,ISBrown pig-ment stones are found more often in the biliary treethan in the gallbladder. Brown stones are convention-ally associated with bacterial infection and parasiticinfestations like fascioliasis (caused by the liver fluke).Recent studies have, however, shown that neitherthe color nor the chemical composition accuratelypredicts the presence or absence of gallbladder bacte-ria and diseases that cause brown pigment stones,like fascioliasis, which may result in CLD, in turnpossibly resulting in the formation of black pig-ment stones.-H,42

Studies have shown that moderate intake of alcohol

actually decreases the risk of GS formation.22,2S,43,44Alcohollowers bile cholesterol saturation with a re-

sultant reduction of cholesterol stonesl8 and maycause an increase in conversion of cholesterol to bile

acids.4S-47An increased high-density lipoprotein cho-lesterol serum concentration is associated with mod-

erate alcohol consumption, and this could result in theImver incidence in cholesterol stone formation.48-;O

1n contrast to this protective role alcohol may haveon GS fonnation, heavy ethanol intake is a majorrisk factor for the development of liver disease bypromoting fibrosis and cirrhosis, both of which arerisk factors for developing GS, especially of the pig-mented type.18,22

It has been suggested that high levels of estro-gens and progesterone in CLD could play a role inthe higher incidence of GS in these patients, by theimpairment of gallbladder emptying similar to thatobserved in pregnancy. SA study evaluating the fastingvolume and meal-stimulated emptying of the gall-bladder, plasma levels of estradiol, progesterone, andbasal and postprandial secretion of cholecystokininin Child-Pugh class A cirrhotic patients comparedthem with results for normal subjects.H Normal ki-netics of postprandial emptying was demonstratedin both groups, although cirrhotic patients showedan increased fasting gallbladder volume and higherlevels of basal and postprandial cholecystokinin.34The circulating estradiol and progesterone levelswere not significantly elevated to be implicated ascausa tive of GS in CLD.34

The study of gallbladder kinetics in the presenceof CLO and cirrhosis has shown on ultrasonographyand radionuclide cholescintigraphy that its emptyingis sluggish.S1-S3 On ultrasonography, the unstimu-lated gallbladder in patients with CLD and cirrhosishas also been found to have sign~fi~antly increasedvolumes with signs of a hypotonia.)2,)4 There is someevidence to suggest that gallbladder contraction isalso under neural control. 32It has also been demon-

strated that patients with moderate to severe liver

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Gallstones in Chronic Liver Disease 741

dysfunction have impaired autonomic function.31 Au-tonomic neuropathy may therefore contribute to theformation of GS in patients with advanced cirrhosis,

perhaps by imBairing gallbladder and sphincter ofOddi motility. 2 Gallbladder disease has also beenfound to be increased in patients with CLO and coex-istent autonomic neuropathy.32

CLINICAL DIAGNOSIS OF GALLSTONESIN PATIENTS WITH CHRONICLIVER DISEASE

A recent study has described upper abdominal painthat is especially postprandial as more commonin those with CLO than in normal controls.s; Earlysymptoms due to GS disease need to be differentiatedfrom those of dyspepsia, peptic ulcer disease, or irrita-ble bowel ~yndrome.;6 1n CLD patients, upper ab-dominal pain in the absence of the abo,=~causes mayresult from gastric motility dysfunction.)) An alterna-tive explanation for these postprandial symptoms in-clude increased portal blood flow and volume changes.Duplex ultrasound and magnetic resonance imaginghave shown that patients with chronic hepatitis Chavea greater volume change to the left lobe of the livercompared with normal controls. This in tlleory mayresult in more congestion and stretch of the Glission'scapsule, resulting in the symptoms of pain.;7 \Viththese in mind, the clinical presentation, liver functiontests, and imaging techniques are usually sufficientto diagnose symptomatic GS disease in patientswith CLD.

THE NATURAL HISTORY OFGALLSTONES IN CIRRHOTIC PATIENTS

The management of GS in patients with CLD isa frequent dilemma. The risks of an operationneed tobe weighed against the likelihood of GS progressingto acute cholecystitis or bile duct obstruction. Thereis, however, a paucity of data on the natural historyof GS in this cohort of patients. Jaundice in thissubpopulation of patients is more commonly due tohepatocellular dysfunction than to bile duct obstruc-tion.H,;8 Ultrasonography and magnetic resonancecholangiopancreatography are the preferred methodsfor the diagnosis of choledocholithiasis in patientswith CLD rather than endoscopic retrograde cholan-giopancreatography.21 Although the risks of the de-velopment of symptoms and complications are low,the mortality associated with acute complications isin comparison higher with symptomatic GS than in

742 Silva and Wong

the general population. 17,59These patients are there-fore best managed in units equipped with suitablediagnostic and therapeutic facilities sueh as that avail-able in specialized hepatobiliary centers.

TREATMENT OF GALLSTONESIN CHRONIC LIVER DISEASE

An overall mortality rate for patients with CLDundergoing anesthesia and operation has beenreported to be as high as 11.6%.60 In a recent meta-analysis of patients with CLD undergoing laparos-copie cholecystectomy, an overall morbidity rate of21 % is described in cirrhotic patients compared withan 8% morbidity in noncirrhotic patients.61 'fhesemorbidities included liver bleeding, bile leaks, wound

infection, new onset of ascites, peritonitis, pulmona~embolism, and cardiopulmonary complications. 1Conversion rates from the laparoscopic procedureto open cholecystectomy was 7% versus 3.6%61,62(P = 0.(23). Mortality rates between the twogroups, however, were not different statistically.61The patients with CLD compared in this study wereprincipa11yofChild-Pugh class A and B. The laparos-copic procedure in patients with Child-Pugh class Cwas avoided, with the potential risks of morbidity andmortality in this group being unacceptable.62-64 Onlyone study included six patients of Child-Pugh classC, with one death (17%),61 but no conclusions canbe drawn regarding the outcome oflaparoscopic cho-lecystectomy in this subset of high-risk patients dueto the lack of data.

\Vhen compared with open cholecystectomy inpatients with CLD, the laparoscopic procedure isassociated with less operative blood loss, a shorteroper?tive time, and a decreased length of hospitalstay.)9,61There ,,,as no statistica11y significant differ-ence in morbidity 01'wound infection rates betweenthe two groups.61 There have, however, been no pro-spective studies comparing laparoscopic and opencholecystectomy in patients with CLD. The dataavailable at present are inadequate for definite conclu-sions to be made on outcomes comparing these twomethods of treatment.

The purpose of cholecystectomy for symptomaticGS is twofold: namely, the relief of symptoms andthe prevention of potentially life-threatening compli-cations.1 Cholecystectomy for asymptomatic GS,however, must be weighed against the hazards oftreatment. In noncirrhotic patients, elective cholecys-tectomy is not indicated because most remain asymp-tomatic and because mortality rates are low afterprompt treatment of those who develop symptoms.1Similarly, there is no place for prophylactic chole-cystectomy for GS in CLD patients.1,19

Journal ofGastrointestinalSurgery

Many GS are discovered for the first time at lapa-rotomy for an unrelated condition.I,19 There havebeen report<; describing the subsequent incidence ofbiliary sY!Tlptoms in these patients, if left un-treated.I,6) In patient<; without CLD, due to the re-ported incidence of biliary symptoms after operation(20-45 %), incidental chole(:ystectomy has been advo-cated. 1,65-69In a study involving 34 patients with CLDand GS, 82% remained asymptomatic over a periodof 6 years fo11owingan abdominal operation for portalhypertension.19 The role of incidental cholecystec-tomy in patients with CLD is unclear.19'rhe emphasistherefore, in patients with CLD, is for close follow-up with early interventional treatment for GS whensymptoms supervene.

The morbidity and mortality rates associated withlaparoscopic cholecystectomy in Child-Pugh class A

and B patients with sf!TIgtomatic GS have been shownto be acceptable.62,6.,Ia-:3The presence, however, ofa prolonged prothrombin time, thrombocytopenia,and portal hypertension in CLD patients is a riskfactor for increased bleeding in these patients. There-fore, appropriate preoperative preparations andmeticulous operative techniques are required toreduce blood loss during the procedure. Laparoscopiccholecystectomy is particularly useful in liver trans-plant candidates who develop significant biliary

symptoms because of its associated fewer J)ostopera-tive adhesions and rapid recuperation. 1,62 Somegroups have even described stenting of the cystic ductendoscopically using biliary stent<; from gallbladderto duodenum, in this group of patients awaitingliver transplantation, to relieve symptoms.74,75

There is an increased risk of morbidity and mor-tality with common bile duct exploration in pati-ents with C~D,76,77 with mortality rates as high as30_50%.21,7/-79As a result, endoscopic managementis preferred when a common bile duct stone is clini-ca11ysuspected in these patients.62,77,78Endoscopicbiliary sphincterotomy is the method of choice for thetreatment of choledocholithiasis in patients withoutCLD, although it is associated with an overall compli-cation rate of about 10% and a mortality rate of0.5%.80,8]'rhe reports on endoscopic sphincterotomyin cirrhotic patients are few, but the reported mortal-ity rate is approximately ] 5%.78,82Endoscopic pap-illary ba1100n dilatation without sphincterotomy andremoval of common bile duct stones has been de-scribed as a safer method in patients with CLD witha lower risk of bleeding83,84 and has been shown tobe suitable for removal of sma11bile duct stones.85

With larger stones, methods combining ba1100ndila-tation with mechanical lithotripsy83 01' sphinctero-tomy are required.85

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Cholecystitis is a known complication in patientswith intact gallbladders following endoscopic biliarysphincterotomy.86,87 The combination of endoscopicsphincterotomy and laparoscopic cholecystectomy istherefore the safer option for patients with Child-Pugh dass A and B cirrhosis with GS and commonbile duct stones.

SYMPTOMATIC GALLSTONE DISEASE INPATIENTS WITH CHILD-PUGH CLASS CCHRONIC LIVER DISEASE

Patients with advanced liver disease continue to

be at risk of excessive mortality and morbidity ratesfollowing surgery despite advances in surgery, an-esthesia, management of coagulopathy, and intensivecare.88 Compared with patients with compensatedliver disease, these patients are more prone to acuteliver failure, severe coagulopathy, encephalopathy,adult respiratory distress syndrome, acute renal fail-ure, and sepsis.88 The degree of malnutrition,control of ascites, leveI of encephalopathy, prothrom-bin time, concentration of serum albumin, and con-centration of serum bilirubin predict the risk ofcomplications and death after surgery. Other deter-

minants of adverse outcomes include emergem?;surgery and the presence of portal hypertension.88, 9Therefore, despite the lackofdefinitive clinical trials, amore conservative approach seems preferable forpatients with Child-Pugh class C cirrhosis and symp-tomatic GS.61,62

Portal hypertension predisposes the patient to vari-ceal hemorrhage, hepatorenal syndrome, hepato-pulmonary syndrome, and uneontrolled aseites.88During the past 15 years, the transjugular intrahepaticportosystemie shunt (TIPS) proeedure has beeome asafe and effective treatment of portal hypertension.90TIPS, however, is most effective and safest whenplaced in patients with preserved hepatocellular func-

tion.88 Child-Pugh class C CLD is a factor that ~re-dicts high mortality rates for this procedure.90, 1 Aswitch to deeompressive surgical shunt procedures isthe obvious ehoice ifTIPS fails to control patients withrecurrent variceal bleeding.92This, too, is only anoption in the well-compensated CLD patient with alow opera tive risk.92 ln addition to expert radiologieand endoseopic faeilities, such a patient needs theinput of a hepatologist, if preoperative optimization isto be aehieved. lu sueh a multidiseiplinary teamanesthetie support, ability to monitor and eontroleoagulopathy are required to address the eommonfeatures of advanced liver disease with a view to redue-

ing complieations and mortality after surgery.88,93A partial eholecysteetomy, performed either lapar-

oscopically or via open technique, has occasionally

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GaUstones in Chronic Liver Disease 743

been reeommended in the Child-Pugh dass C CLDpatient, but the available reports have not used eon-trols.94,95 A larger experienee supports the use ofendoseopic retrograde eholangiopancreatography(ERC) in those high-risk patients who present withbiliary obstruction. Endoscopie drainage of the gall-bladder has been added in some cases but remains an

uncommon proeedure.74,75 AlternativeIy, pereutane-ous cholec..ystostomy may reverse the progression ofinflammation in patients with eholeeystitis and oftenprovides symptomatic relief.96 Percutaneous chole-c..ystostomy is a radiologic procedure that requiresonly local anesthesia and eould be earried out in anIntensive Therapy Unit setting.97-99 It allows imme-diate deeompression of the acuteIy inflamed gallblad-der and can serve as a temporizing measure or asa definitive treatment.97 However, in the presence ofportal hypertension and/or aseites, its use is assoeiatedwith hemorrhage or sepsis. Therefore, there remainsa debate as to whether the transhepatie or thetransperitoneal route is preferable.IOOA Child-Pughdass C CLD patient who presents with aeute chole-cystitis and patients with severe CLD who are hospi-talized for management of their disease and developaeute cholecystitis during their hospital stay are twodistinct groups of patients who benefit from percuta-neous cholecystostomy.98 In the presenee of GS dis-case, recurrent cholec..ystitis can be as frequent as25-30% after removal of the eholecystostomytube.101,102Pereutaneous GS removal or optimizationof the patient where possible, followed by elective

laparoseopie chole~stectomy if indicated, istherefore advisable.97, 8These patients are best man-aged in hepatobiliary eenters where highly speeializedhepatologie, radiologie, anesthetie, surgieal, and in-tensive care faeilities are available.

CONCLUSIONS

The frequency of GS in patients with CLD isgreater than that in noncirrhotie patients and in-ereases with disease severity. Pigment stones seem tobe more eommon in CLD, occurring in up to 80%of cases. Like in the noncirrhotic patient, the vastmajority of GS in CLD remain asymptomatic. .

Asymptomatie GS and ineidental GS, diseoveredat the time of an abdominal surgery for anothercause, in CLD are best managed nonoperatively withdose follow-up and early therapeutie intervention ifbiliary symptoms do oeeur. The treatment of ehoicefor bile duct stones is ERC, because surgical explora-tion of the eommon bile duet has been associated

with an unaeeeptable morbidity and mortality. Thetreatment of Child-Pugh class A and B patients with

I744 Silva and Wong

symptomatic cholelithiasis is best done by the laparos-copie method after optimization of the patient. La-paroscopic cholecystectomy is the treatment of choicein the liver transplant candidate, with its associatedfewer postoperative adhesions and rapid recupera-tion. 'fhe treatment of symptomatic GS in potentialliver transplant recipients is, however, best done afterdirect consultation with regional hepatobiliary andtransplant units.

The treatment of symptomatic cholelithiasis in aChild-Pugh class C cirrhotic patient needs to be ap-proached with caution, because evidence has showna high rate of morbidity and mortality in this groupof patients, even in specialized liver units. For thesereasons, such patients are best managed in units thathave facilities and the necessary expertise with regardto endoscopic, radiologic, hepatologic, anesthetic, andsurgical options.

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Reprinted from the Journal of Gastrointestinal Surgery(2005 May-Jun) 9(5):739-46, MA Silvaand T.wong, withpermission from the author.

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