Best Practice & Research Clinical Gastroenterology

Vol. 20, No. 6, pp. 1103e1116, 2006

doi:10.1016/j.bpg.2006.04.002
available online at http://www.sciencedirect.com

Management of common bile-duct stones and

associated gallbladder stones: surgical aspects

Djamila Boerma* MD, PhD

Surgeon
Department of Surgery, St Antonius Hospital, Postbus 2500, 3430 EM Nieuwegein, The Netherlands

Matthijs P. Schwartz MD, PhD

Director of Endoscopy
Department of Gastroenterology, University Medical Center Utrecht, P.O. Box 85500,
3508 GA Utrecht, The Netherlands

For many years, open exploration of the common bile duct has been the treatment of choice for
patients with common bile-duct stones. During recent decades endoscopic sphincterotomy has
gained wide acceptance as an effective and less invasive alternative. After sphincterotomy, sub-
sequent (laparoscopic) cholecystectomy is warranted in patients with gallbladder stones. This
chapter will discuss whether sphincterotomy should be performed prior to, during or after cho-
lecystectomy, and will also address the question of whether single-stage treatment by laparo-
scopic cholecystectomy and laparoscopic bile-duct exploration is in fact preferable. The rate
of recurrent choledocholithiasis after endoscopic biliary sphincterotomy can reach more than
20%. This review focuses on the risk factors e delayed bile-duct clearance and bactobilia e that
may lead to recurrent primary bile-duct stone formation. Underlying altered bile composition
(relative phospholipid deficiency) should be recognised in a subgroup of patients. Identification
of these risk factors may significantly affect treatment policy.

Key words: choledocholithiasis; laparoscopic cholecystectomy; endoscopic sphincterotomy;

common bile-duct exploration; ursodeoxycholic acid; MDR3 protein.

Up to 15% of patients with gallbladder stones exhibit concomitant stones in the com-
mon bile duct (CBD).1 Symptoms caused by CBD stones consist of colic or may result
from complications such as jaundice, cholangitis or pancreatitis.
In case of symptomatic CBD stones, decompression of the common bile duct and re-
moval of ductal stones is warranted. Decompression may be achieved by endoscopic
methods such as endoscopic sphincterotomy, papillary dilatation, nasobiliary drainage,

* Corresponding author. Tel.: þ31 30 6099111; Fax: þ31 30 6036578.

E-mail address: djamilaboerma@hotmail.com (D. Boerma).
1521-6918/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
1104 D. Boerma and M. P. Schwartz

or biliary stenting. Whether these different modalities represent a permanent solution

remains a subject of discussion. For a long time it has been matter of debate whether re-
moval of CBD stones should be followed by cholecystectomy to prevent recurrent
symptoms. Only recently, prospective randomised trials have suggested benefit of
planned subsequent cholecystectomy. But in which individual patients should we be
more aggressive, and in which situation is an expectant policy preferable? And if we de-
cide that a specific patient will in the end need surgery, why not try to treat that patient in
one procedure by cholecystectomy and surgical stone removal? Should we perform that
procedure laparoscopically? Should we then, avoiding ‘unnecessary’ preoperative drain-
age procedures, perform standard intraoperative cholangiography, and proceed to bile-
duct exploration if stones are present? Or have the skills of today’s gastroenterologists
developed to such a high level that endoscopic sphincterotomy is standard first-choice
therapy for CBD stones? And if so, should a patient with combined cholecystocholedo-
cholithiasis undergo both endoscopic sphincterotomy and laparoscopic cholecystec-
tomy, and should we concentrate on the sequence and timing of both procedures?

INTERVENTIONAL TREATMENT OPTIONS FOR CBD STONES

Open cholecystectomy and CBD exploration

Long before the introduction of endoscopic treatment measures for CBD stones, the
first surgical CBD exploration was reported in 1889 by a Swiss surgeon, Ludwig Cour-
voisier, who removed a gallstone via an incision in the CBD.2 For many years, open
cholecystectomy and exploration of the common bile duct has been standard treat-
ment of patients with combined cholecystocholedocholithiasis. Morbidity and mortal-
ity of this procedure were low, the percentage of retained stones only 1e3%, and
during long-term follow-up revisional surgery was necessary in about 10% of the
patients.3e6 But nowadays surgical experience with the procedure has decreased
dramatically, and open exploration of the common bile duct is reserved for patients
in whom less invasive treatment options are unsuccessful.

Open cholecystectomy and CBD exploration versus

endoscopic sphincterotomy

In the early 1970s, endoscopic sphincterotomy (ES) was introduced as a treatment

modality for common bile-duct stones.7,8 During the following decades, ES gained
wide acceptance as a good, less invasive, highly effective alternative for the treatment
of biliary obstruction due to gallstones. However, in patients with residual stones in
the gallbladder, subsequent cholecystectomy was considered necessary. In a prospec-
tive randomised trial it was demonstrated that ES before (open) cholecystectomy did
not lead to earlier recovery or less postoperative morbidity as compared to primary
open cholecystectomy combined with common bile-duct exploration.5 Thus it was
concluded that routine preoperative ES was not recommended. Why subject these pa-
tients to ERCP with its morbidity and mortality if surgery is to be performed anyway?
On the other hand, patients who were considered unfit for surgery because of old
age or severe co-morbidity were managed expectantly more and more often after
ES. After all, the ‘pseudo-obstruction’ caused by stones at the level of the ampulla of
Vater had been eliminated. And in large retrospective series it appeared that only 10%
of these expectantly managed patients presented after ES with their gallbladder in situ,
 Surgical aspects of bile-duct and gallbladder stones 1105

with recurrent biliary symptoms.9,10 It was then assumed that maybe all patients e even
the young and fit e were adequately treated by endoscopic sphincterotomy alone.
For a long time, the decision whether to operate after ES was taken arbitrarily. In a ret-
rospective analysis of patients who had undergone endoscopic sphincterotomy for CBD
stones, it appeared that referring surgeons were more likely to propose subsequent
cholecystectomy, whereas gastroenterologists tended to manage patients expectantly.11
In a prospective randomised trial, published in 1995 by Hammarstrom et al,4 an ex-
pectant policy after ES was compared to open cholecystectomy combined with CBD
exploration. It appeared that 20% of the patients after ES alone needed cholecystectomy
during follow-up. Similar results were reported in 1996 by Targarona et al.6 In their pro-
spective randomised trial in a group of high-risk patients, the policy of ES and subsequent
open cholecystectomy was compared to ES alone. In that study, patients who under-
went elective open cholecystectomy had significantly fewer recurrent biliary symptoms
(6% versus 21%) and needed fewer readmissions (4% versus 23%) than patients who did
not undergo surgery after ES. Furthermore, no major complications occurred in the
cholecystectomised patients, and the only death due to biliary sepsis occurred in the
ES group.6 Thus it was concluded that ES alone might not suffice, and that after ES cho-
lecystectomy is justified e and may even be indicated e also in high-risk patients.

Endoscopic sphincterotomy followed by planned laparoscopic

cholecystectomy versus endoscopic sphincterotomy alone

After its introduction in 1989 by Dubois et al,12 laparoscopic removal of the gallblad-
der has replaced open surgery and has become the treatment of choice for symptom-
atic cholecystolithiasis. Laparoscopic cholecystectomy (LC) is associated with less
morbidity and a shorter postoperative recovery as compared to open surgery. In a
randomised trial among Dutch patients over 18 years of age, ES alone was compared
with ES combined with planned laparoscopic cholecystectomy.13 Of 59 patients rand-
omised to a wait-and-see policy after sphincterotomy, 27 patients (47%) developed re-
current biliary symptoms during a 2-year follow-up. After planned LC, only 2% of
patients had recurrent biliary events during follow-up. Although this percentage of
post-cholecystectomy pain is lower than generally reported in the literature, planned
cholecystectomy appeared justified for the large majority of cases. However, in the
patients who were managed expectantly after ES, no serious morbidity occurred and
mortality was nil. The only adverse effect in this group (apart from recurrent symp-
toms) was a high conversion rate to open procedure if cholecystectomy ‘on demand’
was subsequently necessary (55%). Quality of life was the same in both groups. An
aggressive treatment of the young and fit appeared justified and also understandable.
But these same results also indicated that the elderly population and patients with
contraindications to surgery, in particular, could be managed expectantly.
Very recently, a similar trial has been performed among Chinese patients, who were
all over 60 years of age.14 Planned cholecystectomy after ES also appeared beneficial in
this older population. It was found that the cumulative probability of recurrent biliary
events after planned cholecystectomy was 5.8%, versus 25.4% in the wait-and-see
group (n ¼ 21 of 89). Of 21 patients with recurrent events in the wait-and-see group,
ten underwent cholecystectomy. And again, the conversion rate to open procedure in
this latter group was very high (50%). But also again, no serious adverse events were
encountered in either group.
Thus, we can inform our elderly patients that the average clinical course after ES
alone is not without unwanted events, but we should maybe still be reluctant in
1106 D. Boerma and M. P. Schwartz

advocating planned cholecystectomy in patients with an increased surgical risk other

than old age.

Laparoscopic cholecystectomy with laparoscopic removal of CBD

stones versus preoperative endoscopic sphincterotomy
and laparoscopic cholecystectomy

With the development of less invasive surgery, the advantages of ES over surgical CBD
exploration were again challenged. After all, the spreading use of ES was partly favoured
because the morbimortality of (open) surgical CBD exploration was avoided. But pos-
sibly a laparoscopic approach could avoid some of the surgical morbidity, and at the
same time enable us to treat the patient in one single stage. After intraoperative de-
tection of CBD stones by cholangiography, subsequent laparoscopic cholecystectomy
combined with CBD exploration might be preferable.
If intraoperative cholangiography is routinely performed in all patients undergoing
laparoscopic cholecystectomy, CBD stones are demonstrated in 10e15% of patients.
In many retrospective case series of patients with intraoperatively detected CBD
stones, laparoscopic transcystic duct clearance is achieved in 25e75% of all pa-
tients.15e20 Operation time is slightly lengthened, but postoperative morbidity remains
low and hospital stay short. Approximately 2% of patients have a false-positive cholan-
giography and undergo unnecessary bile-duct exploration, and an equal amount of pa-
tients require ERCP for retained stones during follow-up.
The advantage of laparoscopic removal of CBD stones may be limited to those that
can be removed transcystically. Laparoscopic CBD exploration is technically more de-
manding than transcystic stone removal, the operation time is longer, and more post-
operative complications occur.19,20 Choledochotomy may be indicated in patients with
stones larger than 6 mm or with a small cystic duct (<4 mm). Furthermore, posterior
or distal entrance of the cystic duct into the CBD may mandate choledochotomy. CBD
exploration is difficult, especially in the case of marked inflammation or a small CBD of
less that 7 mm. Long-term follow-up of CBD exploration does not reveal a high inci-
dence of biliary strictures.20,21
In a prospective analysis of 224 patients who underwent laparoscopic treatment of
CBD stones, 25% of the patients could be treated transcystically.20 The remaining pa-
tients required laparoscopic CBD exploration. Postoperative complications occurred
in 17% of patients who underwent CBD exploration (versus 9% after transcystic duct
clearance), hospital stay was 4.8 days (versus 2.0 days), and conversion rate was 17%
(versus 4%). Most complications occurred in the older patients and were T-tube-
related. Primary closure of the CBD was associated with fewer complications than
closure over a T-tube.19,20,22
In a multicenter trial conducted by the European Association of Endoscopic Sur-
gery, ‘single-stage’ LC combined with laparoscopic removal of bile-duct stones was
compared to ES followed by planned LC. Analysis was performed per protocol. The
main finding of the trial was that, on the whole, both procedures were equally effec-
tive, but that after single-stage treatment total hospital stay was significantly shorter.23
On the basis of these findings the authors concluded that single-stage treatment is
favourable. However, the majority of patients (56/109) in the one-stage group
underwent transcystic removal of stones; these patients had low morbidity rates and
a short hospital stay (3 days). Ten of 11 postoperative biliary complications occurred
among patients undergoing laparoscopic CBD exploration, and in these patients hospital
 Surgical aspects of bile-duct and gallbladder stones 1107

stay was 9 days. Finally, the main outcome parameter that differed between both
groups e i.e. hospital admission time e was influenced by the interval between ES and
LC, and that interval was ‘up to the individual surgeon’ and was not mentioned further.

Laparoscopic cholecystectomy with laparoscopic removal of bile-duct

stones versus laparoscopic cholecystectomy with postoperative
endoscopic sphincterotomy

Thus, in patients in whom transcystic stone removal appears unsuccessful, postoperative

ERCP with ES appears to be preferred over laparoscopic CBD exploration. In a rando-
mised trial published by Rhodes in 1998, patients who underwent LC for symptomatic
cholelithiasis underwent standard intraoperative cholangiography. When CBD stones
were demonstrated on cholangiography, patients were randomised to undergo either
LC with laparoscopic removal of bile-duct stones or LC with postoperative ES.24 Initial
success in CBD clearance was 75% in both groups, and complications were comparable.
But of the 40 patients allocated to laparoscopic stone removal, 28 patients underwent
transcystic removal of stones with a success rate of 82%. The remaining 12 patients re-
quired laparoscopic CBD exploration with a success rate of only 58%; five of these 12
patients required further interventions to achieve complete stone removal. Of all post-
operative complications reported (17.5%) no distinction is made between patients man-
aged transcystically and those requiring CBD exploration. The same accounts for post-
procedural hospital stay: on the whole, hospital stay was shorter after laparoscopic stone
removal (1 versus 3.5 days for LC and ES), but hospital stay after laparoscopic CBD ex-
ploration versus transcystic removal is not mentioned. Two further critical notes should
be made here. Firstly, sample size is small, and sample size calculation remains unmen-
tioned. Secondly, in patients undergoing LC and postoperative ES, the latter procedure
was performed ‘within 48 hours’ of surgery. ERCP during the same anesthesia or on the
same day as LC may shorten hospital stay to comparable lengths.
In a more recent prospective randomised trial, patients with symptomatic gallstones
and suspected CDB stones underwent LC combined with intraoperative cholangiogra-
phy. When bile-duct stones were encountered, an attempt was made for transcystic re-
moval. Inability of transcystic stone clearance led to intraoperative randomisation for
either laparoscopic CBD exploration or postoperative ERCP.25 Of 372 patients with
confirmed CBD stones, 286 patients were successfully managed by transcystic stone
clearance (77%) and 86 patients were randomised. After laparoscopic CBD exploration,
six of 41 patients had bile leakage, of whom four needed reintervention. After ERCP, two
patients required another operation to remove stones that could not be cleared endo-
scopically. These differences did not reach statistical significance; unfortunately, due to
slow accrual of patients, the sample size was lowered, and, as suggested by the authors,
the small sample size may have introduced a type II error in the endpoints.

Laparoscopic cholecystectomy with intraoperative

endoscopic sphincterotomy

If during LC intraoperative cholangiography reveals CBD stones, another option is to

perform intraoperative ERCP with ES. Several studies have shown the safety and effi-
cacy of this approach.26e28 In a recent Italian randomised trial, patients with combined
cholecystocholedocholithiasis who underwent LC were randomised to undergo either
preoperative ES or intraoperative ES. All participants had patient-related risk factors
1108 D. Boerma and M. P. Schwartz

for developing post-sphincterotomy pancreatitis. In the patients who underwent intra-

operative ES, a so-called ‘rendezvous’ technique was used: a guide wire was positioned
during laparoscopy, transcystically through the ampulla, to allow easy and fast access to
the CBD. Thus, papillary edema and pancreatic trauma were avoided. Indeed, this
group of patients suffered less (mild) post-ERCP pancreatitis as compared to patients
who underwent standard (preoperative) ERCP and ES.29 In a Chinese study, LC with
intraoperative ES was compared with LC with laparoscopic removal of bile-duct
stones. Apparently all patients in the latter group underwent choledochotomy. In
this study, both procedures were equally effective (success rates around 90%) and
safe (complication rate 5e10%), and hospital stay was 4.5 days.30
In conclusion, intraoperative ERCP with ES is at least as safe and effective as pre- or
postoperative ES, but requires considerable organisational effort.

Selection patients with CBD stones

Thus far, there is no convincing evidence that LC with concurrent laparoscopic re-
moval of bile-duct stones should replace the combination of ES and LC. Until today,
two-stage therapy e consisting of ES followed by LC in patients with combined cho-
lecystocholedocholithiasis e is standard in many European countries.31 Also in
a North-American nationwide survey over the years from 1979 to 2001, the use of
ERCP has dramatically increased, and CBD exploration is becoming rare. Accordingly,
morbidity of CBD exploration is reported to increase from 4% in 1979 to 17% today
due to less surgical experience.32
In the two-stage treatment strategy, preoperative identification of patients with
concomitant CBD stones is important. In the majority of patients common bile-duct
stones are not suspected and are not present. Unexpected bile-duct stones are ex-
tremely uncommon in these patients (<2%), hence there is no indication to perform
standard ERCP. On the other hand, in patients presenting with severe cholangitis, the
presence of CBD stones undoubtedly requires (emergency) ES as the first treatment.
In the remaining patients, the presence of CBD stones may be suspected. Several risk
factors for CBD stones have been outlined and, if present, appear to warrant preop-
erative ERCP, depending on their effects on likelihood ratios. Important risk factors for
the presence of CBD stones are cholangitis (with a positive likelihood ratio of 18% and
a 95% confidence interval of 9e37), ultrasonographically proven CBD stones, preop-
erative jaundice, or a dilated bile duct on ultrasonography (Table 1).33 Also, severe bil-
iary pancreatitis and the combination of a dilated duct with cholestatic laboratory
parameters have been established as risk factors.34 Appreciation of these risk factors
and likelihood ratios is of great importance in clinical practice. In patients with only
transiently elevated liver biochemistry, or slightly dilated bile ducts in combination
with normal liver tests, only a minority will actually have bile duct stones. Routine pre-
operative ERCP is not indicated in these patients.

Potential adverse effects of delaying laparoscopic cholecystectomy

after endoscopic sphincterotomy
After ES and stone removal, LC is indicated in most patients. In laparoscopic cholecys-
tectomy for uncomplicated cholecystolithiasis e i.e. without preoperative ES e
conversion rates have currently decreased to around 5%.35,36 It seems that conversion
rates of LC after ES are higher than those of LC for uncomplicated cholelithiasis. Con-
version of LC to open cholecystectomy has been shown in multiple studies to lead to
 Surgical aspects of bile-duct and gallbladder stones 1109

Table 1. Predictive value of various findings for presence of bile-duct stones in patients scheduled for
cholecystectomy.33
Parameter LRþ 95% CI LR 95% CI
Cholangitis 18 9e37 0.93 0.89e0.96
Bile-duct stones 14 7e25 0.7 0.63e0.77
by ultrasound
Preoperative jaundice 10 7e14 0.69 0.64e0.74
Common bile-duct 7 6e9 0.77 0.72e0.82
dilatation by ultrasound
Increased bilirubin 4.8 4.4e5.3 0.54 0.49e0.60
Reversible jaundice 3.9 3.3e4.5 0.82 0.78e0.86
Increased alkaline phosphatase 2.6 2.4e2.9 0.65 0.59e0.71
Pancreatitis 2.1 1.6e2.7 0.96 0.94e0.98
Cholecystitis 1.6 1.4e1.9 0.94 0.87e1.01
Increased amylase 1.5 1.1e2.1 0.99 0.96e1.01

LRþ, positive likelihood ratio; LR, negative likelihood ratio; 95% CI, 95% confidence interval.
Theoretical example: bile-duct stones occur in 20% of all patients with symptomatic gallbladder stones.
This prevalence leads to a ‘pre-test odds’ of 1:4. In case of cholangitis, the ‘post-test odds’ is 18.3*1:
4 ¼ 18.3: 4. This leads to a chance of bile-duct stones of 82% (positive predictive value).

more postoperative (especially pulmonary) infections, longer hospital stay and slower
recovery to normal daily activities.37e42 In a prospective cohort study of 2137 patients
who were considered for elective LC for symptomatic gallstone disease, 250 patients
were diagnosed by ERCP with CBD stones and underwent ES. The duration of surgery
after ES was significantly longer than for uncomplicated LC. Also the conversion rate
was higher after ES than in uncomplicated cholecystolithiasis (8.3% versus 3.4%).1 In
both randomised controlled trials comparing planned cholecystectomy after ES with
ES alone, conversion to open surgery was necessary in 20% of patients who underwent
planned LC. Of cholecystectomy on demand, conversion rates were much higher (up to
55%).13,14 Also, if the timing of LC after ES is taken into account, differences in conver-
sion rates become apparent. In large series, the conversion rate of LC that is performed
within days after ES is low 3e8%.1,43e45 In series of patients that underwent LC six
weeks after ES e as is common practice in many European hospitals e operation
time was increased,1,36,43 and the procedure was more often converted to open re-
moval of the gallbladder (20%).13,14,46 Possibly, ES prior to LC is a risk factor for con-
version to open cholecystectomy. Disruption of Oddi’s sphincter has been shown to
lead to gastrointestinal reflux into the hepatoduodenal ligament.43,47 Animal studies
have shown that, in bile, cultures after ES are dominated by enteric bacteria.47 Maybe
this reflux of intestinal fluids leads to chronic inflammation of the ligament, causing
technical problems during the dissection of Calot’s triangle. Nevertheless, the optimal
timing of LC after ES is a matter that has scarcely been addressed yet in literature.
Randomised trials of early versus delayed LC after ES are therefore needed.

Recurrent CBD stones

Stone recurrence rates after ES range between 6% and 21%, as has been reported in
both Western and Asian long-term follow-up cohort studies.48e54 Both patients with
synchronous cholecystocholedocholithiasis and cholecystectomised patients carry
a substantial risk of recurrent CBD stones.51,52,55 Primary bile-duct stones occur
1110 D. Boerma and M. P. Schwartz

frequently in Asia; they are supposed to develop de novo in the extra- or intrahepatic
bile ducts. In the Western world, secondary CBD e stones which have originated
from the gallbladder e occur more frequently. It remains unknown what percentage
of recurrent CBD stones after ES are actually unsuspected retained stones or frag-
ments of stones after lithotripsy.53
In primary stone formation in the bile ducts, two main pathogenetic mechanisms
can be distinguished: morphological or functional bile-duct defects leading to bacto-
bilia, biliary stasis and stone formation, and altered bile composition promoting bile
crystallisation.

Bile-duct dysfunction and primary gallstone formation

Microbial colonisation of bile by microorganisms (bactobilia) and delayed hepatic clear-
ance, as can be investigated by quantitative cholescintigraphy, have been pointed out as
major factors in CBD stone recurrence after ES.56,57 This is illustrated by the fact that
most recurrent CBD stones are brown pigment stones, of which the pathogenesis is
associated with bactobilia.58 The reasons for delayed biliary clearance are largely un-
known, but abnormal biliary motility has been suggested in cholecystectomised pa-
tients.57 The finding of a sustained dilation of the CBD (diameter of >12e15 mm)
has been assigned as the main predictor of recurrent choledocholithiasis,48,50,54,59 as
it probably indicates a poor emptying of the bile duct. In a subgroup of these patients
an underlying congenital fusiform dilatation (type I choledochal cyst) might be the
cause of the dilatation,60 but in the majority of cases CBD dilatation develops later
in life. In fact, whether CBD dilatation is the cause or consequence of recurrent stone
formation remains unresolved. Probably, in a subset of patients, (longstanding) pres-
ence of choledocholithiasis will result in a dilated, decompensated CBD which in
turn promotes further new stone formation. In these patients, stones will continue
to recur and regular (e.g. yearly) ERCP surveillance might be advised, even if the
patients are asymptomatic.61,62 In the literature, there is controversy about the aetio-
logic role of a juxtapapillary diverticulum in CBD stone recurrence.48,52 Theoretically,
compression of the distal CBD could lead to biliary stasis which, in combination with
bacterial overgrowth and ascending colonisation, might promote stone formation.
Post-ES papillary stenosis has been observed to occur in 1e7% of patients,48,49,51,54,63,64
but the (scarce) available data are confounded by varying and unclear definitions of this
condition. If papillary stenosis does indeed occur in a significant proportion of patients,
this could be assigned as a cause of delayed biliary emptying. Incomplete (i.e. too
small) sphincterotomy or precut papillotomy have been suggested as causes of a
papillary stricture after ES, although there is no hard evidence to support this
assumption.

Altered bile composition and gallstone formation

Biliary cholesterol supersaturation is now generally considered to be the major factor
in bile composition which promotes cholesterol gallstone formation.65 As outlined
more extensively in Chapter 2, other factors that may contribute to gallstone forma-
tion are excess of the hydrophobic bile salt deoxycholate and crystallisation-promoting
proteins.
Biliary cholesterol supersaturation occurs if excess cholesterol or not enough bile
salts and phosphatidylcholine are secreted into bile to solubilise all cholesterol mole-
cules in mixed micelles. Under these circumstances, cholesterol may be kept in vesicles
 Surgical aspects of bile-duct and gallbladder stones 1111

(i.e. spherical cholesterolephospholipid bilayers), from which cholesterol crystals may

nucleate, which is the onset of gallstone formation. There are specific transporters in
the canalicular membrane of the hepatocytes, including the multi-drug-resistance 3
(MDR3) protein involved in the secretion of phosphatidylcholine.66 Recent data
show that missense mutations in the MDR3 protein gene can result in relative phos-
phatidylcholine deficiency in bile and enhanced cholesterol crystallisation: so-called
low-phospholipids-associated cholelithiasis.67,68 The exact prevalence of this syn-
drome is unknown, but probably low. The diagnosis must be considered in cases of
early presentation of biliary problems (i.e. under the age of 40 years), intrahepatic
bile-duct stones, hyperechogenic foci in the liver, recurrent biliary complications after
cholecystectomy, a first-degree family history of cholelithiasis, or a history of intrahe-
patic cholestasis of pregnancy.69

Treatment and prevention of recurrent common bile-duct stones

In a number of studies, endoscopic reintervention for recurrent choledocholithiasis
has proved easy to perform, effective and safe.51,59 In some cases, re-recurrences,
which have a multifactorial cause, do occur, but again are probably mostly related
to bactobilia and biliary stasis. Post-ES papillary stenosis, as a cause of recurrent
CBD stones, can be treated by extending the sphincterotomy, after which CBD stones
can again be removed endoscopically.51,63 In some cases, however, papillary stenosis
and subsequent complications will recur. As mentioned before, in selected cases
with a dilated CBD and ongoing stone formation, regular ERCP surveillance could
be considered, even when there are no symptoms.61
Surgical treatment of recurrent choledocholithiasis (choledochoduodenostomy) is
more complex and invasive than endotherapy, and should be reserved for patients
with high rates of recurrent biliary complications, such as those with an irreversible
severe dilatation of the CBD or other patients in whom endoscopic therapy fails.70
In elderly patients with endoscopically difficult or non-extractable CBD stones, there
is a place for long-term biliary stenting.71 However, the considerable risk of cholangitis
with this approach should be taken into account.72
It has been known for many years that (small) cholesterol stones in the gallbladder
can be dissolved with the bile salts ursodeoxycholic acid (UDCA) and chenodeoxy-
cholic acid (CDCA).73 UDCA, administered once daily in a dose of 10 mg/kg, is the
drug of choice because it has fewer side-effects than CDCA.73 In patients with clinical
suspicion of an MDR3 gene mutation, who suffer from recurrent intraductal choles-
terol stones or sludge, treatment with UDCA might be considered to prevent further
recurrences.68 Patients with recurrent primary CBD stones, without suspicion of an
MDR3 gene mutation, most likely have pigment stones and do not benefit from
UDCA therapy. In patients with suspected recurrent secondary CBD stones, who
are unfit or unwilling to undergo cholecystectomy, UDCA treatment could be consid-
ered to dissolve small gallbladder stones to prevent secondary choledocholithiasis,
although this treatment is not evidence-based.

SUMMARY

In most countries, endoscopic sphincterotomy is the first-choice treatment for com-

mon bile-duct stones. In patients with residual gallbladder stones, laparoscopic chole-
cystectomy is the next step. The optimal timing of laparoscopic cholecystectomy after
1112 D. Boerma and M. P. Schwartz

endoscopic sphincterotomy remains to be determined. An alternative approach of

combined cholecystocholedocholithiasis consists of laparoscopic cholecystectomy to-
gether with laparoscopic stone removal. The advantage of this ‘single-stage’ therapy ap-
pears to be limited to patients with stones that can be removed transcystically. This
approach is successful in about half of the patients. Laparoscopic common bile-duct ex-
ploration is technically more demanding, more time-consuming, and associated with in-
creased postoperative morbidity. If transcystic removal is not possible, a postoperative
ERCP with endoscopic sphincterotomy is a good option. Intraoperative ERCP and en-
doscopic sphincterotomy are also feasible, but require specific organisational efforts.
Recurrence of choledocholithiasis after ES is reported in a considerable number of
patients (6e21%), resulting from de novo primary stone formation or recurrent sec-
ondary migration from the gallbladder. Primary choledocholithiasis is associated with
bactobilia and delayed bile-duct clearance, indicated by CBD dilation. Endoscopic
reintervention is safe and usually easy to perform. Surgery should be reserved for
intractable cases. In selected patients, an underlying lithogenic bile composition
(low-phospholipid-associated cholelithiasis) should be identified, and preventive
medical treatment with UDCA could be considered.

Practice points

 in patients with combined cholecystocholedocholithiasis, endoscopic sphinc-

terotomy should be followed by elective laparoscopic cholecystectomy, even
in the elderly; however, a ‘wait-and-see’ policy does not lead to higher mortal-
ity, and therefore expectant management can be advocated in case of significant
contraindications to surgery
 laparoscopic cholecystectomy combined with laparoscopic stone removal of-
fers a one-stage treatment of patients with combined cholecystocholedocholi-
thiasis. Laparoscopic transcystic duct clearance is associated with low
morbidity and short hospital stay. In contrast, laparoscopic common bile-
duct exploration remains a procedure with increased risk of biliary complica-
tions and prolonged hospital stay. In case of stones that cannot be removed
transcystically, it may be wise to perform an intraoperative or early postoper-
ative ERCP
 performing an endoscopic sphincterotomy during laparoscopic cholecystec-
tomy using a ‘rendezvous’ procedure may be beneficial in selected patients
(especially in case of earlier failed ERCP)
 laparoscopic cholecystectomy after endoscopic sphincterotomy is associated
with increased conversion rates to open procedure compared to laparoscopic
cholecystectomy for uncomplicated gallstones; laparoscopic cholecystectomy
planned early after endoscopic sphincterotomy may reduce this risk
 morphological or functional bile-duct defects, indicated by a dilated CBD, may
lead to bactobilia and biliary stasis, thus promoting primary stone formation
 in a subgroup of patients with recurrent bile-duct stones, an MDR3 gene mu-
tation must be considered, resulting in low-phospholipid-associated cholelithi-
asis. These patients are characterised by early onset of symptoms, recurrence
after cholecystectomy, hyperechogenic foci in the liver, and often a history of
intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid is beneficial in
these patients
 Surgical aspects of bile-duct and gallbladder stones 1113

Research agenda

 the optimal timing or ERCP in patients scheduled for laparoscopic cholecystec-

tomy (before, during, or after the operation) still needs to be defined.
 further data are needed to determine potentially increased incidence of con-
version and postoperative complications for laparoscopic cholecystectomy
after endoscopic sphincterotomy compared to laparoscopic cholecystectomy
for uncomplicated gallstones

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