Hepatology Snapshot:

Gallstone disease: Optimal timing of treatment

Philipp-Robert Scherber1, Frank Lammert2,*, Matthias Glanemann1
1
Department of General, Visceral, Vascular and Paediatric Surgery; 2Department of Medicine II, Saarland University, Saarland University Medical Center, Homburg, Germany
*Corresponding author. Address: Department of Medicine II, Saarland University, Saarland University Medical Center, 66421 Homburg, Germany.

Prevention Treatment algorithm for symptomatic gallstones

UDCA temporary treatment Symptoms

Normal body weight
in weight loss (biliary colic)

ABCB4
risk gene Abdominal ultrasonography
! Prevention of gallstones:
HRP in
Lifestyle
postmenopausal
Start early Laboratory tests
women (WBC, γ-GT, AP, ALT, bilirubin, lipase)

Regular physical activity Food choices Strong evidence Moderate probability No indication of
of bile duct stones of bile duct stones bile duct stone

Endoscopic ultrasound/MR imaging

Symptoms <24 h
if acute
cholangitis Detection of bile duct stones <24 h
Indications for laparoscopic cholecystectomy if acute
cholecystitis
• Symptomatic gallstone disease Preoperative ERC + stone extraction

• Acute cholecystitis (<72 h)

• Asymptomatic gallstone disease with calcification of the gallbladder Early laparoscopic cholecystectomy

• Gallbladder polyps >1 cm or growing in size

• Asymptomatic gallstone disease with gallstone >3 cm
Treatment algorithm for acute cholecystitis
When to treat: Timing is everything!
Symptoms
(pain, peritonitis, muscular defence in the right hypochondrium, fever, Murphy sign)
Timing of endoscopy and surgery for gallstone disease
• Early laparoscopic cholecystectomy for symptomatic gallbladder stones Abdominal ultrasonography
• Early laparoscopic cholecystectomy for acute cholecystitis <24 hours
Laboratory tests
• ERC in acute cholangitis with biliary obstruction by bile duct stone (WBC, CRP, γ-GT, AP, ALT, bilirubin, lipase)

as soon as possible
Strong evidence for No evidence for
• ERC in severe biliary pancreatitis with obstruction <72 hours acute cholecystitis acute cholecystitis
• Early cholecystectomy after ERC for bile duct stones <72 hours <24 h >72 h
• Early cholecystectomy after mild biliary pancreatitis <48-72 hours Early laparoscopic Conservative treatment Search for
cholecystectomy (antibiotics) differential diagnosis
Unsuccessful Successful
Indications for laparoscopic cholecystectomy
Cholecystectomy in unfavourable Laparoscopic cholecystectomy
period (>3 days, <4 weeks after >4 weeks after initial
appearence of symptoms) appearence of symptoms
Symptomatic gallstone disease, acute cholecystitis <72 h

Symptom burden after cholecystectomy in 126 patients (5)

Pain at 12 weeks after surgery, No pain:

but not at long-term follow-up: 39 patients (37.5%)
24 patients (23.1%)

No pain at 12 weeks
after surgery,
but pain at long-term follow-up:
13 patients (12.5%)

Acute cholecystitis >72 h Persistent pain:

28 patients (26.9%)

Postoperative outcome depending on the timing of surgery

Early cholecystectomy

↓ Morbidity
↑ Morbidity
↓ Conversion rate to
open surgery ↑ Conversion rate to
open surgery
↓ Total hospital stay
↑ Total hospital stay
↓ Hospital costs
↑ Hospital costs

Delayed cholecystectomy

Received 07 February 2017; received in revised form 03 April 2017; accepted 07 April 2017 Journal of Hepatology 2017 vol. 67 | 645–647
Hepatology Snapshot
In this unfolding conundrum of life and history there is such a thing as
being too late.
Martin Luther King
Gallstones are common and affect up to 20% of the European popu-
lation. In general, symptomatic gallstones represent an indication for
treatment. The European Association for the Study of the Liver has
published the latest Clinical Practice Guidelines on the prevention,
diagnosis and treatment of gallstones.1 In this Snapshot, we visualize
the current treatment algorithms and discuss the optimal timing of
the recommended interventions. These recommendations are based
on new randomized controlled clinical trials in patients with biliary
symptoms or complications. Although the genetics and pathophysi-
ology of gallstones have been clarified, medical preventive measures
would be too complex and expensive and the treatment algorithms re-
main predominantly invasive and based on surgery.2 Therefore future
studies should focus on preventive strategies to overcome the onset of
gallstones, particularly in at-risk patients, but also in the general pop-
ulation.
Prevention of gallstone disease: Start early
Healthy lifestyle and food, regular physical activity and maintenance of
normal body weight not only prevent cholesterol gallbladder stones but
reduce the risk of symptoms due to gallstones (panel A).1 In contrast,
hormone replacement therapy in postmenopausal women or contra-
ceptives increase the gallstone risk. In specific situations that are associ-
ated with rapid weight loss (e.g. very low calorie diet, bariatric surgery),
temporary ursodeoxycholic acid ([UDCA] ≥500 mg per day until stable
body weight) is an evidence-based prevention for gallstones. Prophy-
lactic cholecystectomy during bariatric surgery is not recommended.1
Patients with mutations of the gene encoding the phosphatidylcholine
translocator ABCB4 have a genetic predisposition for low phospholip-
id-associated cholelithiasis (LPAC). Due to biliary phospholipid defi-
ciency, cholesterol gallstone disease often develops before 40 years of
age, with intrahepatic bile duct and gallbladder stones and recurrent
biliary symptoms after cholecystectomy.1,3 After the diagnosis is made
based on clinical criteria and family history (and confirmed by genetic
testing), most of the ABCB4 deficient patients benefit from prophylactic
or long-term therapy with UDCA (15 mg/kg body weight and day).
Gallbladder stones: Timing is everything
As highlighted in recent “Choosing wisely” campaigns, no treatment
is recommended for patients with asymptomatic gallbladder stones.
Exceptions are patients with porcelain gallbladder, large (≥6-10 mm)
or growing gallbladder polyps, as well as patients with primary
sclerosing cholangitis and a gallbladder mass <10 mm in diameter1,3
(panel B).
In patients who have experienced biliary colic, performing laparo-
scopic cholecystectomy as early as possible is the treatment of choice
(panel B, C and D). There are no medical reasons for delaying surgery
in an anaesthetically fit patient, which exposes the patient to a risk of
gallstone complications. In one trial, early laparoscopic cholecystecto-
my decreases morbidity during the waiting period for surgery (mean
waiting time4 months), hospital stay, and operating time.4
Notwithstanding, the patient-reported surgery success rate after
>5 years of follow-up after cholecystectomy does not exceed 90%, and
about 40% of patients report residual abdominal pain (panel G), high-
lighting the need for realistic medical information prior to cholecystec-
tomy.5 In fact, patients with a better health status with episodic pain
lasting for one year at the most have the highest chance of being free
of pain after cholecystectomy. Nevertheless, cholecystectomy should
not be withheld on the basis on chronological age alone. Of note, elec-
tive cholecystectomy rates in older patients with no comorbidities de-
crease from 34% in the low-risk group to 27% in the high-risk group,
indicating that the risk of recurrent acute biliary symptoms requiring
hospitalization does not guide the decision to perform elective chole-
cystectomy after an initial symptomatic episode.6
Early laparoscopic cholecystectomy should be performed in patients
with acute cholecystitis (panel B and H), which is the most common
complication of gallstone disease.7–9 In the large, randomized German
multicenter trial,7 laparoscopic cholecystectomy within 24 hours of
646 Journal of Hepatology 2017 vol. 67 | 645–647
hospital admission was shown to be superior to the conservative ap-
proach concerning morbidity and costs (panel D, E and F). Early laparo-
scopic cholecystectomy does not increase the rate of serious complica-
tions; in fact, the conversion rate is lower and the duration of hospital
stay is shorter the earlier the operation takes place (panel H) [7-9]. Sus-
pected bile duct injury after cholecystectomy warrants urgent imaging.
Bile duct lesions should be treated endoscopically, unless the common
bile duct has been completely transected.1
Bile duct stones: Therapeutic splitting
Endoscopic retrograde cholangiography (ERC) with sphincteroto-
my and stone extraction is the recommended treatment of bile duct
stones (panel E). In patients with simultaneous gallbladder and bile
duct stones, early laparoscopic cholecystectomy should be performed
within 72 hours after pre-operative ERC for choledocholithiasis (panel
C and E). In a randomized trial to evaluate timing of surgery after endo-
scopic sphincterotomy, laparoscopic cholecystectomy within 72 hours
after ERC leads to significantly less recurrent biliary events compared
to delayed laparoscopic cholecystectomy after six to eight weeks; there
are no differences in conversion rate, operation time, or surgical com-
plications.10
In acute cholangitis, the timing of biliary decompression depends on
severity of the cholangitis and the effects of medical therapy including
antibiotics, and should ideally be performed within 24 hours; urgent
decompression should be considered in cases of severe cholangitis not
responding to fluid resuscitation and intravenous antibiotics panel E.1,2
Antibiotic treatment should be started immediately in acute cholan-
gitis and acute cholecystitis with bacteraemia/sepsis, abscess, or per-
foration. Initial therapy should cover Enterobacteriaceae, in particular
Escherichia coli,2 and often consists of a third-generation cephalo-
sporine, e.g. ceftriaxone, or a fluorchinolone e.g. ciprofloxacine, in com-
bination with metronidazole.
For biliary pancreatitis, urgent ERC (within 24 hours at the latest) is
indicated in cases of acute cholangitis and is potentially indicated in
cases of persistent bile duct obstruction.1,2 In the absence of cholangitis
or obstruction, mild biliary pancreatitis should not be treated by ERC,
and severe biliary pancreatitits (defined as pancreatitis with system-
ic inflammatory response syndrome (SIRS) at admission and after 48
hours) probably should not be either. In patients with suspected biliary
pancreatitis without cholangitis, endoscopic ultrasound or magnetic
resonance cholangiopancreatography prevents ERC and its potential
risks, if no stones are detected.
In patients with mild biliary pancreatitis, same-admission cholecys-
tectomy reduces the rate of recurrent gallstone-related complications
significantly from 17% to 5%11 (panel C). In contrast, cholecystectomy
should be delayed in patients with severe biliary pancreatitis until per-
ipancreatic collections are dissolved or in case of persistent collections,
until at least six weeks after the onset of pancreatitis.12
© 2017 European Association for the Study of the Liver. Published by
Elsevier B.V. All rights reserved.
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