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Home , Alcoholic liver disease, Cholecystitis, Common bile duct stone, Gallbladder disease, Gallstone, Portal hypertension

Review Article

Gallstones in Chronic 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 of liver discase, and the majority remain a~ymptomatie. \Vhen symptoms do oeeur, morbidity and mortality are mueh higher than in noneirrhotie patients. A~)'mptomatie gallstones in eirrhotie patients are best managed eonservatively with dose follow-up and surgery if ~ymptoms oeeur. The management of asymptomatie gallstones found ineidentally at abdominal surgery for another indieation is controversial. Laparoseopie eholeeysteetomy is the treatment of ehoiee for symptomatie eholelithiasis in patients with well-eompensated , whereas patients with eholedoeholithiasis are best managed endo- seopieally. Symptomatie eholclithiasis in the deeompensated patient remains a ehallenge, and these patients are best managed in speeialized hepatobiliary ecnters. This review examines the evidenee eurrently available 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, , ehoic<.ystectomy, cholecystostomy

Gallstones (GS) are common in the general popu- a.lso co~firmed t~e hig~er prevalence of GS in pa- lation, and it is estimated that about 10-20% of the nents Wlth CLD,,6,8-IO:L.16(fable 1). adult population in developed countries have GS.I-3 These studies report the prevalence of asymptom- The prevalence is higher in women, the obese, and atic GS. The prevalence of c\inically manifest GS in older patients.I-3 The reported frequencies of GS in patients with CLO is largely unknown.17 A reeem (CLD), in comparison, tends to retrospective review of medical records of 38,459 in- be higher.l-6 In autopsy studies, the frequency of GS patients with various forms of liver disease found in patients with CLD ranges from 3.6% to 46%, with the prevalence of symptomatic GS to be 7.5%,18 a 1.2- to 3-fold increasc comparcd with the general although the possibility of occasional detection bias population.I-3,7 Studies using ultrasonography report cannot be exc\uded. In a longitudinal cohort study of a group of 34 patients with asymptomatic GS and urevalence GS ranging between 22% and 54%.1.2, . ,8-11Oespite this high prevalence, the management CLO, 18% developed symptoms over 6 years.191\1- of GS in patients with CLD remains controversial, 1-4 though the number of patients in the study was and the aim of this review was to examine the evidence small and the duration of follow-up was short, this for current treatment strategies. figure is comparable to that of asymptomatic GS in noncirrhotic patients.1 In noncirrhotic patient~,there THE EPIDEMIOLOGY OF GALLSTONES is a mean delay of about 8 years between stone forma- IN PATIENTS WITH CHRONIC tion and the onset of symptoms.20 Ir is not clc.ir LIVER DISEASE whether this holds true for GS in CLO. There exists a 3:I female predominanec for the GS are found in 10-20% of the general adult popu- incidence of GS in the population without CLD.!.!,12 lation.I-3,12 In comparison, autopsy studies have This pattem is similar in patients with CLD,II,!I!' shown up to a threefold increase in GS among cir- although some early reports indica.ted that the inei- rhotic ~atients compared with noncirrhotic con- dence of GS was higher in males.) GS oceur more trolS.7,1,13,14Similarly, ultrasonographic studies have frequently 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: [email protected]

@ 2005 The Society tor Surgcry of the Alimemary Tract 1091-255X105/$- see tTom mancr Published by Elsevier lnc. doi: 10.10 16/j.gassur.2004.09.041

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Joumalof 740 Silvaand Wong Gastrointestinal Surgery

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

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

Bouchier IAD7 1969 Autopsy Patients with CLD (n = 235) 29.4 Contrais (n = 4460) 12.8 Iber FLIO 1977 Autopsy Paticnts with CLD (n = 460) 33 Contrais (n = 316) 13 Iber FUo 1990 Autopsy Patients with CLD (n = 299) 46 Contrais (n = 178) 21 Fornari F5 1990 Patients with CLD (n = 410) 31.9 ContraIs (n = 414) 20 with chronic ,9 and pigment stones occur disease. 17Male gender and alcoholic cir- more frequently in GS of patients with CLD, while rhosis have interestingly been found to have an in- its incidence also increases with age.8,15.24,25 verse relationship to the presence of symptoms.17

MECHANISMS OF GALLSTONES IN RELATION TO FORMATION IN CHRONIC LIVER ETIOLOGY AND SEVERITY OF LIVER DISEASE DISEASE The mechanisms leading to the increased inci- dence ofGS in CLD are notwell understood.18 About The risk of GS appears to be indep.endent of the underlying etiology of liver disease.4. 5,26ln a study 80% of GS in patients with CLD are pigmem looking at the etiology of CLD, in 313 cirrhotic pa- stones compared with 20% in noncirrhotic pa- tiems, its cause did not seem to be importam as a risk tients.17,18.21;25.36Patiems with liver cirrhosis may also factor for GS formation.26 In another study of the have increased secondary to hypersplen- prevalence of GS in CLO in relation to the etiology ism, resulting in a higher incidence of pigmem of disease, 356 cirrhotic patients were compared with stones.4.10 Studies have shown that however effi- 247 cases of chronic hepatitis B and C without cirrho- ciem, the liver does not convert ali the unconjugated sisj a multivariate analysis showed that the duration into bilirubin monoglucuronides and diglu- and severity of cirrhosis were the only factors inde- curonides: a small fraction of the unconjugated pendently related to the development of GS in CLD, moiety escapes conjugation and 'spills' imobile.37 In whereas hepatitis B surface anti~en (HBsAg) positi- CLO, the fraction of bilirubin escaping conjuga- vity behaved as a negative factor. Several other stud- tion increases. The resultam excess unconjugated bi- ies have confirmed that the risk of developing GS is lirubin in is vulnerable to polymerization and/ correlated with severity of CLD as graded by the 01' to co-precipitation with free ionized .37.38 Childs-Pugh classification, rather than the etiology Deconjugation may also be catalyzed by glucuroni- of the disease.5.6.8.9.18.21 dases of bacterial 01'mucosal origin,39 and bilirubin The etioloR of symptoms in patients with GS monoglucuronide may also undergo nonenzymatic is unknown.2 It may be partly due to chance, de- hydrolysis to form unconjugated bilirubin. Even in pending on the movement of stones and their im- normal bile, therefore, tlle low concentration of paction in Hartmann's pouch 01'in the .1 unconjugated bilirubin still exceeds its aqueous 5011.1- It follows that the relative size of the calculi and bility by 100- to 1000-fold.39.4oThis unconjugated the caliber of various parts of the biliary tree may be bilirubin has been identified as a component ofbiliary importam. 1 It is, however, cIear that other factors sludge, which is believed to precede GS, especially play a role. Stasis may precipitate symptoms and pigmem stones.39 Additionally, decreased apolipo- is considered particularly relevam in tlle etiology of protein A-I and A-II levels in advanced CLO have postoperative .28-30 Stasis to bile flow is also been implicated as cause for a higher incidence of increased in CLD and may be a cause for the in- GS in these patients.zz creased incidence of GS in these patients.31-35 Ad- Pigment GS could be either black 01'brown. Black vanced age, female gender, viraI etiology of cirrhosis, pigment stones, which commonly occur in the gall- family history of GS, and duration of GS disease are, bladder only, are small (approximately 3 mm) and however, factors that are associated witll symptomatic occur witll increased frequency in patiems with CLD

107 Vol. 9, No. 5 2005 Gallstones in Chronic Liver Disease 741

and in those with hemolytic disease.9,11,ISBrown pig- dysfunction have impaired autonomic function.31 Au- ment stones are found more often in the biliary tree tonomic neuropathy may therefore contribute to the than in the gallbladder. Brown stones are convention- formation of GS in patients with advanced cirrhosis, ally associated with bacterial infection and parasitic perhaps by imBairing gallbladder and sphincter of infestations like fascioliasis (caused by the liver fluke). Oddi . 2 has also been Recent studies have, however, shown that neither found to be increased in patients with CLO and coex- the color nor the chemical composition accurately istent autonomic neuropathy.32 predicts the presence or absence of gallbladder bacte- ria and diseases that cause brown pigment stones, like fascioliasis, which may result in CLD, in turn possibly resulting in the formation of black pig- CLINICAL DIAGNOSIS OF GALLSTONES ment stones.-H,42 IN PATIENTS WITH CHRONIC Studies have shown that moderate intake of LIVER DISEASE actually decreases the risk of GS formation.22,2S,43,44 A recent study has described upper Alcohollowers bile saturation with a re- that is especially postprandial as more common sultant reduction of cholesterol stonesl8 and may in those with CLO than in normal controls.s; Early cause an increase in conversion of cholesterol to bile symptoms due to GS disease need to be differentiated acids.4S-47An increased high-density lipoprotein cho- from those of dyspepsia, , or irrita- lesterol serum concentration is associated with mod- ble bowel ~yndrome.;6 1n CLD patients, upper ab- erate alcohol consumption, and this could result in the dominal pain in the absence of the abo,=~causes may Imver incidence in cholesterol stone formation.48-;O result from gastric motility dysfunction.)) An alterna- 1n contrast to this protective role alcohol may have tive explanation for these postprandial symptoms in- on GS fonnation, heavy intake is a major clude increased portal blood flow and volume changes. risk factor for the development of liver disease by Duplex ultrasound and magnetic resonance imaging promoting and cirrhosis, both of which are have shown that patients with chronic hepatitis Chave risk factors for developing GS, especially of the pig- a greater volume change to the left lobe of the liver mented type.18,22 compared with normal controls. This in tlleory may It has been suggested that high levels of estro- result in more congestion and stretch of the Glission's gens and progesterone in CLD could play a role in capsule, resulting in the symptoms of pain.;7 \Vith the higher incidence of GS in these patients, by the these in mind, the clinical presentation, liver function impairment of gallbladder emptying similar to that tests, and imaging techniques are usually sufficient observed in . SA study evaluating the fasting to diagnose symptomatic GS disease in patients volume and meal-stimulated emptying of the gall- with CLD. bladder, plasma levels of , progesterone, and basal and postprandial secretion of in Child-Pugh class A cirrhotic patients compared them with results for normal subjects.H Normal ki- THE NATURAL HISTORY OF netics of postprandial emptying was demonstrated GALLSTONES IN CIRRHOTIC PATIENTS in both groups, although cirrhotic patients showed The management of GS in patients with CLD is an increased fasting gallbladder volume and higher a frequent dilemma. The risks of an operationneed to levels of basal and postprandial cholecystokinin.34 be weighed against the likelihood of GS progressing The circulating estradiol and progesterone levels to acute cholecystitis or obstruction. There were not significantly elevated to be implicated as is, however, a paucity of data on the natural history causa tive of GS in CLD.34 of GS in this cohort of patients. in this The study of gallbladder kinetics in the presence subpopulation of patients is more commonly due to of CLO and cirrhosis has shown on ultrasonography hepatocellular dysfunction than to bile duct obstruc- and radionuclide that its emptying tion.H,;8 Ultrasonography and magnetic resonance is sluggish.S1-S3 On ultrasonography, the unstimu- cholangiopancreatography are the preferred methods lated gallbladder in patients with CLD and cirrhosis for the diagnosis of choledocholithiasis in patients has also been found to have sign~fi~antly increased with CLD rather than endoscopic retrograde cholan- volumes with signs of a hypotonia.)2,)4 There is some giopancreatography.21 Although the risks of the de- evidence to suggest that gallbladder contraction is velopment of symptoms and complications are low, also under neural control. 32It has also been demon- the mortality associated with acute complications is strated that patients with moderate to severe liver in comparison higher with symptomatic GS than in

108 Journal of 742 Silva and Wong GastrointestinalSurgery the general population. 17,59These patients are there- Many GS are discovered for the first time at lapa- fore best managed in units equipped with suitable rotomy for an unrelated condition.I,19 There have diagnostic and therapeutic facilities sueh as that avail- been report<; describing the subsequent incidence of able in specialized hepatobiliary centers. biliary sY!Tlptoms in these patients, if left un- treated.I,6) In patient<; without CLD, due to the re- TREATMENT OF GALLSTONES ported incidence of biliary symptoms after operation IN CHRONIC LIVER DISEASE (20-45 %), incidental chole(:ystectomy has been advo- cated. 1,65-69In a study involving 34 patients with CLD An overall mortality rate for patients with CLD and GS, 82% remained asymptomatic over a period undergoing anesthesia and operation has been of 6 years fo11owingan abdominal operation for portal reported to be as high as 11.6%.60 In a recent meta- .19 The role of incidental cholecystec- analysis of patients with CLD undergoing laparos- tomy in patients with CLD is unclear.19'rhe emphasis copie , an overall morbidity rate of therefore, in patients with CLD, is for close follow- 21 % is described in cirrhotic patients compared with up with early interventional treatment for GS when an 8% morbidity in noncirrhotic patients.61 'fhese symptoms supervene. morbidities included liver bleeding, bile leaks, wound The morbidity and mortality rates associated with infection, new onset of , , pulmona~ laparoscopic cholecystectomy in Child-Pugh class A , and cardiopulmonary complications. 1 and B patients with sf!TIgtomatic GS have been shown Conversion rates from the laparoscopic procedure to be acceptable.62,6.,Ia-:3The presence, however, of to open cholecystectomy was 7% versus 3.6%61,62 a prolonged prothrombin time, , (P 0.(23). Mortality rates between the two = and in CLD patients is a risk groups, however, were not different statistically.61 factor for increased bleeding in these patients. There- The patients with CLD compared in this study were fore, appropriate preoperative preparations and principa11yofChild-Pugh class A and B. The laparos- meticulous operative techniques are required to copic procedure in patients with Child-Pugh class C reduce blood loss during the procedure. Laparoscopic was avoided, with the potential risks of morbidity and cholecystectomy is particularly useful in liver trans- mortality in this group being unacceptable.62-64 Only plant candidates who develop significant biliary one study included six patients of Child-Pugh class C, with one death (17%),61 but no conclusions can symptoms because of its associated fewer J)ostopera- tive adhesions and rapid recuperation. 1,62 Some be drawn regarding the outcome oflaparoscopic cho- lecystectomy in this subset of high-risk patients due groups have even described stenting of the cystic duct to the lack of data. endoscopically using biliary <; from gallbladder \Vhen compared with open cholecystectomy in to , in this group of patients awaiting patients with CLD, the laparoscopic procedure is , to relieve symptoms.74,75 associated with less operative blood loss, a shorter There is an increased risk of morbidity and mor- oper?tive time, and a decreased length of hospital tality with exploration in pati- stay.)9,61There ,,,as no statistica11y significant differ- ents with C~D,76,77 with mortality rates as high as ence in morbidity 01'wound infection rates between 30_50%.21,7/-79As a result, endoscopic management is preferred when a is clini- the two groups.61 There have, however, been no pro- spective studies comparing laparoscopic and open ca11ysuspected in these patients.62,77,78Endoscopic cholecystectomy in patients with CLD. The data biliary sphincterotomy is the method of choice for the available at present are inadequate for definite conclu- treatment of choledocholithiasis in patients without sions to be made on outcomes comparing these two CLD, although it is associated with an overall compli- methods of treatment. cation rate of about 10% and a mortality rate of The purpose of cholecystectomy for symptomatic 0.5%.80,8]'rhe reports on endoscopic sphincterotomy GS is twofold: namely, the relief of symptoms and in cirrhotic patients are few, but the reported mortal- the prevention of potentially life-threatening compli- ity rate is approximately ] 5%.78,82Endoscopic pap- cations.1 Cholecystectomy for asymptomatic GS, illary ba1100n dilatation without sphincterotomy and however, must be weighed against the hazards of removal of common bile duct stones has been de- treatment. In noncirrhotic patients, elective cholecys- scribed as a safer method in patients with CLD with tectomy is not indicated because most remain asymp- a lower risk of bleeding83,84 and has been shown to tomatic and because mortality rates are low after be suitable for removal of sma11bile duct stones.85 prompt treatment of those who develop symptoms.1 With larger stones, methods combining ba1100ndila- Similarly, there is no place for prophylactic chole- tation with mechanical lithotripsy83 01' sphinctero- cystectomy for GS in CLD patients.1,19 tomy are required.85

109 Vol. 9, No. 5 2005 GaUstones in Chronic Liver Disease 743

Cholecystitis is a known in patients been reeommended in the Child-Pugh dass C CLD with intact following endoscopic biliary patient, but the available reports have not used eon- sphincterotomy.86,87 The combination of endoscopic trols.94,95 A larger experienee supports the use of sphincterotomy and laparoscopic cholecystectomy is endoseopic retrograde eholangiopancreatography therefore the safer option for patients with Child- (ERC) in those high-risk patients who present with Pugh dass A and B cirrhosis with GS and common biliary obstruction. Endoscopie drainage of the gall- bile duct stones. bladder has been added in some cases but remains an uncommon proeedure.74,75 AlternativeIy, pereutane- SYMPTOMATIC GALLSTONE DISEASE IN ous cholec..ystostomy may reverse the progression of PATIENTS WITH CHILD-PUGH CLASS C in patients with eholeeystitis and often CHRONIC LIVER DISEASE provides symptomatic relief.96 Percutaneous chole- c..ystostomy is a radiologic procedure that requires Patients with advanced liver disease continue to only local anesthesia and eould be earried out in an be at risk of excessive mortality and morbidity rates Intensive Therapy Unit setting.97-99It allows imme- following surgery despite advances in surgery, an- diate deeompression of the acuteIy inflamed gallblad- esthesia, management of , and intensive der and can serve as a temporizing measure or as care.88 Compared with patients with compensated a definitive treatment.97 However, in the presence of liver disease, these patients are more prone to acute portal hypertension and/or aseites, its use is assoeiated , severe coagulopathy, encephalopathy, with hemorrhage or sepsis. Therefore, there remains adult respiratory distress syndrome, acute renal fail- a debate as to whether the transhepatie or the ure, and sepsis.88 The degree of malnutrition, transperitoneal route is preferable.IOOA Child-Pugh control of ascites, leveI of encephalopathy, prothrom- dass C CLD patient who presents with aeute chole- bin time, concentration of serum albumin, and con- cystitis and patients with severe CLD who are hospi- centration of serum bilirubin predict the risk of talized for management of their disease and develop complications and death after surgery. Other deter- aeute cholecystitis during their hospital stay are two minants of adverse outcomes include emergem?; distinct groups of patients who benefit from percuta- surgery and the presence of portal hypertension.88, 9 neous .98 In the presenee of GS dis- Therefore, despite the lackofdefinitive clinical trials, a case, recurrent cholec..ystitis can be as frequent as more conservative approach seems preferable for 25-30% after removal of the eholecystostomy patients with Child-Pugh class C cirrhosis and symp- tube.101,102Pereutaneous GS removal or optimization tomatic GS.61,62 of the patient where possible, followed by elective Portal hypertension predisposes the patient to vari- laparoseopie chole~stectomy if indicated, is ceal hemorrhage, , hepato- therefore advisable.97, 8These patients are best man- pulmonary syndrome, and uneontrolled aseites.88 aged in hepatobiliary eenters where highly speeialized During the past 15 years, the transjugular intrahepatic hepatologie, radiologie, anesthetie, surgieal, and in- portosystemie (TIPS) proeedure has beeome a tensive care faeilities are available. safe and effective treatment of portal hypertension.90 TIPS, however, is most effective and safest when placed in patients with preserved hepatocellular func- CONCLUSIONS tion.88 Child-Pugh class C CLD is a factor that ~re- dicts high mortality rates for this procedure.90, 1 A The frequency of GS in patients with CLD is switch to deeompressive surgical shunt procedures is greater than that in noncirrhotie patients and in- the obvious ehoice ifTIPS fails to control patients with ereases with disease severity. Pigment stones seem to recurrent variceal bleeding.92This, too, is only an be more eommon in CLD, occurring in up to 80% option in the well-compensated CLD patient with a of cases. Like in the noncirrhotic patient, the vast low opera tive risk.92 ln addition to expert radiologie majority of GS in CLD remain asymptomatic. . and endoseopic faeilities, such a patient needs the Asymptomatie GS and ineidental GS, diseovered input of a hepatologist, if preoperative optimization is at the time of an abdominal surgery for another to be aehieved. lu sueh a multidiseiplinary team cause, in CLD are best managed nonoperatively with anesthetie support, ability to monitor and eontrol dose follow-up and early therapeutie intervention if eoagulopathy are required to address the eommon biliary symptoms do oeeur. The treatment of ehoice features of advanced liver disease with a view to redue- for bile duct stones is ERC, because surgical explora- ing complieations and mortality after surgery.88,93 tion of the eommon bile duet has been associated A partial eholecysteetomy, performed either lapar- with an unaeeeptable morbidity and mortality. The oscopically or via open technique, has occasionally treatment of Child-Pugh class A and B patients with

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Joumal of 744 Silva and Wong Gastrointestinal Surgery

symptomatic cholelithiasis is best done by the laparos- 15. Conte D, Fraquelli M, Fornari F, Lodo L, Bodini P, Buscar- copie method after optimization of the patient. La- ini L. Close relation between cirrhosis and gallstones. Arch Intern Med 1999;159:49-52. paroscopic cholecystectomy is the treatment of choice 16. Steinberg I-IV, Becken WW, Chezmar JL. Incidence of in the liver transplant candidate, with its associated cholelithiasis among patients with eirrhosis and portal fewer postoperative adhesions and rapid recupera- hypertension. Gastointest RadioI1988;13:347-350. tion. 'fhe treatment of symptomatic GS in potential 17. Acalovschi M, Blendea MD, Feier C, et aI. Risk factors for liver transplant recipients is, however, best done after symptomatic gallstones in patients with liver cirrhosis: A direct consultation with regional hepatobiliary and case control stUdy. AmJ GasroenteroI2003;98:1856-1860. 18. Buchner AM, Sonnenberg A. 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Reprinted from the Journal of Gastrointestinal Surgery (2005 May-Jun) 9(5):739-46, MA Silvaand T.wong, with permission from the author.

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