1. No category

ANTTI SIIKI
Acta Universitatis Tamperensis 2079
Endoscopic Management of Benign Biliary Strictures
ANTTI SIIKI
Endoscopic Management
of Benign Biliary Strictures
AUT 2079
ANTTI SIIKI
Endoscopic Management
of Benign Biliary Strictures
ACADEMIC DISSERTATION
To be presented, with the permission of
the Board of the School of Medicine of the University of Tampere,
for public discussion in the Small Auditorium of Building M,
Pirkanmaa Hospital District, Teiskontie 35,
Tampere, on August 28th, 2015, at 12 o’clock.
UNIVERSITY OF TAMPERE
ANTTI SIIKI
Endoscopic Management
of Benign Biliary Strictures
Acta Universitatis Tamperensis 2079
Tampere University Press
Tampere 2015
ACADEMIC DISSERTATION
University of Tampere, School of Medicine
Tampere University Hospital, Department of Gastroenterology and Alimentary Tract Surgery
Finland
Supervised by Reviewed by
Docent Johanna Laukkarinen
Docent Jorma Halttunen
University of Tampere
University of Helsinki
FinlandFinland
Docent Juhani Sand
Docent Sari Venesmaa
University of Tampere
University of Eastern Finland
FinlandFinland
The originality of this thesis has been checked using the Turnitin OriginalityCheck service
in accordance with the quality management system of the University of Tampere.
Copyright ©2015 Tampere University Press and the author
Cover design by
Mikko Reinikka
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Acta Universitatis Tamperensis 2079
ISBN 978-951-44-9869-5 (print)
ISSN-L 1455-1616
ISSN 1455-1616
Acta Electronica Universitatis Tamperensis 1573
ISBN 978-951-44-9870-1 (pdf )
ISSN 1456-954X
http://tampub.uta.fi
Suomen Yliopistopaino Oy – Juvenes Print
Tampere 2015
CONTENTS
Abstract ....................................................................................................................................... 7
Tiivistelmä .................................................................................................................................. 9
List of original communications ......................................................................................... 11
Abbreviations .......................................................................................................................... 12
1
Introduction ................................................................................................................. 15
2
Review of the literature ............................................................................................
2.1 Biliary anatomy ..............................................................................................
2.2 Benign biliary strictures ...............................................................................
2.2.1 Pathophysiology .................................................................................
2.2.2 Incidence ..............................................................................................
2.2.3 Classification ......................................................................................
2.3 Radiologic imaging of biliary strictures ....................................................
2.3.1 Magnetic resonance imaging ...........................................................
2.3.2 Other imaging modalities ................................................................
2.4 Endoscopic retrograde cholangio-pancreatography (ERCP) ................
2.4.1 Cannulation and cholangiography ................................................
2.4.2 Endoscopic cholangioscopy .............................................................
2.5 Complications of ERCP ...............................................................................
2.5.1 Incidence ..............................................................................................
2.5.2 Mortality .............................................................................................
2.5.3 Risk factors ..........................................................................................
2.6 Obtaining and analysing samples from biliary strictures ......................
2.6.1 Brush samples and cytologic analysis .............................................
2.6.2 Flow cytometry, digital image analysis and FISH ......................
2.6.3 Cholangiography and endoscopy guided biopsies .....................
2.6.4 Visually guided biopsies ...................................................................
2.7 Serum diagnostics ..........................................................................................
2.8 Non-endoscopic treatment of benign biliary strictures .........................
2.8.1 Percutaneous management ..............................................................
2.8.2 The role of surgery .............................................................................
18
18
18
18
22
26
27
28
29
30
30
31
32
34
36
36
39
39
40
40
41
42
43
43
44
2.9
Endoscopic treatment and outcome of biliary strictures by aetiology . 45
2.9.1 Post-cholecystectomy ........................................................................ 45
2.9.2 Post-liver transplantation ................................................................ 47
2.9.3 Chronic pancreatitis .......................................................................... 49
2.9.4 Primary sclerosing cholangitis ........................................................ 51
2.9.5 Autoimmune cholangitis ................................................................ 53
2.9.6 Other causes of BBS .......................................................................... 54
2.10 Treatment with endoscopic stents .............................................................. 54
2.10.1Plastic stents ........................................................................................ 55
2.10.2Covered self-expandable stents ....................................................... 56
2.10.3Biodegradable stents .......................................................................... 59
3
Aims of the study ....................................................................................................... 62
4
Materials and methods .............................................................................................
4.1 Study I: ERCP success rates and complications in a Finnish
central hospital ..............................................................................................
4.2 Study II: Initial experience of SpyGlass cholangioscopy in biliary
strictures secondary to sclerosing cholangitis ..........................................
4.3 Study III: Meta-analysis comparing covered self-expanding metal
stents and multiple plasic stents in benign biliary strictures ................
4.4 Study IV: Protein expression in benign biliary strictures before
and after treatment with metal and biodegradable biliary stents ........
4.5 Study V: Biodegradable biliary stent in the endoscopic treatment
of cystic duct leak after cholecystectomy. ..................................................
63
63
63
64
67
69
5
Statistics ....................................................................................................................... 72
6
Ethical aspects ............................................................................................................ 73
7
Results ..........................................................................................................................
7.1 Study I: ERCP success rates and complications in a Finnish
central hospital ...............................................................................................
7.2 Study II: Initial experience of SpyGlass cholangioscopy in biliary
strictures secondary to sclerosing cholangitis ..........................................
7.3 Study III: Meta-analysis comparing covered self-expanding metal
stents and multiple plasic stents in benign biliary stricture ..................
7.4 Study IV: Protein expression in benign biliary strictures before
and after treatment with metal and biodegradable biliary stents ........
7.5 Study V: Biodegradable biliary stent in the endoscopic treatment
of cystic duct leak after cholecystectomy ..................................................
74
74
77
79
81
83
8
Discussion .................................................................................................................... 84
9
Summary and conclusions ....................................................................................... 89
10
Future perspectives .................................................................................................... 90
Acknowledgements ............................................................................................................... 92
References ................................................................................................................................ 94
Original communications .................................................................................................. 109
ABSTRACT
Benign biliary strictures (BBS) develop most commonly secondary to previous surgery
or chronic pancreatitis (CP). The molecular level pathogenesis of BBS as well as the
response to biliary stents is poorly understood. The role of endoscopy (endoscopic
retrograde cholangio-pancreatography, ERCP) in the management of BBS is crucial
not only in terms of diagnostic tissue sampling, but also as the first line of treatment.
This thesis summarises the clinically most relevant aspects of the current endoscopic
diagnostic and treatment methods of BBS in adults.
For the first time, the outcome of ERCP procedures in a Finnish central hospital was
investigated. The study showed that acceptable success rate and complication frequency
can be achieved even in a low-volume unit, when the procedures are all assigned to a
few endoscopists, and the indication and treatment are carefully considered for each
patient. In relatively infrequent BBS, the proper assessment of the risks and benefits of
the endoscopic interventions is especially important.
In the evaluation of indeterminate biliary strictures, single-operator cholangioscopy
(SOC) has proven helpful by facilitating biopsies under direct visual control. However,
its role has been unclear in primary sclerosing cholangitis (PSC), which is a progressive
stenosing autoimmune biliary disease carrying a risk for cholangiocarcinoma with
challenging diagnostics. We investigated the feasibility and safety of Spyglass
cholangioscopy (Boston Scientific, MA, USA) in PSC patients and obtained
encouraging results on this novel reported experience in Finland.
Although covered self-expandable metal stents (CSEMS) are widely used in
extrahepatic BBS with good clinical experience, no long-term results supporting their
use have been available until recently. Therefore we performed a systematic review with
a meta-analysis comparing these methods in various aetiologies of BBS. We found that
CSEMS may be superior to multiple plastic stents in the treatment of BBS related to
CP.
Biodegradable biliary stents (BDBS) could potentially overcome the drawbacks
associated with plastic and metal stents, rendering numerous endoscopy sessions for
stent removal or exchange unnecessary. We first evaluated the expression of healingrelated proteins in an experimental BBS and found that the changes in the protein
pattern occurring during stricture formation seem to return closer to the level of an
intact bile duct after treatment with BDBS than with CSEMS. With these promising
results, we undertook a study on the clinical use of endoscopically inserted BDBS, for
which a device for endoscopic insertion has not previously been available. An excellent
clinical outcome was achieved with the first endoscopic insertion of BDBS that was
initially tested in the setting of post-operative bile leak and is reported herein.
From these abovementioned studies we conclude that 1) ERCP performance and
complication rate is at an acceptable level in a Finnish central hospital, 2) peroral
cholangioscopy may contribute to the diagnostics of PSC, 3) CSEMS use is well
justified in BBS secondary to CP, 4) protein expression pattern of BBS reflecting
the stricture development is different after BDBS and CSEMS therapy and 5) in the
future the drawbacks of conventional endoscopic stent therapy may be circumvented
by BDBS. The endoscopic diagnostics and therapy of BBS are continuously developing,
warranting critical examination of the novel methods in terms of effectiviness and
patient safety.
TIIVISTELMÄ
Hyvänlaatuisten sappitieahtaumien yleisimmät syyt ovat leikkauksen jälkitila ja
pitkäaikainen haimatulehdus. Suun kautta tähystimellä tehtävä endoskopia (endoskooppinen retrogradinen kolangio-pankreatografia, ERCP) on nykyään ensisijainen
tutkimus- ja hoitomenetelmä. Se mahdollistaa diagnostiikan näytteenotolla ahtaumasta ja hoitotoimenpiteet muovisten- tai itsestään laajenevien metalliverkkostenttien
(CSEMS) avulla. Väitöskirja vetää yhteen hyvänlaatuisten sappitiehtaumien nykyaikaisen diagnostiikan ja hoidon.
Tämän väitöskirjan ensimmäinen osatyö kuvasi ERCP-aineiston suomalaisessa keskussairaalassa. Sen tulosten perusteella pienessäkin yksikössä voidaan päästään kansainvälisestikin hyväksyttäviin onnistumis- ja komplikaatiolukuihin, kunhan ERCP
toiminta keskitetään pienelle määrälle osaavia endoskopisteja. Vastaavaa komplikaatiolukuja selvittävää työtä suomalaisesta keskussairaalasta ei ole aiemmin julkaistu.
Toisessa osatyössä selvitettiin uuden ERCP:n yhteydessä tehtävän sappitietähystyksen eli kolangioskopian (SOC) käyttöä sklerosoivaan kolangiittiin (PSC) liittyvissä ahtaumissa, joissa syövän esiastetasoisten muutosten varhaisella diagnostiikalla on
suuri vaikutus ennusteeseen. Epäselvien sappitieahtaumien diagnostiikan on aiemmin todettu tarkentuvan SpyGlass –kolangioskopian (Boston Scientific, MA, USA)
avulla, koska läpivalaisulla otettujen solunäytteiden lisäksi saadaan videokuvan avulla
kohdennettuja koepaloja. Tutkimuksessa todettiin, että kolangioskopiassa otettavat
näytteet saattavat tuoda lisäinformaatiota PSC-diagnostiikkaan. Tämän pienen potilasmateriaalin perusteella Spyglass -kolangioskopia ja kohdennettut koepalat vaikuttaa
olevan turvallinen menetelmä PSC:ssa yhdistettynä jo käytössä oleviin kuvantamiseen,
sappitien harjairtosolunäytteisiin, virtaussytometriaan ja verikokeisiin.
Kolmannessa osatyössä verrattiin muovi- ja metallistenttien paremmuutta sappitieahtaumissa kirjallisuuskatsauksen ja meta-analyysin avulla. Metallistenttejä käytetään
potilaille hyvänlaatuisissa ahtaumissa, vaikka vertailevia tutkimuksia perinteisesti käytettyihin muovistentteihin on julkaistu vasta hiljattain. Tuloksemme puoltavat metallistenttien käyttöä pitkäaikaiseen haimatulehdukseen liittyvissä sappitieahtaumissa,
joissa niillä saadaan muovistentteihin verrattuna turvallisesti parempia onnistumislukuja vähemmällä endoskopioiden määrällä.
Endoscopic Management of Benign Biliary Strictures
9
Uusilla biohajovilla sappitiestenteillä voitaisiin välttää perinteisiin stentteihin liittyvät toistuvat endoskopiat stenttien vaihtamiseksi ja poistamiseksi. Sappitieahtaumien kehittymisen ja biohajoavien stenttien aiheuttaman kudosvasteen tutkimiseksi
neljännessä osatyössä koeläimille aiheutettiin sappitieahtauma, jota hoidetttiin joko
metallistentillä tai biohajoavalla stentillä. Proteiinien, kuten galectin-2 ja annexin-A4
esiintyminen muuttui selvästi ahtaumassa verrattuna koskemattomaan sappitiehen.
Toisaalta biohajoavat stentit vaikuttivat palauttavan proteiinien esiintymistasot lähemmäs normaalia sappitietä ja ne saattaisivat siten olla parempi hoitomuoto hyvänlaatuisissa sappitieahtaumissa. Viidennessä osatyössä raportoitiin ensimmäinen potilastapaus, jossa asennettiin endoskooppisesti biohajova sappitiestentti sappirakon poiston
jälkeisen sappivuodon hoidossa. Yhdessä aiempien tutkimusten kanssa tuloksemme
uuden instrumentin käytettävyydestä ja potilasturvallisuudesta puoltavat jatkotutkimuksia biohajoavilla stenteillä hyvänlaatuisissa sappitieahtaumissa.
Väitöskirjan yhteenvetona todetaan, että 1) ERCP toimenpiteet aiheet ja komplikaatioluvut ovat asianmukaisella tasolla suomalaisessa keskussairaalassa, 2) endoskooppinen kolangioskopia on käyttökelpoinen, täydentävä menetelmä myös sklerosoivassa kolangiitissa, 3) pitkäaikaiseen haimatulehdukseen liittyviä ahtaumia kannattaa
hoitaa päällystetyillä metallistenteillä, 4) proteiinien ilmeneminen muuttuu sappitieahtauman muodostuessa ja kudosreaktio voi jopa olla suotuisampi biohajoavilla kuin
metallistenteillä sekä 5) ensimmäiset käytännön kokemukset biohajovien stenttien
käytöstä ihmisen sappitiessä ovat lupaavia ja ne saattavat olla endoskooppisen ahtaumanhoidon tulevaisuutta. Diagnostiikan tarkentumisella ja turvallisimman menetelmän valinnalla on olennainen merkitys potilaiden hoidossa.
10
Antti Siiki
LIST OF ORIGINAL COMMUNICATIONS
1. ERCP procedures in a Finnish community hospital: a retrospective analysis of
1207 cases. A Siiki, A Tamminen, T Tomminen, P Kuusanmäki. Scand J Surg
2012;101:45–50.
2. Spyglass single operator peroral cholangioscopy seems promising in the evaluation of primary sclerosing cholangitis related biliary strictures: a case series and
initial experience of a tertiary referral center. A Siiki, I Rinta-Kiikka, T Koivisto,
K Vasama, J Sand, J Laukkarinen. Scand J Gastroenterol 2014;49:1385–90
3. Covered self-expanding metal stents may be preferable to plastic stents in the
treatment of chronic pancreatitis related biliary strictures; a systematic review
comparing two methods of stent therapy in benign biliary strictures. A Siiki, M
Helminen, J Sand, J Laukkarinen. J Clin Gastroenterol. 2014;48:635–43.
4. Protein expression in benign biliary strictures before and after treatment with
metal and biodegradable biliary stents. A Siiki, R Jesenofsky, M Löhr, I Nordback, M Kellomäki, J Mikkonen, H Gröhn, J Sand, J Laukkarinen. Submitted.
5. Biodegradable biliary stent in the endoscopic treatment of cystic duct leak after
cholecystectomy: the first case report and review of literature. A Siiki, I Rinta-Kiikka, J Sand, J Laukkarinen. Laparoendosc Adv Surg Tech. 2015; 25(5):
419–22.
Endoscopic Management of Benign Biliary Strictures
11
ABBREVIATIONS
ASA
American Society of Anesthesiologists
IAC
immunoglogulin associated cholangitis
IAH
immunoglobulin associated hepatitis
IAP
immunoglobulin associated pancreatitis
BBS
benign biliary stricture
BDBS
biodegradable biliary stent
CA19-9
carbohydrate antigen 19-9
CBD
common bile duct (ductus choledochus)
CCAcholangiocarcinoma
CCYcholecystectomy
CEA
carcino-embryonal antigen
CHD
common hepatic duct (ductus hepaticus communis)
CP
chronic pancreatitis
CRP
C-reactive protein
CSEMS
covered self-expanding metal stent
CT
computed tomography
DIA
digital image analysis
ERC
endoscopic retrograde cholangiography
ERCP
endoscopic retrograde cholangio-pancreatography
EST
endoscopic sphincterotomy
EUS
endoscopic ultrasound
FCSEMS
fully covered self-expanding metal stent
PET
positron emission tomography
FISHFluorescence in situ hybridisation
FNA
fine needle aspirate
HJ
hepatico-jejunostomy anastomosis, e.g. roux-en-y
i.v.intravenously
IgG4immunoglobulin-4
KHKS
Kanta-Häme Central Hospital, Hämeenlinna, Finland
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Antti Siiki
LC
laparoscopic cholecystectomy
LFT
liver function tests (enzymes)
LT orthotopic liver transplantation
m-Amsterdam
modified Amsterdam classification of PSC
mPS
multiple plastic stents (polyethylene)
MRI
magnetic resonance imaging
MRCP
magnetic resonance cholangiopancreatography
PLApolylactide
PCSEMS
partially covered self-expandable metal stent
PD
pancreatic duct
PDXpolydioxanone
PEP
post-ERCP pancreatitis
PS
plastic stent (polyethylene)
PSC
primary sclerosing cholangitis
PSHP
Pirkanmaa Hospital District, Tampere, Finland
PTD
percutaneous transhepatic cholangiography and drainage
RCT
randomised controlled trial
SEMS
self-expanding metal stent
SOC
single-operator peroral cholangioscopy
SOD
dysfunction of sphincter of Oddi
UCSEMS
uncovered self-expanding metal stent
WBC
white blood cell count
Endoscopic Management of Benign Biliary Strictures
13
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Antti Siiki
1INTRODUCTION
Benign biliary strictures (BBS) are a rare entity of biliary diseases having diverse
aetiologies and natural courses requiring different management strategies, most of
which include endoscopic retrograde cholangio-pancreatography (ERCP) (Figure 1AB). Any biliary stricture eventually leading to biliary obstruction requires primarily
endoscopic interventions both to diagnose the type of stricture and to prevent secondary
biliary cirrhosis. At the time when biliary obstruction is observed, typically due to
elevated liver function tests (LFT) or acute cholangitis, the aetiology of the stricture
is often anything but clear. Strictures which are initially indeterminate turn out to be
malignant far more frequently than benign (Enochsson et al 2010). Management of
biliary strictures typically requires co-ordinated multi-disciplinary management by
surgeons, endoscopists, gastroenterologists, radiologists as well as pathologists (Baron
and Davee 2013; Chan and Telford 2012; Shimada et al. 2012).
The incidence of BBS in Finland is not known. In the literature, BBS is the indication
for ERCP in 3–7% of cases (Testoni et al. 2010; Wang et al. 2009). However, endoscopic
BBS management necessitates more than one procedure and frequencies vary between
centres (Baron and Davee 2013; Enochsson et al. 2010). The most common aetiologies
of BBS are post-operative strictures as well as chronic pancreatitis (CP) and primary
sclerosing cholangitis (PSC); less frequent causes may include autoimmune disorders,
chemotherapy, stone disease and infections (Chan and Telford 2012).
The risk for complications associated with ERCP makes it crucial to always weigh
up the indications of the procedure against the diagnostic and therapeutic benefit. The
incidence of post-ERCP pancreatitis (PEP) is 2–5% with an overall complication rate of
5–15% (Andriulli et al. 2007; Enochsson et al. 2010). While CP patients are not prone
to acute PEP, in PSC the risk is doubled to up to 7–8% (Cotton et al. 2009; Ismail et
al. 2012; von Seth et al. 2015). Research is required to assess the benefits and risks for
informing the patients, quality control and for the evaluation of the effectiviness and
safety of any novel methods (Baron and Davee 2013; Lorenzo-Zuniga et al. 2014; Rey
et al. 2014). In addition to highly specialised tertiary centres in Finland, ERCPs are also
performed in the low-volume non-academic central hospitals, whose ERCP practice has
not so far been described.
Endoscopic Management of Benign Biliary Strictures
15
Figure 1A. A flexible duodenoscope
(left) used in ERCP (endoscopic
retrograde cholangio-pancreatography)
with the Spyglass single-operator
peroral cholangioscopy device (Boston
Scientific, MA, USA) attached (right).
Figure 1B. A drawing of a duodenoscope
introduced in the descending part of the
duodenum. The duodenal papilla and
the bile duct are cannulated with a guide
wire in the right hepatic duct. For clarity,
the most of the stomach is removed
to reveal common bile duct (CBD)
and illustrate the pancreas and the
pancreatic duct (PD). The human biliary
tract converges from the intrahepatic
biliary ducts into a common hepatic duct
(CHD) and after joining with the cystic
duct, into the common bile duct (CBD),
draining downstream via the duodenal
papilla into the duodenum.
The primary aim in the diagnostics of indeterminate strictures is to exclude malignancy.
In addition to radiologic imaging, cytology samples are often needed to confirm a
diagnosis of BBS. This is especially challenging in PSC, where disease progression often
leads to ERCP in order to find dysplasia before the development of cholangiocarcinoma
(CCA) (de Valle et al 2012). Endoscopic brush cytology, flow cytometry, cholangiography
image and serum markers are used in combination to estimate the risk of CCA or to
plan the timing of liver transplantation (LT) (Halme et al. 2012; Lindberg et al. 2002).
The current methods are far from perfect and a promising new diagnostic method could
be single-operator peroral cholangioscopy (SOC) with visually guided biopsies, which
16
Antti Siiki
has been proven beneficial in indeterminate biliary strictures (Draganov et al. 2011;
Kalaitzakis et al. 2012; Ramchandani et al. 2011; Rey et al. 2014; Woo et al. 2014). In
PSC, data on SOC use is scarce, but it seems that visual image and guided biopsies may
be helpful in diagnostics and in detecting changes in PSC related strictures (Awadallah
et al. 2006; Tischendorf et al. 2007; Arnelo 2015). The molecular background of
stricture pathophysiology, the natural course and response to stent therapy in BBS are
little investigated issues that may offer answers for choosing the right type of stent, for
the development of new diagnostic or prognostic markers of BBS or for finding target
molecules for future drug-eluding biodegradable biliary stents (BDBS) (LorenzoZuniga et al. 2014; Tokar et al. 2011).
Endoscopic treatment of BBS has evolved from dilation and plastic stents (PS)
to the use of covered self-expanding metal stents (CSEMS) (Baron and Davee 2013;
Deviere et al. 2014; Kaffes and Liu 2013; Perri et al. 2011; Van Boeckel et al. 2009).
Strictures with various aetiologies, e.g. secondary to PSC, LT or CP require different
treatment strategies (Baron and Davee 2013; Dumonceau et al. 2011; Kaffes and Liu
2013). While intrahepatic strictures often require balloon dilation followed by PS
insertion, extrahepatic strictures may also be treated with CSEMSs (Baron and Davee
2013; Perri et al. 2011). The post-operative strictures at the biliary confluence especially
are treated with single or preferably with increasing numbers of multiple plastic stents
(mPS) with good results (Costamagna and Boškoski 2013). In short, while treatment
with the inexpensive PS is technically challenging associated with numerous stent
exchanges and stent clogging as a major disadvantage, CSEMSs are currently ten times
costlier, need removal and are best suitable for strictures below the biliary confluence
(Dumonceau et al. 2011). However, despite a large number of cohort studies, controlled
trials comparing mPSs and CSEMSs have been presented only recently of strictures
secondary to liver transplantation and chronic panreatitis (Haapamaki et al. 2015;
Kaffes et al. 2014). The most recent promising alternative to CSEMSs are BDBSs,
which do not necessitate removal, but of which no clinical experience in endoscopic use
has so far been reported (Lorenzo-Zuniga et al. 2014).
This thesis summarises the clinically most relevant aspects of the current endoscopic
diagnostic and treatment methods of BBS in adults. The aim was (1) to assess the
complication and success rates of ERCPs in a Finnish central hospital, (2) to study the
usefulness of SOC in PSC diagnostics, (3) to determine an optimal stent therapy for
the treatment of BBS, (4) to investigate the protein expression in a surgically induced
biliary stricture and in response to CSEMS and BDBS and (5) to report the feasibility
and safety of a novel endoscopically inserted BDBS.
Endoscopic Management of Benign Biliary Strictures
17
2 REVIEW OF THE LITERATURE
2.1 Biliary anatomy
The human biliary duct consists of an extrahepatic part and an intrahepatic part, which
are lined with biliary epithelial cholangiocytes (Tietz and Larusso 2002). Intrahepatic
biliary tree converges through the right and left main hepatic ducts through the hepatic
confluence into the common hepatic duct (CHD). Further downstream the cystic duct
from the gallbladder joins the CHD and continues as a common bile duct (CBD) to
drain through the duodenal papilla (papilla Vateri) into the duodenum. In most cases,
except in pancreas divisum, the pancreatic duct drains into the duodenum through
the papilla (Figure 1B). This tiny structure functions as a natural access route to the
biliary duct and to the pancreatic duct (PD) and plays a crucial role in the success
rate and complications of ERCP (Halttunen et al. 2014). The boundary between the
intra- and extrahepatic biliary ducts in the proximal part of the CHD below the biliary
confluence is also clinically important because it determines the methods that may be
used in surgical or endoscopic treatment (Costamagna and Boškoski 2013; Strasberg
and Helton 2011).
2.2 Benign biliary strictures
2.2.1Pathophysiology
The pathophysiologic changes occurring in the biliary epithelium in BBS are
imperfectly understood in the majority of aetiologies (Tietz and Larusso 2002). There
are few studies on the molecular and protein level development of strictures and also
on their response to treatment methods. The most common aetiologies for BBS include
post-operative strictures and strictures associated with chronic pancreatitis (CP) or
autoimmune diseases.
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Antti Siiki
Post-operative strictures
Post-operative strictures may appear either immediately after cholecystectomy (CCY)
if a surgical clip or a suture is accidentally placed to compress the bile duct or up to years
later by ischaemic injury and fibrosis (Strasberg and Helton 2011). In post-operative
injury the underlying mechanism is typically a compromise in arterial supply e.g. after
CCY, CBD exploration or anastomotic strictures after orthotopic liver transplantation
(LT) (Akamatsu et al. 2011; Gunji et al. 2006; Strasberg and Helton 2011). While
the liver parenchyma and the intrahepatic part of the biliary tree are supplied by the
circulation of the portal vein and hepatic artery, the vascular supply of CHD and CBD
is only arterial and mostly axial, running on both sides of the duct. About 60% of
arterial perfusion of CBD comes from the gastroduodenal artery and only 30–40%
downwards from the hepatic artery, making the preservation of circulation crucial
in surgery (Gunji et al. 2006). On the other hand, cholangiocytes are vulnerable to
ischaemia, resulting in ischaemic cholangiopathy and eventual stricture formation
(Noack et al. 1993).
Strictures secondary to liver transplantation
The most common type of liver transplantation is the orthotopic deceased donor
transplantation with duct-to-duct anastomosis (LT) (Aberg et al. 2011). The post-LT
strictures are divided to two distinct categories with different aetiology and outcome;
anastomotic and non-anastomotic strictures, the latter of which has shown a far less
favourable response to treatment (Williams and Draganov 2009). Less used options
are living donor transplantation and reconstruction with roux-en-Y hepatico-jejunal
anastomosis (HJ), with which anastomotic strictures are associated more commonly
than with LT with duct-to-duct anastomosis (Aberg, Isoniemi and Hockerstedt 2011;
Akamatsu et al. 2011; Damrah et al. 2012; Tarantino et al. 2012a; Williams and
Draganov 2009).
An anastomotic biliary stricture developing typically during the first year after LT is
the most common complication (Akamatsu et al. 2011; Graziadei et al. 2006; Verdonk
et al. 2006). Anastomotic strictures account for up to 80% of post-LT strictures and are
typically short and located in the middle portion of the CBD (Baron and Davee 2013;
Williams and Draganov 2009). A post-operative biliary leak is a risk factor for later
anastomotic stricture, likewise small duct size (Akamatsu et al. 2011). Early anastomotic
strictures resulting from oedema and inflammation respond best to endoscopic therapy
within the first few months (Pasha et al. 2007; Verdonk et al. 2006). Late onset
Endoscopic Management of Benign Biliary Strictures
19
anastomotic strictures presenting later than six months after LT result from fibrosis
and scarring necessitate prolonged therapy (Pasha et al. 2007; Verdonk et al. 2006).
The risk factors for non-anastomotic strictures are devascularisation, prolonged
ischaemia time, hepatic artery thrombosis, immunologic incompatibility, chronic and
acute rejection episodes as well as advanced recipient age and profoundly impaired liver
function (Akamatsu et al. 2011). Especially in PSC, disease recurrence may be the cause
of a non-anastomotic stricture (Chan and Telford 2012). Non-anastomotic strictures
typically occur earlier than anastomotic strictures, and may be diffusely located in
the hilum, occasionally progressing to multiple sites intrahepatically but they may be
concomitant to anastomotic strictures or be located in the CHD (Chan and Telford
2012; Verdonk et al. 2007). The multi-focality of strictures, associated sludge and
recurrence of the underlying liver disorder are the reasons for the poor prognosis (Chan
and Telford 2012).
Chronic pancreatitis
BBS may also result from external compression of the CBD as in CP, where fibrosis
and calcifications in the head of pancreas compress the intrapancreatic biliary duct
(Figure 1B). A tumour-like process associated with CP in the head of the pancreas may
sometimes be indistinguishable from pancreatic cancer (Abdallah et al. 2007). Due
to the increased risk of pancreatic cancer in CP related CBD strictures, an adequate
radiologic diagnostic work-up and adeaquate sampling during ERCP should be
performed before biliary stenting. This is particularly important in patients belonging
to the high-risk groups: age over 50 years, female gender, presenting with jaundice,
pancreatic exocrine insufficiency or hereditary pancreatic cancer or present without
pancreatic calcifications (Dumonceau et al. 2012).
Primary sclerosing cholangitis
PSC is an autoimmune-mediated chronic, cholestatic progressive liver disease of
unknown aetiology characterised by inflammation and fibrosis affecting both intraand extrahepatic bile ducts with LT as the only curative treatment (Chapman et al.
2010; Eaton et al. 2013). The inflammation of the biliary epithelium causes gradual
fibrotic and multi-focal stenosis, which is macroscopically hard to differentiate from
malignancy (Awadallah et al. 2006; Chapman et al. 2010; Tischendorf et al. 2006).
Small-duct PSC is a better prognosis variant occurring in 9% of all PSC patients
and characterised by cholestatic and histologic features of PSC without the typical
20
Antti Siiki
cholangioraphy findings (Boonstra et al. 2013; Ehlken and Schramm 2013). About
4% of PSC patients have an overlap syndrome: diagnostic features from both PSC and
immunoglobulin-4 (IgG4) associated autoimmune hepatitis (IAH) (Boonstra et al.
2013; Chapman et al. 2010; Eaton et al. 2013).
Immunoglogulin associated strictures
The pathogenesis of the autoimmune mediated and IgG4 related diseases such as IgG4
associated cholangitis (IAC) is unknown (Okazaki et al. 2014). The patients commonly
have concomitant autoimmune pancreatitis (IgG4 -associated pancreatitis, IAP), which
is another poorly understood IgG4-related systemic disorder frequently characterised
by obstructive jaundice in intrapancreatic CBD with or without pancreatic mass
(Okazaki et al. 2014). A biliary obstruction is caused by either direct involvement of
the biliary duct epithelium or by external compression in IAP (Okazaki et al. 2014).
The response to steroid treatment is a strong indicator of correct diagnosis; when the
stricture does not resolve and the stent cannot be removed, and when LFT, serum
IgG4 and CA19-9 do not decrease, the presence of malignancy should be reconsidered
(Boonstra et al. 2014). Both IAC and IAP are easily confused with PSC or cancer and
differential diagnosis may not be possible (Chan and Telford 2012).
Other causes
Less frequent causes of BBS (Table 1) include e.g. strictures secondary to transarterial
chemoembolization and radiofrequency ablation, commonly used percutaneously
in hepatocellular carcinoma (Baron and Davee 2013). A gallstone impacted in the
gallbladder neck or in the cystic duct (Mirizzi syndrome) may induce an inflammatory
stricture in the CHD sometimes associated with a biliary fistula (Chan and Telford
2012). Similarly, long-standing stones in the biliary duct may occasionally cause a
Endoscopic Management of Benign Biliary Strictures
21
stricture in the CBD due to scarring; however, a malignant stricture may promote stone
formation upstream (Chan and Telford 2012).
Table 1. Aetiology of benign biliary strictures
Iatrogenic
Cholecystectomy
Orthotopic liver transplant
Biliary-enteric anastomosis, e.g. hepaticojejunostomy
ERCP
Percutaneous transarterial chemoembolization and
radiofrequency ablation for hepatocellular carcinoma
Percutaneous ethanol injection
Endoscopic sclerotherapy of duodenal ulcer
Radiation therapy
Chemotherapy
Ischaemic
Hypotension
Hepatic artery thrombosis or stenosis
Prolonged transplant organ ischemia
Portal biliopathy
Infectious
Recurrent pyogenic cholangitis (oriental cholangiohepatitis)
Parasitosis
Granulomatous: tuberculosis, histoplasmosis
Human immunodeficiency virus
Inflammatory
Mirizzi syndrome
Choledocholithiasis
Chronic pancreatitis
Primary sclerosing cholangitis
Immunoglobulin IgG4 associated cholangiopathy
Vasculitis
Other
Abdominal trauma
Strictures in surgically altered anatomy
The biliary strictures in surgically altered anatomy, e.g. in biliary-enteric roux-en-Y
HJ anastomosis require special instrumentation and require a learning curve that is
different from that of ERCP (Baron and Davee 2013). Balloon-assisted endoscopes
allow access to the anastomosis with consequent cholangiography and interventions;
success rates of up to 75–90% have been reported in balloon dilation or stent insertion
via single-balloon or double-balloon endoscopes in surgically altered anatomy (Itokawa
et al. 2014; Saleem et al. 2010).
2.2.2Incidence
The most common and clinically most relevant causes of BBS are surgical injuries,
particularly after open or laparoscopic cholecystectomy (LC), followed by CP related
strictures (Baron and Davee 2013). The various aetiologies of BBS are presented in
Table 1 as described in the literature (Baron and Davee 2013; Chan and Telford 2012;
Costamagna and Boškoski 2013). Estimates of the incidence of BBS may be based on
the numbers of ERCPs performed for BBS and the incidence of the most common
aetiologies.
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Antti Siiki
According to an Italian multicentre study, BBS was an indication in 3.5% (Testoni
et al. 2010) while in a Chinese tertiary centre in 7.1% of ERCPs (Wang et al. 2009).
In a Swedish national register study, the most common finding in ERCPs was CBD
stone in 37% followed by biliary stricture in 30% of ERCPs, the aetiology of which
was perioperatively considered malignant, benign and unclear in 47%, 15% and 38%
of cases respectively (Enochsson et al. 2010). While 4000–4500 ERCPs are yearly
performed in Finland (THL 2012), an estimate of the number of ERCPs for BBS may
thus be 200–300 per year.
A bile duct injury occurs in about 0.5–1.5% of patients after CCY (Barbier et
al. 2014; Tornqvist et al. 2012; Vitale et al. 2008). The majority of these injuries are
recognised early post-operatively and consist mostly of bile leaks, isolated strictures
being rare (Karvonen et al. 2011; Tornqvist et al. 2012; Vitale et al. 2008). CBD injury
is accompanied by vascular injury in an estimated 25% of cases (Strasberg and Helton
2011). The most common type of injury immediately after surgery is a Strasberg A
leak (Figure 2) from the cystic duct or the aberrant duct that is amenable to treatment
with ERCP and stent insertion, often with a percutaneous drain (Karvonen et al.
2011; Strasberg and Helton 2011; Wu and Linehan 2010). The rationale in biliary leak
management is to ensure the downstream flow of bile facilitating closure of the leak site
(Karvonen et al. 2011).
When a complex biliary injury (Strasberg D-E) is excluded and reconstructive
surgery is not necessary, the majority of simple injuries as well as later strictures may
be treated endoscopically with ERCP, EST and stent insertion (Karvonen et al. 2011;
Strasberg and Helton 2011; Wu and Linehan 2010). It has been suggested that even in
complex lesions, ERCP may be attempted as the first-line effort to locate and classify
the injury and, if successful, to avoid the problems associated to surgical repair (Wu and
Linehan 2010).
Endoscopic Management of Benign Biliary Strictures
23
Figure 2. Strasberg’s classification (A–D, E1–E5) of biliary injury after cholecystectomy. Type A bile
leak (star) from the stump of a cystic duct or an aberrant cystic duct (duct of Luschka), B an occluded
right posterior sectoral duct or an aberrant right sided hepatic duct, C a bile leak from right posterior
sectoral duct or aberrant right sided hepatic duct, D a lateral injury to the main bile duct, E1 and
E2 transection of the common hepatic duct more or less than 2 cm from the biliary confluence, E3
communication with right and left duct only intact, E4 confluence interrupted and E5 main duct injury
associated with aberrant right sectoral hepatic duct involvement.
A biliary stricture typically located in the CHD or proximal CBD is the most common
late complication of CCY, presenting up to 15 years after surgery (Barbier et al. 2014;
Shanbhogue et al. 2011). The incidence of surgically reconstructed post-CCY biliary
strictures is 0.4% (Waage and Nilsson 2006). In Finland approximatelly 8,000 CCYs
are performed annually with 88% of operations being laparoscopic (THL 2012). The
number of strictures resulting from CCY treated or attempted to treat endoscopically
is unknown. In suspected late post-CCY strictures, other benign causes such as CBD
stones are encountered in over 20% and occult malignancy in up to 7% (Vitale et al.
2008).
The incidence of anastomotic and non-anastomotic strictures occurring after LT is
10–12% and 2–20% respectively (Akamatsu et al. 2011; Graziadei et al. 2006; Verdonk
et al. 2006; Verdonk et al. 2007). ERCP is the first choice of treatment also offering
diagostic yield in duct-to-duct anastomotic strictures (Akamatsu et al. 2011; Williams
24
Antti Siiki
and Draganov 2009). In Finland 50-60 LTs are performed yearly (Aberg et al. 2011;
THL 2012).
A biliary stricture develops secondary to an inflammatory process in the head of the
pancreas in 10–30% of patients with CP, the incidence of which is at least 6-10/100,000
(Jakobs and Riemann 1999; Lankisch et al. 2002; Lohr et al. 2013). CP itself being a
progressive inflammatory disease with pancreatic exocrine and endocrine insufficiency,
malnutrition, pain, pancreatic duct stenosis or stones and pancreatic cyst formation
as leading features, the majority of the CP related biliary stenoses are asymptomatic
or intermittent. The clinical presentation of CP related biliary stricture fluctuates,
with exacerbations and remissions as well as transient or asymptomatic cases being
characteristic. Secondary biliary cirrhosis is rare and acute cholangitis occurs in only
10% of patients with varying degree of severity (Abdallah et al. 2007). While transient
self-limiting jaundice due to acute pancreatitis or a pseudocyst in the head of the
pancreas warrants primary conservative treatment or pseudocyst drainage, persistent
biliary obstruction with elevated LFT, progression of a stricture, associated with
cholangitis or CBD stones necessitates endoscopy as the first line of therapy (Abdallah
et al. 2007; Dumonceau et al. 2012; Lohr et al. 2013).
The incidence of PSC is 1.2/100,000 and prevalence 16/100,000 (Lindkvist et al.
2010). It is increasingly common in the Nordic countries, accounting for 1–15% of
ERCPs (Enochsson et al. 2010; Ismail et al. 2012). Patients with PSC are predominantly
men, the median age at the time of diagnosis is 38-39 years, and there is an associated
inflammatory bowel disease in two thirds of cases (Boonstra et al. 2013; Lindkvist et al.
2010). Eventual development of CCA and biliary cirrhosis with consequent liver failure
are the most feared complications of PSC (Chapman et al. 2010) with respectively 30%
and 7–14% of cases leading to LT or hepato-biliary cancer at 10-year follow-up (Burak
et al. 2004; de Valle et al. 2012).
Up to 30–50% of PSC patients develop a dominant biliary stricture over the years
and these are most commonly benign; in a series of 230 patients only 19% of strictures in
PSC were caused by CCA (Charatcharoenwitthaya et al. 2008; Ehlken and Schramm
2013). However, PSC associated CCA tumours typically emerge in the dominant
strictures of liver hilum. Up to 26% of these dominant strictures have been reported
to eventually lead to CCA (Chapman et al. 2012; Tischendorf et al. 2006). The mean
survival in patients with a dominant stricture is 13 years, compared to 23 years in those
with diffuse intrahepatic disease (Chapman et al. 2012). However, the definition of
a dominant stricture in PSC has not been established. Despite the strong association
of dysplasia with development of CCA (dysplasia-carcinoma sequence) in PSC, the
incidence of CCA does not correlate with the duration of the inflammation (Burak et
al. 2004). The incidence of hepato-biliary cancer is 180-fold and CCA over 800-fold
Endoscopic Management of Benign Biliary Strictures
25
in PSC patients compared to that in general population (de Valle et al. 2012) with a
yearly incidence of 0.6–1.2% for CCA (Burak et al. 2004; Charatcharoenwitthaya et
al. 2008). The estimated median survival of patients from diagnosis until LT or PSC
-related death is 21 years (Boonstra et al. 2013). In Finland PSC is the most common
indication for LT, with 10-year patient survival after transplantation being 84% (Aberg
et al. 2011). The majority of CCAs arise within a few years after the diagnosis of PSC,
making it critical to have a surveillance protocol and to exclude dyplasia or malignancy
at the diagnosis of PSC for early potentially curative treatment with LT (Boberg et al.
2006; Boonstra et al. 2013; Boyd et al. 2014; Ehlken and Schramm 2013; Lindkvist
et al. 2010). Differentiating biliary strictures secondary to PSC from malignancy and
excluding dysplasia is one of the most challenging issues in hepato-biliary endoscopy.
ERCP forms the cornerstone for obtaining samples and treating dominant strictures
(Eaton et al. 2013).
2.2.3 Classification
The most commonly used Bismuth´s classification (Bismuth and Majno 2001) of BBS
is based on the level of stenosis and extent of reconstruction surgery required (Figure
3). It may also be used to describe acute biliary injuries (Bismuth and Majno 2001).
The degree of post-CCY biliary injury is often graded with Strasberg’s classification
(Strasberg et al. 1995), which involves both bile leaks and strictures according to similar
principles as those in Bismuth’s classification (Figure 2). A more detailed classification
system for post-CCY biliary injuries has been developed to also consider vascular
involvement (Bektas et al. 2007).
Figure 3. Bismuth’s classification of BBS, graded I-V is based on the level of stricture and the extent
of reconstructive surgery required: Type I stricture with a common hepatic duct stump longer than 2
cm, II with stump shorter than 2 cm, III with only the ceiling of the biliary confluence intact, IV with
the biliary confluence interrupted and V with a stricture of common hepatic duct associated with a
stricture of a separate aberrant right branch.
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Antti Siiki
In PSC specifically, the radiological progression of biliary duct involvement is graded
with the Amsterdam classification (Majoie et al. 1991) presented in Table 2. A
modified Amsterdam (m-Amsterdam) classification may be used in PSC surveillance
in determining the severity by summing the intra- and extrahepatic grades with the
exception that intrahepatic grade I equals two points and slighter change in ductal
irregularity and variation in calibre equals one point on the m-Amsterdam scale, which
therefore ranges between 0 and 8 (Rajaram et al. 2001; Boyd et al. 2014).
The chances of successful ERCP and consequent endoscopic diagnosis and therapy
depend on whether or not the stricture can be passed with guide wire; an impassable
intra- or extrahepatic stricture or total discontinuity of the bile duct requires surgery
(Baron and Davee 2013; Bismuth 2003).
Table 2. Radiologic grading of intrahepatic and extrahepatic changes in cholangiography image in
PSC according to the Amsterdam classification (Majoie et al. 1991, Rajaram et al. 2001)
Type of duct involvement Cholangiographic abnormalities
Intrahepatic
0
I
II
III
Normal
Multiple strictures; normal calibre of bile ducts or minimal dilation
Multiple strictures, saccular dilations, decreased arborization
Only central branches filled despite adequate filling pressure, severe pruning
Extrahepatic
0
I
II
III
IV
Normal
Slight irregularities of duct contour, no stenosis
Segmental stenosis
Stenosis of almost entire length of duct
Extremely irregular margin; diverticulum-like out-pouchings
2.3 Radiologic imaging of biliary strictures
When biliary obstruction is suspected from visible icterus and/or elevated liver LFT,
the diagnosis of BBS is often initiated with radiologic imaging. In practice, the first
imaging modality is often transabdominal ultrasound followed by magnetic resonance
imaging (MRI) and magnetic resonance cholangiography (MRCP) or contrast
enhanced computed tomography (CT). The long, irregular, asymmetric, abruptly
ending strictures are traditionally considered more often malignant than the smooth,
symmetric tapering strictures often present in benign disease. The findings from MRI
or CT require cytologic or histologic confirmation and treatment by ERCP or surgery
as a therapeutic intervention for a biliary stricture, except in cases where surgery is
required for an evident malignant tumour (Shanbhogue et al. 2011).
Endoscopic Management of Benign Biliary Strictures
27
2.3.1 Magnetic resonance imaging
MRCP is the current standard in the diagnostics of biliary strictures (Katabathina
et al. 2014; Shanbhogue et al. 2011). Performed with heavily T2-weighted sequences,
it offers the advantage of non-invasive cholangiography imaging of the bilary tract
beyond a tight stricture enabling evaluation of the liver parenchyma and abdominal
viscera as well as providing an assessment in the immediate post-operative phase and
in cases of bilio-enteric anastomosis (Katabathina et al. 2014; Shanbhogue et al. 2011).
The present day MRCP is excellent in the diagnostics of a biliary obstruction; however,
the accuracy in differentiation between benign and malignant strictures varies
widely, from 30 to 98% (Katabathina et al. 2014). In the evaluation of post-operative
strictures, MRCP combined with contrast enhanced MRI of the liver is the definitive
investigation method of choice, showing not only the level of obstruction, arterial
stenosis or thrombosis, possible biliary leak but also excluding occult malignancy as
well as revealing any recurrence of primary liver disease after LT (Shanbhogue et al.
2011). MRCP is also widely used in the diagnosis of PSC, where diagnostic sensitivity
of 80–88% and specificity of 87–99% have been reported (Shanbhogue et al. 2011).
MRCP is currently considered to be the optimal non-invasive method for the
evaluation of suspected post-LT complications, with an accuracy of 95% (Baron and
Davee 2013; Chan and Telford 2012; Williams and Draganov 2009). The radiologic
appearance of post-LT strictures differs in anastomotic or non-anastomotic cases and
the type of anastomosis (Shanbhogue et al. 2011). While dilated donor bile ducts are an
unreliable sign of a stricture in LT patients, the diagnosis of post-LT strictures is based
on a combination of symptomatic or asymptomatic elevated LFT, contrast enhanced
MRI as well as Doppler ultrasound to exclude arterial thrombosis (Chan and Telford
2012). In suspected post-CCY complication, a trans-abdominal ultrasound is often
followed by MRCP to evaluate fluid collections, the location of surgical clips, CBD
stones and site of the bile leak (Shanbhogue et al. 2011; Wu and Linehan 2010).
A typical radiologic finding seen in MRI in CP related biliary stricture is intraand extrahepatic bile duct dilatation of varying degrees with a smooth tapering
stricture in the intrapancreatic part of the CBD; evidence of chronic pancreatitis
such as parenchymal atrophy, dilated main pancreatic duct or pseudocysts support the
diagnosis (Shanbhogue et al. 2011).
The diagnosis of PSC is based on characteristic multi-focal “beaded” strictures
with alternating segments of dilated or normal duct findings in MRCP or ERCP
when secondary causes of sclerosing cholangitis have been excluded (Chapman et al.
2010; Ehlken and Schramm 2013; Shanbhogue et al. 2011). Although MRCP does not
28
Antti Siiki
reliably differentiate CCA from PSC, the sensitivity and specificity of MRCP in PSC
diagnosis are well over 80% (Shanbhogue et al. 2011).
In IAP a characteristic bulky and sausage-like pancreas may be seen in MRI or
abdominal CT (Chan and Telford 2012; Shanbhogue et al. 2011). The biliary stricture
associated with IAC is typically located in the distal CBD but diffuse intra- and
extrahepatic biliary strictures or perihilar strictures in isolation or combination may
also be encountered (Shanbhogue et al. 2011).
In strictures associated with chemotherapy MRI may reveal a stricture reminiscent
of PSC, typically affecting the CHD with little intrahepatic involvement; the distal
CBD is also usually spared from stricture formation secondary to separate arterial
supply (Shanbhogue et al. 2011). Radiologic diagnosis of Mirizzi’s syndrome with MRI
and CT is usually straightforward, but as in any indeterminate biliary stricture, the
possibility of occult malignancy has to be considered (Shanbhogue et al. 2011).
2.3.2 Other imaging modalities
Multiphase contrast enhanced CT scan is a standard imaging method in acute
abdominal pain and trauma, in the evaluation of complications of surgery and in the
assessment of tumour spread. In indeterminate biliary strictures CT scan is helpful in
detecting the underlying cause of the obstruction, occult malignancy, complications
such as cholangitis, fluid collections and arterial stenosis or thrombosis as well as in
showing lymphadenopathy and lesions suspectible to metastasis (Shanbhogue et al.
2011). A contrast-enhanced CT scan is often used to complement and in combination
with MRI in post-CCY and post-LT situations to evaluate liver ischaemia, vascular
anatomy and arterial thrombosis (Shanbhogue et al. 2011; Wu and Linehan 2010). The
CT scan is also a primary method in the evaluation of CP to assess parenchymal and
morphological changes, such as calcifications and pseudocysts or tumour-like lesions,
while MRI is used to show morphology of the pancreatic duct (Abdallah et al. 2007).
Endoscopic ultrasound (EUS) offers the advantage of guided fine needle aspirate
(FNA) in the diagnosis of indeterminate strictures and CCA. When EUS and FNA
may be used in combination with ERCP, improved accuracy may be achieved in the
diagnosis of BBS (Shanbhogue et al. 2011). However, EUS is highly user-dependent in
diagnosing malignancy (Shanbhogue et al. 2011). Although the benefits of EUS with
FNA over ERCP and brush samples are the most apparent in pancreatic masses where
a malignant biliary obstruction is suspected, it is also useful in other indeterminate
biliary strictures and suspected CCA (Weilert et al. 2014).
Endoscopic Management of Benign Biliary Strictures
29
FDG positron emission tomography (PET), the current disadvantages of which are
price and availability, appears to be extremely accurate in differentiating between benign
and malignant biliary strictures, with sensitivity and specificity of 92% (Shanbhogue et
al. 2011). Inflammation in PSC may cause a false positive finding, and thus the role of
PET is not established in PSC, despite the recent encouraging findings on its utility in
excluding CCA (Eaton et al. 2013; Sangfelt et al. 2014).
2.4 Endoscopic retrograde cholangio-pancreatography (ERCP)
The first reports on ERCP in humans appeared in literature in the 1970s (Cotton
1972). An experimental endoscopic cannulation or duodenal papilla with subsequent
pancreatography was documented even earlier (McCune, Shorb and Moscovitz 1968).
The first ERCP in Finland was performed in the University Hospital of Oulu in 1978,
followed by the Surgical Hospital in Helsinki in 1979. The University Hospitals of
Helsinki and Tampere set up the ERCP practice soon afterwards in the early 1980s.
The first Finnish reports of ERCP concentrated on complications (Halme et al.
1999; Nordback and Airo 1988). The wider use of ERCP and understanding of the
complications resulted in the avoidance of purely diagnostic procedures (Cotton et al.
1991; Freeman et al. 1996). Since then ERCP has established its position as a diagnostic
and therapeutic procedure of the pancreato-biliary duct system. It is performed
perorally with a flexible side-viewing duodenoscope, the tip of which includes an
elevator to control instruments in the working channel and is steerable in vertical and
horizontal directions. The cannulation, i.e. access through the papilla to the desired
duct by a guide wire facilitating further interventions, continues to be the critical part
of the procedure (Halttunen et al. 2014). In addition to the procedure itself, ERCP
practice entails the interpretation of radiologic images beforehand and the analysis
of tissue samples as well as subsequent decision-making, which are a good example of
a multi-disciplinary approach. ERCP currently forms a well-established basis for the
diagnosis and treatment of biliary strictures as well as selected cases of post-operative
bile leaks (Shanbhogue et al. 2011; Karvonen et al. 2011; Baron and Davee 2013).
2.4.1 Cannulation and cholangiography
In a difficult cannulation, a variety of methods may be used to open the papillary orifice
and access the biliary duct according to the endoscopist’s preference (Halttunen et
al. 2014). Precut sphincterotomy with a needle-knife sphincterotome or fistulotomy
(Gullichsen et al. 2005), pancreatic sphincterotomy (Halttunen et al. 2009) or double30
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guide wire technique (Gyokeres et al. 2003; Huang et al. 2015) may be used separately
or in combination (Halttunen et al. 2014). If cannulation fails, a second attempt is
usually more succesful when the inflammation of papilla has subsided (Palm et al.
2007). A prophylactic pancreatic stent may be introduced over the guide wire in the
PD to reduce the risk for PEP (Dumonceau et al. 2014). In urgent cases of failed
ERCP, a PTD (percutaneous transhepatic cholangiography and drainage) is typically
used in malignancy as a bridge to surgery or in other cases to facilitate the next ERCP
attempt with rendezvous technique associated with a high success rate and low risk of
complications (Swahn et al. 2013). Rendezvous ERCP may be used as an option to pass
a tight stricture allowing balloon dilation and stent therapy (Costamagna et al. 2001).
A successful biliary cannulation is followed by the cholangio- or pancreatography
image produced by a radioopaque contrast injection and x-ray. A diagnostic
cholangiography image reveals the intrahepatic biliary tree and extrahepatic bile
duct often crucial for the diagnosis of stricture or stones. The cholangiography itself
is not adequate for the diagnosis of indeterminate biliary strictures (Chen et al.
2011). However, the morphology of the stricture in cholangiography may give clues
to the aetiology; when a smooth and tapering, “birds-beak-like” or “hour-glass-like”
narrowing in the CBD may indicate CP, a blunt-ended duct should lead to a suspicion
of pancreatic cancer (Abdallah et al. 2007; Shanbhogue et al. 2011). Although the
cholangiographic findings in ERCP are not reliable in differentiating PSC or CCA
from IAC; IgG4 associated strictures may be longer and more segmental with a more
frequent affision of the distal CBD than in PSC (Baron and Davee 2013; Kalaitzakis et
al. 2011). After cholangiography, an endoscopic sphincterotomy (EST) and necessary
interventions may be performed; tissue sampling with brush, sweeping and flushing
of debris with extraction balloon, stone management, balloon dilation and insertion
of stents. SOC instruments are also introduced through the working channel of the
duodenoscope over the guide wire (Chen and Pleskow 2007).
2.4.2 Endoscopic cholangioscopy
The endoscopic cholangioscopy instruments have evolved from the prototypes of
the early 1980s to mother-baby-scope double-operator procedures and eventually to
present-day single-operator cholangioscopy (Urakami 1980). The currently widely used
SOC with SpyGlass instruments (Boston Scientific Corp, MA, USA) offers a visual
image inside the biliary duct and a controlled way to take biopsies for histologic analysis
(Chen 2007). SOC includes a probe that is inserted through the working channel of
a duodenoscope containing channels for the optical fibre transmitting video image,
Endoscopic Management of Benign Biliary Strictures
31
irrigation and instruments such as mini-biopsy forceps or stone management. With the
turning wheels of the instrument the tip of the probe can be adjusted in four directions.
In addition to visually guided biopsies and stone management, SOC may be used for
selective access through an otherwise impassable stricture e.g. in post-CCY strictures
or PSC (Kuroda et al. 2010; Arnelo 2015).
The visual image showing smooth biliary mucosa without neovascularization and
homogeneous granular mucosa is characteristic of benign disease. The presence of
irregularly dilated tortuous “tumour vessels’’ at the strictures is indicative of malignancy
(Kim et al. 2000). In a recent retrospective Chinese study, high sensitivity and negative
predictive values have been proposed for visual assessment (Woo et al. 2014). In other
studies, SOC image without tissue samples has been considered unreliable (Awadallah
et al. 2006). In addition, the intraobserver agreement of visual image provided by
SOC in indeterminate strictures in terms of hyperplasia and ulceration has also been
questioned (Sethi et al. 2014). Especially in PSC, visual evaluation may be unreliable
because of the multi-focality and inflammatory and fibrotic nature of the stricture,
making predicting malignancy in PSC harder than in patients with non-PSC strictures
that have an otherwise normal biliary epithelium (Awadallah et al. 2006; Arnelo 2015).
Interestingly, indeterminate filling defects seen in previous ERCPs may occasionally
turn out to be biliary stones without a stricture in SOC (Ramchandani et al. 2011).
Biliary stones unseen in cholangiography may be encountered in SOC in up to 30% of
PSC patients with symptom-relief after the stone management (Awadallah et al. 2006,
Arnelo 2015).
2.5 Complications of ERCP
Like any surgical or invasive procedure, ERCP and sphincterotomy carry a risk for
severe and potentially fatal complications. Thus adequate pre-operative investigations,
a careful consideration of procedure indications and alternative management options as
well as keeping up procedure volume are always warranted (Freeman 2012; Silviera et
al. 2009). The rate of complications and that of procedure success are connected; when
cannulation is difficult and advanced attempts are needed to access the biliary duct, the
complication rate is higher, especially for PEP (Halttunen et al. 2014). However, the
term complication is sometimes used interchangeably in the literature for adverse event
to underline that a successful procedure with a mild complication may sometimes be
preferable to a failed procedure attempt without any obvious complication (Freeman
2012). A stent clogging, for instance, may be considered merely an adverse event than
a complication during stent therapy. Although a critical analysis of own complications
32
Antti Siiki
is a part of quality management (Anderson et al. 2012), it is often neglected and only
few studies are available from non-academic centres (Colton and Curran 2009; GarciaCano Lizcano et al. 2004).
The present day endoscopic techniques allow such complex procedures to be
performed that major surgical or percutaneous interventions, both with considerable
morbidity, mortality and costs, may often be avoided (Freeman 2012). The studies
assessing typical ERCP related complications (PEP, haemorrhage, cholangitis,
perforation) grade complications according to a well-established classification (Table
3) as mild, moderate or severe according to duration of hospitalisation and need for
interventions (Cotton et al. 1991). Post ERCP pancreatitis is defined as a new-onset or
increasing abdominal pain and elevation of serum amylase three times above normal
at 24 hours after the procedure combined with pancreatitis-related hospitalisation
(Cotton et al. 1991). Early ERCP related complications are recorded during the first
30 days after the procedure, with most events occurring within a few days, although
cases of delayed bleeding, for example, may occur (Christensen et al. 2004; Silviera et
al. 2009).
Table 3. Definitions of complications of ERCP used in research. An intensive care unit admission or a
death after the ERCP grades the complication as severe. Any other complication is graded according
to duration of hospitalisation. C: Celsius (Cotton et al. 1991)
Mild
Pancreatitis
Moderate
Clinical pancreatitis, amylase Pancreatitis requiring hospiat least 3 times normal at
talisation of 4–10 d
more than 24 h after the procedure, requiring admission
or prolongation of planned
admission to 2–3 d
Severe
Hospitalisation for more
than 10 d, pseudocyst, or
intervention (percutaneous
drainage or surgery)
Transfusion (4 units or less),
Haemorrhage Clinical (i.e. not just endoscopic) evidence of bleeding, no angiographic intervention
haemoglobin drop more <3g, or surgery
no transfusion
Transfusion 5 units or more,
or intervention (angiographic
or surgical)
Perforation
Possible, or only slight
leakage of fluid or contrast,
treatable by i.v. fluids and
suction <3 d
Any definite perforation
treated medically 4–10 d
Medical treatment of more
than 10 d, or intervention
(percutaneous or surgical)
Infection
(cholangitis)
Temperature >38 C for
24–48 h
Febrile or septic illness
requiring more than 3 d of
hospital treatment or percutaneous intervention
Septic shock or surgery
Endoscopic Management of Benign Biliary Strictures
33
2.5.1 Incidence
Two systematic reviews report the incidence of PEP to be 3–7% with cholangitis,
haemorrhage and perforation occurring at rate of 1–3%, 1–2% and 0.5% respectively
(Andriulli et al. 2007; Silviera et al. 2009). The reported incidence of other adverse
events such as cardio-pulmonary and thromboembolic events varies between 0.5 and
10% (Christensen et al. 2004; Cotton et al. 2009; Wang et al. 2009). Cholecystitis may
occur in 0.5% of cases (Silviera et al. 2009). Technical problems, e.g. trapping of a stone
extraction basket are occasional curiosities (Wang et al. 2009). In the largest register
study so far of nearly 38,000 ERCPs in Sweden, the incidence of pancreatitis was 5.6%
and the overall complication rate was 12% (Enochsson et al. 2013).
In the literature it is usually assumed that in in-patient procedures the complications
mainly emerge during the surveillance period of some 24 hours on the hospital ward and
that patients with complications arising later or in outpatient procedures are eventually
admitted to the same unit. There is, however, variation in the length and thoroughness
of the follow-up; studies presenting the highest figures of overall complications often
have a close 30-day follow-up protocol instead of relying on data gathered during
primary hospital stay. Furthermore, the early studies may include diagnostic ERCPs
and procedures performed with quite different equipment than that in present-day
ERCPs in centres with varying expertise and procedure volume. Additionally, the
studies on complications exclude procedures with already sphincterotomised papilla
and thus repeated ERCPs for stent exchange, for example, which are characteristic of
BBS management. The incidence of complications according to the key studies from
the 2000s is summarised in Table 4.
34
Antti Siiki
Table 4. Key-studies of 30d-ERCP complications from the 2000s. Prosp: prospective. Retro:
retrospective study. PEP: post-ERCP pancreatitis. Bleed: haemorrhage. Perf: perforation. Chol:
cholangitis. Compl: overall complications. Mort: ERCP -related mortality rate. *The study reported
only severe or fatal complication
Percentages (%)
N
Country
Setting
PEP
Bleed
Perf
Chol
Comp
Mort
0.1
(Masci et al. 2001)
2462
Italy
Prosp
1.8
1.2
0.6
0.6
4.9
(Barthet et al. 2002)
1159
France
Retro
3.5
1.2
1.8
1.2
7.7
0.9
(Vandervoort et al. 2002)
1223
USA
Prosp
7.2
0.8
0.1
0.7
11
0.002
(Christensen et al. 2004)
1177
Denmark
Prosp
3.8
0.9
1.1
5.0
16
1.0
Spain
Retro
5.5
1.6
1.6
1.6
11
0.8
Finland
Retro
4.8
0.6
0.8
0.5
7.3
0.5
UK
Prosp
1.6
1.3
0.4
1.0
5.0
0.4
(Garcia-Cano Lizcano et al. 2004)
(Palm et al. 2007)
507
602
(Williams et al. 2007)
4561
(Salminen et al. 2008)
2788*
Finland
Retro
0.2
0.2
0.2
0.1
0.8
0.1
805
USA
Prosp
3.2
0.6
0.1
0.8
5.0
0
(Cotton et al. 2009)
11497
USA
Prosp
2.6
0.3
0.1
0.3
4.0
0.06
(Wang et al. 2009)
2597
China
Prosp
4.3
1.7
0.2
1.4
7.9
0.3
(Colton and Curran 2009)
(Enochsson et al. 2010)
11074
Sweden
Prosp
2.7
0.9
0.3
NA
5.9
NA
(Kapral et al. 2012)
13513
Austria
Prosp
4.2
3.6
0.6
1.4
10.
0.1
The effect of procedure volume on ERCP success rate has been discussed in several
studies. While it is obvious that personnel’s experience improves ERCP outcomes,
comparisons of complication rates between centres may be misleading due to different
indications, case-mix and success rates; high-volume endoscopists generally attempt
higher-risk and more challenging cases, but despite that have a higher success rate of
cannulation (Freeman 2012). In a few multi-centre studies, high-volume tended to be
associated with higher success rates of cannulation and slightly elevated complication
rates (Freeman et al. 1996; Kapral et al. 2008; Loperfido et al. 1998). In the Swedish
nationwide study, a tendency for more frequent haemorrhage and contrast extravasation
was observed when low-volume was defined as less than 200 procedures a year
(Enochsson et al. 2010). Interestingly, in the same study the rate of PEP was increased in
high-volume centres, probably secondary to the frequency of more complex procedures
involving e.g. manipulation of the PD in the high volume referral centres (Enochsson
et al. 2010). In an Italian multi-centre study the PEP rate did not differ between lowand high-volume centres or between expert- and non-expert operators, even though
the high-volume centres performed more complex procedures (Testoni et al. 2010). In
a study from the United Kingdom no difference was found in the overall post-ERCP
complications between endoscopists with differing case loads or hospital type, although
a decrease in PEP rate in the university hospitals was observed (Williams et al. 2007).
Endoscopic Management of Benign Biliary Strictures
35
While it is hard to define a minimum volume to maintain optimal proficiency,
estimates of 50–100 cases for routine biliary therapy and 200–250 per year for advanced
pancreatic techniques have been proposed (Freeman 2012). Concentrating procedures
on a few endoscopists, referral of the most complex cases to specialised centres and
optimising the risk and benefit for the individual patient according to endoscopist’s
expertise are the ways to control the risks (Freeman 2012). No description of ERCP
practice or complication figures has so far been published on Finnish low-volume
hospitals.
2.5.2 Mortality
The majority of adverse events are self-containing and graded as mild or moderate in
87–99% of cases (Christensen et al. 2004; Cotton et al. 2009; Freeman et al. 2001;
Testoni et al. 2010; Vandervoort et al. 2002; Wang et al. 2009). Mortality due to ERCP
is rare (Table 4) being 0.3–0.5%. However, PEP and perforation may carry 3% and
9% risks of death respectively (Andriulli et al. 2007). Mortality due to severe PEP has
reportedly been as high as 29% (Testoni et al. 2010). In a study of nearly 3,000 ERCPs
at a Finnish university hospital, the incidence of severe complications was 0.8% with
related mortality of 0.08% (Salminen et al. 2008). It has been previously noted that
overall 30-day mortality (also other than ERCP-related) is predictably much lower
when the indication is a CBD stone (1.5%) compared to a malignant stricture (15%)
(Enochsson et al. 2010). Furthermore, the mortality rate is strongly associated with
comorbidities (ASA classification, American Society of Anesthesiologists), being
0.2% and 5% in ASA1 and 4% and 21% in ASA3 with CBD stones and malignancy
respectively (Enochsson et al. 2010). The overall all-cause mortality rate 30 d from
ERCP is up to 1.4–6%, reflecting the frequency of co-morbidites in unselected patients
undergoing ERCP (Christensen et al. 2004; Colton and Curran 2009; Williams et al.
2007).
2.5.3 Risk factors
The risk factors of ERCP complications have been investigated in several studies and it
seems that the risk for pancreatitis especially is associated with the manipulation of the
papilla or pancreatic duct in a difficult cannulation (Enochsson et al. 2010; Halttunen et
al. 2014). In Freeman’s pioneering studies with PEP incidence 5–7%, the risk factors in
multivariate analysis included young age, precut sphincterotomy, prior PEP, suspected
dysfunction of Sphincter of Oddi (SOD) as ERCP indication, female gender, normal
36
Antti Siiki
bilirubin, absence of chronic pancreatitis, balloon dilation of the biliary sphincter and
difficult cannulation (Freeman et al. 1996; Freeman et al. 2001). These results have been
substantiated with small variations over the years, but difficult cannulation with several
attempts and contrast injections to the PD seems to be the main procedure-related factor
increasing the risk for PEP (Cotton et al. 2009; Kapral et al. 2012; Testoni et al. 2010;
Vandervoort et al. 2002; Wang et al. 2009; Williams et al. 2007). A periampullary
diverticulum has reportedly also been associated with an increased risk for PEP (Wang
et al. 2009). Precut sphincterotomy, performed to facilitate cannulation in difficult
situations, has been noted to be an independent risk factor for PEP (Freeman et al.
1996; Freeman et al. 2001; Testoni et al. 2010; Vandervoort et al. 2002). While young
patients with SOD or a history of PEP seem to be prone to pancreatitis (Christensen
et al. 2004; Cotton et al. 2009; Freeman et al. 1996; Freeman et al. 2001; Kapral et al.
2012; Testoni et al. 2010; Vandervoort et al. 2002; Williams et al. 2007), older patients
with a history of CP and thus with less potential for pancreatic inflammation are at
less risk (Cotton et al. 2009; Freeman et al. 2001; Vandervoort et al. 2002). The use
of prophylactic pancreatic stents, pre-procedural rectal administration of non-steroidal
anti-inflammatory drugs and the rendezvous cannulation technique have been shown
to reduce the risk for PEP (Dumonceau et al. 2014; Swahn et al. 2013).
Predictably, haemorrhage seems to be related to visible bleeding during ERCP,
sphincterotomy as well as comorbidities, haemodialysis or anticoagulation treatment
and urgent procedures (Cotton et al. 2009; Enochsson et al. 2013; Kapral et al. 2012;
Williams et al. 2007). It has been noted that the incidence of haemorrhage is nowadays
lower than proposed by older series, perhaps due to the development of CBD stone
therapy and diathermy equipment decreasing the risk of bleeding related to EST
(Enochsson et al. 2010).
Perforations are associated with cases with sphincterotomy, difficult cannulation,
precut sphincterotomy, previous surgery involving biliary diversions, or malignancy
(Christensen et al. 2004; Cotton et al. 2009; Kapral et al. 2012; Williams and
Draganov 2009). Cholangitis is more likely if biliary access failed or drainage was
insufficient, and in men (Christensen et al. 2004; Freeman et al. 1996; Kapral et al.
2012). In the prevention of cholangitis, complete and successful biliary drainage is the
most important issue; routine prophylactic antibiotics are recommended in patients
with incomplete biliary drainage, in PSC and in LT patients (Anderson et al. 2012;
Freeman 2012).
The role of patient’s age and co-morbidities in relation to complications other than
PEP is contradictory: while background illnesses and age over 65 years have been related
to increased cardio-pulmonary complications (Kapral et al. 2012) as well as severe or
Endoscopic Management of Benign Biliary Strictures
37
fatal complications (Cotton et al. 2009) earlier, no such connection was substantiated
in the large prospective Danish study with a close follow-up (Christensen et al. 2004).
As an indication for ERCP, BBS and PSC carry a 10% and 21% risk for PEP, which
is high compared to the 4% risk in unselected ERCP patients (Testoni et al. 2010).
Simple procedures like exchange of biliary stent (Cotton et al. 2009) and stone removal
(Garcia-Cano Lizcano et al. 2004) are associated with fewer complications than
complex procedures (Cotton et al. 2009; Enochsson et al. 2010; Testoni et al. 2010;
Vandervoort et al. 2002). In a Finnish study of PSC related ERCP complications, the
rate of PEP was 9.2% in patients with an intact papilla and 2.7% in patients with a
previous EST (Ismail et al. 2012). In Sweden, the risk for PEP and cholangitis has been
reported to have more than doubled in PSC patients compared to other ERCPs, any
advese events occurring in 18% and 7% and PEP in 8% and 3% of the PSC and nonPSC patients respectively (von Seth et al. 2015). In PSC, acute cholangitis occurs in
1–7% and perforation in 0.6–0.7% of procedures, but incidences of mild perforations
(contrast extravasation) as high as 6% have been reported (Etzel et al. 2008; Ismail et
al. 2012; Navaneethan et al. 2015b; von Seth et al. 2015). A difficult cannulation and
insertion of the guide wire more than twice into the PD also greatly increased the PEP
risk in PSC (Ismail et al. 2012; Navaneethan et al. 2015b; von Seth et al. 2015). Much
lower PEP risks of 1.2% and cholangitis of 2.4% in PSC patients have also been reported,
possibly explained by the large proportion of previously sphincteromised papillas and
liberal use of prophylactic pancreatic stents (Navaneethan et al. 2015b). The PEP rate
has been 5–9% and the cholangitis rate 5% in studies specifically assessing the risks of
stricture management in PSC (Kaya et al. 2001; Ponsioen et al. 1999).
According to studies on adverse events of SOC, complications occur in 3–19% of
cases and are seldom severe and consist most commonly of cholangitis, PEP and postsphincterotomy bleeding (Chen et al. 2011; Draganov et al. 2011; Kalaitzakis et al. 2012;
Manta et al. 2013; Woo et al. 2014; Lubbe et al. 2015). The complications seen with
SOC have been proposed to be associated with female sex, previous ERCP, and hilar or
multifocal strictures, but to have no relation to patient’s age, sex, pre-existing cholangitis
or duration of the procedure of over 30 minutes (Chen et al. 2011; Kalaitzakis et al.
2012). Interestingly, most of the adverse events involved acute cholangitis and no cases of
PEP occurred (Kalaitzakis et al. 2012). This perhaps indicates a different complication
pattern than in ERCP without SOC and may explain why previous EST appeared as
a protecting factor. PSC is not a known risk factor for SOC related complications, but
biliary cannulation may be more difficult in PSC (Halttunen et al. 2009; Kalaitzakis
et al. 2012). In the most recent study of SOC use in PSC, a 15% of overall complication
rate was reported with 9% incidence of PEP (Arnelo et al. 2015) Although SOC is used
in cases where other diagnostic methods remain inconclusive and thus a increased risk
38
Antti Siiki
is acceptable to achieve the correct diagnosis, a careful consideration of the additional
diagnostic yield of SOC is warranted (Lubbe et al. 2015).
2.6 Obtaining and analysing samples from biliary strictures
In clinical practice, the diagnosis of BBS is in most cases primarily to exclude malignancy
and secondly about a specific diagnosis. The diagnosis is based on a combination of all
available information, patient’s history, previous ERCPs, radiologic imaging, results of
blood samples including LFTs, immunoglobulins and tumour markers, cholangiography
image and cytologic results of brush samples with DNA analysis (Chan and Telford
2012). The brush samples acquired in ERCP offer a fundamental diagnostic method
in ERCP. However, they offer only cytologic and not histologic diagnosis with a poor
sensitivity (Dumonceau 2012). Thus a stepwise approach is often needed in unclear
cases, including further radiologic imaging and repeated ERCPs with or without SOC
to aquire imaging and biopsies under direct visual guidance (Baron and Davee 2013;
Chan and Telford 2012; Draganov et al. 2011; Shanbhogue et al. 2011).
2.6.1 Brush samples and cytologic analysis
Brush samples and subsequent cytologic analysis from the biliary tract have a poor
sensitivity of less than 60%, but a high specificity (Burnett, Calvert and Chokshi 2013;
Dumonceau 2012). While a preceding balloon dilation of a stricture does not affect
the diagnostic yield of brush cytology, repeated sampling may improve the sensitivity
of brush cytology (de Bellis et al. 2003). A minimum of five passes of the brush
through the stricture is considered sufficient. However, flushing the brush catheter and
including the transsected tip of the brush within the sample markedly increases the
cytologic yield (Halme et al. 2012; Lindberg et al. 2002). Cytological examination of
the aspirated bile juice itself gives only little further information in addition to brush
cytology – the method is recommended as an adjunct to bare brushing to acquire
more cells for analysis in a suspected malignacy (Dumonceau 2012). Although the
role of diagnostic markers in bile juice is unclear in indeterminate strictures, improved
accuracy when combining measurement of e.g. pyruvate kinase M2 from the bile juice
to brush cytology and serum samples has been recently proposed (Navaneethan et al.
2015). In some studies, protein analysis of bile juice has identified variety of biomarkers
that may be of potential benefit in stricture diagnostics, but the clinical significance of
which is not yet known (Farina et al. 2014; Lukic et al. 2014)
Endoscopic Management of Benign Biliary Strictures
39
Cytologic specimens acquired from brush samples are graded as malignant,
suspected malignant, atypical, or benign using well-established criteria (Lemon and
Byrnes 1949). In PSC, brush cytology has a high specificity but the sensitivity generally
remains as low as 40–71% in detecting malignancy (Chapman et al. 2010). However,
whenever high-grade dysplastia is detected in brush cytology, this is fairly successful
in predicting (73% sensitivity and 95% specificity) a finding of high-grade dysplasia or
adenocarcinoma in the following surgery (Boberg et al. 2006). The interpretation of a
standard cytology specimen is subjective, and depends on the skills of the pathologist
(Baron et al. 2004). The rate of false positives due to PSC-related inflammation can be
reduced when the pathologist is provided with adequate background data (Dumonceau
2012).
2.6.2 Flow cytometry, digital image analysis and FISH
The cytology sample acquired by endoscopic brushing may also be used for advanced
analyses to diagnose pre-malignant or malignant lesions. An abnormal nuclear DNA
content of the cells, (aneuploidy, abnormal DNA index) as well as number of cells in the
S-phase of the cell cycle with rapid duplication rate is assessed by the flow cytometry
(Ryan and Baldauf 1994). Assesment of DNA index has been shown to increase
sensitivity of brush cytology to 62–72%, making an aneuploidic DNA content a strong
indicator of a developing dysplasia or malignancy (Lindberg et al. 2006; Halme et al.
2012). Similar analysis of DNA content may be performed with digital image analysis
(DIA) or with fluorescence in situ hybridization (FISH) that have been shown to be a
valuable adjunct to cytology in detecting malignancy of the biliary tract (Baron et al.
2004; Kipp et al. 2004).
The poor sensitivity of brush cytology in the diagnosis of biliary strictures may
thus be improved by using flow cytometry, DIA or FISH as an adjunct. Although these
are especially valuable in indeterminate strictures in PSC and strong predictors of
malignancy when positive, the analysis of DNA content or cell morphology should not
be used as a screening tool, but selectively in combination with cytology in patients with
other signs indicating dysplasia or CCA, e.g. in dominant stricture (Bangarulingam et
al. 2010).
2.6.3 Cholangiography and endoscopy guided biopsies
Adding a routine cholangiography guided forceps biopsy to brush cytology does not
necessarily improve sensitivity, at least in extraluminal pancreatic cancer, but provides
40
Antti Siiki
nearly 100% specificity at the cost of a perforation risk (Dumonceau 2012; Pugliese et
al. 1995). Given that the biopsy forceps are not wire guided, manoevering the forceps
beyond the inferior margin of the CBD stricture and thus acquiring reliable samples is
questionable (Baron et al. 2004). An endoscopically guided papillary biopsy is valuable
in the diagnostics of malignancy and in IgG4-related diseases (Chan and Telford
2012; Dumonceau 2012). In IAP and IAC, the histologic features include plasma cell
infiltration and fibrosis as well as presence of IgG4 stained cells (Boonstra et al. 2014;
Okazaki et al. 2014).
2.6.4 Visually guided biopsies
Obviously the accuracy of biopsies depends on whether the biopsies are taken at the
intended site. Thus SOC with visually controlled biopsy provides an attractive method
to improve the diagnostics of BBS. Although the biopsy forceps of the currently most
widely used Spyglass SOC are tiny, visually controlled biopsies still provide more tissue
material for analysis than brush cytology samples, and thus potentially a more precise
diagnosis (Rey et al. 2014). Accordingly, visually controlled biopsies with SOC have
been able to provide an accurate definitive diagnosis in unclear bilary strictures in 82%
of cases where previous ERCP guided samples were inconclusive (Ramchandani et al.
2011) and to provide additional information or affect clinical decision-making in 67%
(Chen et al. 2011). SOC with biopsies has been proven to be technically feasible and
safe in the case of an indeterminate biliary stricture. Procedural technical success rates
of 90-100% and rates of 72–98% for acquiring biopsies eligible for diagnosis have been
reported (Awadallah et al. 2006; Chen et al. 2011; Draganov et al. 2011; Kalaitzakis et
al. 2012; Woo et al. 2014).
The diagnostic value of ERCP, visual impression on SOC and biopsies in the
diagnostics of indeterminate biliary strictures are presented in Table 5 according to the
largest prospective multi-centre study to date of 226 patients. SOC visual evaluation
has been shown to have higher sensitivity while biopsies have high specificity (Chen et
al. 2011).
Supporting results have been published on the high accuracy of SOC guided
biopsies in confirming or excluding malignancy: the overall sensitivity in diagnosing
malignant lesions is up to 95% for visual assessment and 82% for biopsies, with overall
specificity of 78% and 82% respectively (Ramchandani et al. 2011). In addition, SOC
biopsies have been proven more accurate in diagnosing biliary strictures than brush
cytology and cholangiography guided biopsies with sensitivity, specificity and negative
predictive value of 77, 100 and 69% respectively (Draganov et al. 2011).
Endoscopic Management of Benign Biliary Strictures
41
Table 5. The diagnostic value of ERCP, SOC visual impression and biopsies in differentiating between
malignant and benign biliary strictures in a study of single-operator peroral cholangioscopy (SOC) use
in indeterminate biliary strictures. Expressed by sensitivity, specificity, positive predictive value (PPV),
negative predictive value (NPV) and accurancy according to a multi-centre study of SOC use (Chen
et al. 2011)
Specificity
PPV
NPV
Accuracy
ERCP impression
Sensitivity
51%
54%
88%
77%
53%
SOC impression
78%
82%
80%
80%
80%
Biopsy histology
49%
98%
100%
72%
75%
The use of SOC in PSC diagnostics and surveillance has not been established due
to the small number of studies available (Kalaitzakis et al. 2012; Ramchandani et al.
2011; Arnelo et al. 2015). However, a cholangioscopy has reportedly been helpful in
distinguishing between malignant and benign dominant strictures in PSC compared
to cholangiography or brush cytology; sensitivity of 92%, specificity of 93%, accuracy
of 93%, positive predictive value of 79% and negative predictive value of 97% were
achieved in 53 PSC patients in median follow-up of 47 months (Tischendorf et
al. 2006). When malignancy is suspected in a macroscopically ulcerous mucosa but
biopsies remain benign, repeating SOC in a few weeks or months is recommended
(Tischendorf et al. 2006).
It has been suggested that the diagnostic value of SOC guided biopsies is best in
difficult cases with inconclusive previous diagnostic modalities, and better for patients
with hilar or proximal strictures than in distal CBD strictures (Draganov et al. 2011).
2.7 Serum diagnostics
Carbohydrate antigen 19-9 (CA19-9) is used in the diagnosis of tumours located in the
head of the pancreas and CCA. This serum tumour marker should be interpreted with
caution, especially in the presence of biliary obstruction; however, marked elevation to
levels over 1000 U/ml are strongly suggestive of cancer (Pearce et al. 1994; Steinberg
1990). While the overall sensitivity of CA19-9 in the diagnostics of pancreatic cancer is
79% and specificity of 82%, a higher cut-off value (e.g. 300 U/ml instead of routine 37
U/ml) with obstruction increases the specificity to 87% (Goonetilleke and Siriwardena
2007). Being the least inaccurate of the markers available, the value of CA19-9 is in
repeated measurement after relief of jaundice: a normalised level suggests that pancreatic
cancer is unlikely in a patient with a normal CT (Goonetilleke and Siriwardena 2007).
Serum IgG4 is used in the diagnostics of autoimmune disorders IAC and IAP.
While 15% of PSC patients have slightly elevated levels of serum IgG4, patients with
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Antti Siiki
IAC usually have higher levels. When fourfold IgG4 (>5.6 g/L) was used as cut-off,
sensitivity of 42% and specificity and positive predictive value of 100% were reached
(Boonstra et al. 2014). In PSC, combining cytology, flow cytometry, CA19-9 with a
cut-off value of 100 U/ml and CEA (carcino-embryonal antigen) provided sensitivity,
specificity and NPV of 100, 85 and 100% respectively (Lindberg et al. 2002).
2.8 Non-endoscopic treatment of benign biliary strictures
While percutaneous technique is a secondary method in BBS treatment, surgery has
a definitive role in providing treatment in unresponsive cases and confirming the
diagnosis in unclear cases where malignancy is suspected (Abdallah et al. 2007; Larghi
et al. 2008).
2.8.1 Percutaneous management
Percutaneous interventions via PTD are an alternative to endoscopy in relieving biliary
obstruction and treating strictures. A therapeutic PTD is used when endoscopy fails as
a bridge to surgery or continued percutaneous treatment and to facilitate a rendezvous
ERCP (Swahn et al. 2013). In a post-CCY biliary injury, a percutaneous drain may be
inserted to provide access to the biliary tract and to collect samples (Wu and Linehan
2010).
Percutaneous biliary drainage is associated with a success rate of up to 98% in
biliary cannulation with 9% and 0.7% complication and mortality risk respectively
(Weber et al. 2009). Patients with non-dilated ducts are at greater risk of up to 14%
for complications, most commonly bleeding, cholangitis, sepsis and acute pancreatitis
(Weber et al. 2009). The complication risk of PTD in malignant cases and a mortality
rate of up to 2% are considered acceptable in palliative situations with patients unfit for
surgery (Yee and Ho 1987).
A traditional method in the percutaneous treatment of BBS is to dilate with balloon
or plastic bougies, followed by the exchange of PTD catheters with gradually increasing
diameters of up to 18F across the stricture. In refractory or endoscopically inaccessible
strictures success rates of 77–90% have been reported with this method (Janssen et
al. 2014; Weber et al. 2009). The percutaneous insertion of retrievable covered selfexpanding metal stents has been successfully used in strictures of the bilio-enteric HJ
anastomosis in strictures secondary to LT, with 16%, 87% and 20% rates of migration,
resolution and recurrence respectively (Gwon et al. 2013). In two case series of BBS
secondary to HJ anastomosis and CP, the novel BDBS was used percutaneously with a
Endoscopic Management of Benign Biliary Strictures
43
high success rate and predictable degradation pattern in six months (Mauri et al. 2013;
Petrtyl et al. 2010).
2.8.2 The role of surgery
The well-established surgical treatment of BBS has long experience in use and good
long-term results (Larghi et al. 2008). Surgical approach is preferred if endoscopy
fails or is not possible due, for example to total obstruction or major duct leakage in
the post-operative situation as well as in selected cases of CP and PSC. Despite the
associated morbidity, burden on the patient and on the health care system, resection
not only provides definite diagnosis but has also been associated with good long-term
results (Ahrendt and Pitt 2001; Gourgiotis et al. 2007; Lillemoe et al. 2000). However,
with successful endoscopy, surgery may be avoided, which is especially important in
patients with co-morbidities or in difficult surgical circumstances, e.g. immediately
after complicated biliary surgery, in CP or in stricture of a duct-to-duct anastomosis
after LT (Ahrendt and Pitt 2001; Damrah et al. 2012; Gourgiotis et al. 2007).
In post-operative strictures, most commonly after LC or open CCY or CBD
exploration, an initial success rate of up to 98% with late recurrence after surgical
anastomosis in 9% was observed in five-year follow-up after Roux-en-Y HJ
reconstruction (Lillemoe et al. 2000). Performing a surgical HJ anastomosis on lesions
at less than two centimeters from the biliary confluence (Bismuth II–IV) becomes
more complex (Bismuth and Majno 2001). Surgery due to CCY related late strictures is
associated with morbidity and mortality rates of up to 19% and 3% respectively (Bektas
et al. 2007). However, the complex injuries affecting or transecting the bile duct at the
biliary confluence (Bimuth IV–V, Strasberg E) typically require surgery (Larghi et al.
2008; Lillemoe et al. 2000). In post-LT anastomotic strictures surgical revision and retransplantation are the final options if all others fail (Akamatsu et al. 2011; Chan and
Telford 2012; Williams and Draganov 2009).
In CP related biliary strictures the surgical approach is most commonly intended
to not only bypass the stricture but also to manage intractable pain, involvement of the
adjacent organs, e.g. duodenal obstruction and suspected malignancy. Surgical options
include complete duodenal preserving resection of the head of the pancreas with endto-end pancreato-jejunostomy (Beger) and currently more commonly its modification
without division of pancreas (Berne) or a local resection of the pancreatic head with
a longitudinal pancreato-jejunostomy (Frey). Radical pancreato-duodenectomy is a
definite option when there is any concern about an underlying malignancy or duodenal
obstruction (Abdallah et al. 2007; Dumonceau et al. 2012; Gourgiotis et al. 2007; Yin
44
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et al. 2012). An isolated HJ may be performed with good long-term results in a minority
of patients who are pain-free with CBD stricture (Abdallah et al. 2007).
In advanced PSC, a curative treatment is LT with preferably duct-to-duct
anastomosis (Damrah et al. 2012) with indications similar to those of other chronic
liver diseases: complications of portal hypertension, impaired quality of life and liver
failure (Chapman et al. 2010). Extrahepatic resection in PSC is controversial, and there
is no evidence of non-transplant surgery actually affecting the natural history or disease
progression (Chapman et al. 2010). It is still debated if an LT with neo-adjuant therapy
should be advocated for the therapy of early stage PSC associated CCA (Chapman et
al. 2010).
While endoscopic diagnostics has improved hugely due to improvements in tissue
analysis and the availability of visually controlled biopsies, it is still far from perfectly
accurate. Even in combination with radiology and serum samples, predicting CCA in
PSC patients, for example is still extremely difficult. The false positive results of the
diagnostic tests may lead to unnecessary surgery, which offers an ultimate diagnostic
and therapeutic option, the cost being the associated morbidity. Thus further research is
needed to improve and simplify the diagnostics of BBS (Chan and Telford 2012; Baron
and Davee 2013).
2.9 Endoscopic treatment and outcome of biliary strictures by aetiology
The optimal endoscopic treatment method depends on stricture aetiology, location and
timing of the intervention (Baron and Davee 2013). The strictures secondary to PSC
require a quite different strategy than post-operative strictures, which respond well
compared to strictures in distal CBD due to CP, which are relatively resistant to any
endoscopic treatment method (Abdallah et al. 2007). The different types of strictures
also have different outcomes, ranging from a good response in LT to a long-lasting
stent therapy in patients with CP unfit for surgery (Baron and Davee 2013; Chan and
Telford 2012).
2.9.1 Post-cholecystectomy
Treatment of post-CCY strictures with an increasing number of tri-monthly exchanged
and added multiple PSs (mPS) has been successful with a low rate of adverse events. An
Italian study of 45 patients with post-CCY strictures by Costamagna et al. evaluated
the long-term results of aggressive therapy with increasing numbers of up to six plastic
stents for 12 months. This achieved an excellent 89% success rate with no recurrences in
Endoscopic Management of Benign Biliary Strictures
45
the follow-up of four years. In this retrospective study of mPS therapy where over half
of the cases were Bismuth I–II, and one fourth were Bismuth III–IV, stent occlusion
necessitating early exchange occurred in 18% and complications such as cholangitis or
pancreatitis in 9% of patients (Costamagna et al. 2001). In smaller patient populations
post-CCY strictures graded as Bismuth I-II and Bismuth III have been associated with
respective success rates of 80% and 25% with mPS therapy (Draganov et al. 2002).
However, good results have also been achieved by inserting three or fewer PSs
in Strasberg B and C lesions not mandating HJ; 78% of stricture resolution after 12
months with only 6% of patients requiring early stent exchange due to cholangitis or
stent clogging (Vitale et al. 2008). In a similar protocol involving the insertion of 2-4
simultaneous PSs, long-term success rates of up to 67% and 82% have been presented in
the follow-up of over six years in Bismuth II–III strictures with single and additional
treatment periods respectively. However, a considerable rate of adverse events has been
reported with 10% PEP and 2% perforation rate as well as an incidence of symptomatic
stent clogging and migration of 7% and 2% respectively (Tuvignon et al. 2011). In two
large multi-centre studies in France, recurrences after stent therapy became evident in
the first 12–24 months of follow-up. Half of the recurrences responded to additional
stenting with either PSs or CSEMSs and half underwent surgery (Tuvignon et al. 2011;
Vitale et al. 2008). Over 80% long-term success rates and incidence of adverse events
of up to 19% have been presented in other studies with mPS therapy of post-CCY
strictures (De Palma et al. 2003; Draganov et al. 2002; Kuroda et al. 2010). The poorest
results for mPSs have been associated with the complex hilar strictures of Bismuth III–
IV (Costamagna et al. 2001; de Reuver et al. 2007).
The number of ERCPs required for mPS therapy usually ranges from four to up
to seven during the treatment period of 12 months (Costamagna et al. 2001). The
benefits of aggressively increasing mPS therapy have not been substantiated in all
studies. Although mPS treatment may be the most obvious when the largest possible
number of stents are inserted early in the course of therapy in CCY-related strictures,
problems such as post-insertional pain in 28% and stent related problems in 42% were
reported with a failure rate of 33% in a Dutch study of over 100 patients (de Reuver et
al. 2007). While the main advantage of mPS therapy appears to be the gradual dilation
effect with the ability also to treat the strictures affecting the biliary confluence, the
main drawback is the laborious protocol of multiple ERCP sessions (Costamagna and
Boškoski 2013).
Studies evaluating the use of fully covered self-expanding metal stents (FCSEMS)
in post-CCY strictures include strictures below the biliary confluence where primary
therapy with mPS has failed. A success rate of 90% with safe removal has been achieved
in several studies with in dwelling times ranging from four to 11 months (Deviere
46
Antti Siiki
et al. 2014; Irani et al. 2014; Kahaleh et al. 2013; Tarantino et al. 2012b). Rate of
adverse events during treatment have been up to 39%, most commonly cholangitis or
fever as well as PEP (Deviere et al. 2014). The migration rate, apparently rising rapidly
after an indwelling time exceeding six months, has ranged from 10% to over 50% in
recent studies (Deviere et al. 2014; Tarantino et al. 2012b). The incidence of stricture
recurrence in 18-month follow-up has been up to 17% (Deviere et al. 2014).
The use of FCSEMS seems to allow a short time and relatively simple treatment
with potentially only two ERCP sessions, but is usually restricted to strictures below
the biliary confluence.
2.9.2 Post-liver transplantation
In the treatment of post-LT strictures, balloon dilation with plastic stenting is considered
superior to dilation only (Zoepf et al. 2006). The well-established endoscopic method
with mPS has been successful in 80–90% of cases (Graziadei et al. 2006; Pasha et al.
2007). With maximal mPS therapy with 2–4 PSs for a shorter duration of 4-9 months,
an immediate success rate of 88% was achieved with a 5% rate of mild complications
(Pasha et al. 2007). Treatment with two PSs for 8–12 months resulted in a long-term
success rate of 90% with a stent-related cholangitis rate as low as 4% (Morelli et al.
2003). The good clinical outcome with infrequent problems associated with mPS
therapy was also sustantiated in a study by Tabibian et al, where mPS therapy of 38
anastomotic post-LT strictures led to a 94% success rate (Tabibian et al. 2010). However,
an incidence of up to 37% for ERCP or stent-related adverse events has been reported,
consisting mainly of cholangitis and PEP (Verdonk et al. 2006). The recurrences
occurred after ERCP in 3-5% (Pasha et al. 2007; Tabibian et al. 2010; Verdonk et al.
2006). To overcome the main drawback of mPS therapy of multiple ERCPs and shorten
the treatment, a rapid sequence mPS therapy with accelerated increase in the number
of stents at two-week intervals with indwelling of maximum number of stents for 5–7
months resulted in an 87% success rate with low complications (Morelli et al. 2008).
Although endoscopy is considered to be the primary management method, also in rare
living donor anastomotic strictures, these respond less favourably to endoscopic therapy
with dilation and mPS: Outcomes of 65–70% have been reported, which may be due
to technical difficulties in traversing the stricture and multiple peripheral anastomoses
(Tsujino et al. 2006; Williams and Draganov 2009).
The development of stents and the relative complexity of mPS therapy have led to
a growing interest in and several studies on FCSEMS usage in post-LT anastomotic
strictures. In the only randomised controlled trial (RCT) of the treatment of anastomotic
Endoscopic Management of Benign Biliary Strictures
47
strictures in 20 patients, the 4-month FCSEMS therapy had an excellent outcome (80–
90%), and was associated with fewer complications, fewer endoscopic interventions and
lower costs than the 12-month mPS therapy with follow-up of 26 months (Kaffes et
al. 2014). By using a special short stent with an anti-migration waist and long removal
threads, neither severe complications nor cases of migration were encountered (Kaffes
et al. 2014). Although a systematic review comparing mPS treatment and small series
of FCSEMS or partially covered self-expanding metal stent (PCSEMS) studies from
2013 did not suggest a clear advantage of CSEMS over mPS, the indwelling time of
over three months was associated with a very similar success rate of 80–90% compared
to mPS, the disadvantage being the migration rate of 16% (Kao et al. 2013). Similarly,
while immediate success rates of up to 86–5% with FCSEMS have been reported, the
drawback has been the migration rate of 23% with recurrence rates up to 48% (Chaput
et al. 2010; Garcia-Pajares et al. 2010). In a Finnish study, an outstanding success rate
has been reported with 13% migration rate with a similar stent to that used in the RCT
by Kaffes et al. which was kept in place for seven months (Haapamaki et al. 2012).
However, the study of 54 patients by Tarantino et al. with success rates of 53–72%
achieved by stent indwelling time as short as two months found an alarming migration
rate of 33–47% with a standard FCSEMS and led to the conclusion that metal stents
should be used only if conventional therapy with mPS fails (Tarantino et al. 2012a).
The most recent large studies of FCSEMS use have reported success rates of 61–
88% with incidence of adverse events of 33%, consisting mostly of mild cholangitis and
migration (Deviere et al. 2014; Kahaleh et al. 2013; Tarantino et al. 2012b). Although
the removal has been unproblematic after the stent indwelling time of 4–6 months in
post-LT anastomotic strictures, recurrences occurred in one out of four patients during
the follow-up of 16–18 months (Deviere et al. 2014; Kahaleh et al. 2013; Tarantino et
al. 2012b). Interestingly, a case report has suggested an effective treatment of post-LT
and post-CCY strictures with FCSEMS even when stenosis necessitates stent placement
over the biliary confluence by securing the contra-lateral duct with a single PS (Poley
et al. 2011). FCSEMSs appear effective in treatment of post-LT anastomotic strictures,
but migration remains an issue to be resolved.
The diagnostic and therapeutic approach to non-anastomotic strictures is similar
to that for anastomotic strictures with endoscopic extraction of sludge, dilation of
accessible strictures and stent placement. The response to endoscopic therapy is at
best 50% with the rate of eventual re-transplantation up to 16–50% due to recurrent
cholangitis or cirrhosis (Baron and Davee 2013; Chan and Telford 2012; Graziadei et
al. 2006; Verdonk et al. 2007). Non-anastomotic strictures require more endoscopic
interventions over prolonged periods of time with sludge extraction and stenting aimed
to decrease or at least delay the need for re-transplantation; endoscopic therapy may
48
Antti Siiki
serve as a bridge to re-transplantation (Baron and Davee 2013; Graziadei et al. 2006;
Verdonk et al. 2007).
2.9.3 Chronic pancreatitis
Chronic pancreatitis -related strictures are the most difficult BBSs to treat with
endoscopic stenting, presumably due to the tight fibrotic calcificating tissue in the
head of the pancreas (Kahl et al. 2003; Pozsár et al. 2004). The 2012 guideline for
endoscopic therapy of CP-related CBD strictures recommended mPS therapy over a
12-month period (Dumonceau et al. 2012). Multiple PSs has been found superior to
both single PSs and to UCSEMSs (uncovered self-expanding metal stent) in CP related
strictures (Van Boeckel et al. 2009). Although the use of a short-term single PS may be
adequate in biliary obstruction related to acute inflammation and concomitant acute
pancreatitis, it has proved insufficient in a long-standing CP related stricture. With
single PS treatment, all recurrences have been reported to occur during the first year
(Cahen et al. 2005; Kahl et al. 2003).
The success rate with mPS therapy has been much poorer in CP than in post-operative
strictures, although CP related strictures occur predominantly in the distal CBD
(Abdallah et al. 2007). Chronic pancreatitis with calcifications especially is associated
with a poor response: A failure rate of up to 83% has been reported while in strictures
associated with non-calcifying CP therapy very seldom fails (Draganov et al. 2002).
In calcifying and non-calcifying cases CP combined, other studies with mPS protocol
have reported success rates as low as 31–44% (Eickhoff et al. 2001; Sakai et al. 2009).
At best, the success rates of 50–60% have been achieved in patients with calcifying CP
treated aggressively with mPS (Pozsár et al. 2004) . However, encouraging results of up
to 92% success rate in four years of follow-up with mPS have been reported in a single
study where half of the patients reportedly had calcifying CP (Catalano et al. 2004).
Adverse events such as PEP have occurred in 2–5%, cholangitis in 3–10% and stent
clogging in up to 34% when mPSs have been used in CP related strictures (Draganov et
al. 2002; Pozsár et al. 2004; Sakai et al. 2009).
Poor compliance of patients with alcohol-related CP is often behind the
complications, such as cholangitis due to stent clogging (Kiehne et al. 2000). It is
noteworthy that in one study the lengthened interval of stent exchange, secondary to
poor compliance, led to two deaths (7%), both of then related to a septic infection of
biliary origin (Pozsár et al. 2004).
The most prominent disadvantages of mPS therapy in CP are the need for repeated
ERCP sessions, high rate of stent dysfunction and poor long-term resolution rate.
Endoscopic Management of Benign Biliary Strictures
49
The latter is possibly due to the inadequate dilation effect of PSs in a fibrotic stricture
(Abdallah et al. 2007) .
The use of CSEMSs would be tempting in CP related strictures because of the
stricture location in the distal CBD, the tight fibrotic nature of the stricture and the
poor resolution rate even with increased number of mPSs in repeated ERCP sessions. In
the early experiments, the treatment of BBS without intention to remove an UCSEMS
was discarded due to eventual stent dysfuntion (Cantu et al. 2005). Next, PCSEMSs
were tried in CP related strictures: In two reports of mPS resistant strictures, PCSEMSs
indwelled for four to five months resulting in 80% clinical success (Behm et al. 2009;
Kahaleh et al. 2004). Tissue ingrowth or secondary stricture at the uncovered part of
the stent was predictably observed in 13% after PCSEMS therapy (Kahaleh et al. 2008).
Tissue hyperplasia and embedding associated with PCSEMS often lead to difficult
removal (Irani et al. 2014).
The first pioneering study showing that FCSEMSs are feasible in CP-related
strictures was originally published as an abstract in 2005; it included six patients, in
two of whom the stent could not be removed after indwelling of 4–6 months due to
proximal migration, one ended up in HJ due to recurrence at six months and three
were strictureless for three years of follow-up (Cahen et al. 2008). After this study
several researchers concentrated mainly on determining the safety of removal in various
FCSEMS designs: In a study with three months of FCSEMS indwelling, 58–65%
success rate in four-month follow-up was achieved with a cost of non-severe adverse
events occurring at placement in 11% and during stent therapy or removal in 16% of
patients. While the anchoring fins of the early stents prevented migration, they caused
ulceration and bleeding from the mucosa as the FCSEMS was extracted (Mahajan et al.
2009). In another stent design without fins, removal was unproblematic but migration
occurred in nearly half of the patients (Park et al. 2011a). When a stent exchange at
two months was then tried to ascertain the safe removal of FCSEMSs equipped with
flared ends for anti-migration, it was noticed that CP-related strictures only achieved
a success rate of 46% (Poley et al. 2012). This finding was substantiated in a recent
series of 75 CP-related CBD strictures, one third of which were treated with PCSEMSs
and two thirds with modern FCSEMSs for seven months: stricture resolution of only
48% with a recurrence rate of 10% in 20 months of follow-up was achieved, again a
much poorer outcome than in other aetiologies. Although these findings supported
the earlier findings of CP-related strictures being more resistant to treatment due to the
fibrotic encasing process of CP, they did also speak for the usefulness of FCSEMSs in
patients in whom prior PS therapy was unsuccessful (Irani et al. 2014).
In 2013, larger multi-centre studies with unvarying treatment protocols started to
appear in the literature about FCSEMS usage in BBS (Deviere et al. 2014; Kahaleh et
50
Antti Siiki
al. 2013). In a study of 127 patients with long-standing CP-related biliary strictures,
a 91% resolution rate after median indwelling period of 11 months was achieved.
The recurrence rate was 10% during the 18-month follow-up, which was better than
in the strictures secondary to CCY or LT. Interestingly, a 3% rate of moderate PEP
was higher than in LT patients. Migration was less frequent than in other aetiologies,
being only 5% in six months of follow-up (Deviere et al. 2014). Finally in 2015, a multicenter RCT directly comparing mPS to FCSEMS in CP-related biliary stricture was
published. The Finnish researchers noticed that in 60 patients six-month treatment
with mPS or FCSEMS provided similarly good clinical result of in two-year follow-up:
90% of the patients in mPS group and 92% of those in FCSEMS group were stricturefree at the end of the follow-up, without difference in rate of stent migration or stricture
recurrence (Haapamaki et al. 2015).
The main conclusion of these largest studies to date was that even with long
indwelling time, modern FCSEMSs could be safely removed. In addition, stricture
resolution and migration outcome, achieved with a reduced number of ERCPs in CP,
suggests a potential advantage over mPSs (Deviere et al. 2014; Haapamaki et al. 2015).
2.9.4 Primary sclerosing cholangitis
In the endoscopic treatment of biliary strictures secondary to PSC, balloon dilation
with or without plastic stents is considered the mainstay of treatment intended to relieve
symptoms, prevent recurrent cholangitis, improve quality of life and survival without
LT (Eaton et al. 2013). On the other hand, endoscopy should not jeopardize timely LT
(Chan and Telford 2012). Since ERCP in PSC setting is associated with complications
far more commonly than ERCPs in the non-PSC population, careful patient selection
is crucial (Ismail et al. 2012; von Seth et al. 2015).
PSC-related strictures usually respond well to dilation: the correct use of stents
that offers optimal resolution with minimal complications has not yet been evaluated
in prospective studies (Eaton et al. 2013). However, dilation followed by short-term
plastic stenting of median nine days (ranging up to 23 days) is safe and effective, and
relieved cholestatic symptoms and LFT in 83% of patients. This strategy has resulted
in re-intervention-free follow-up of one and three years in 80% and 60% of patients
respectively (Ponsioen et al. 1999). A later study of PSC patients who underwent
interventions for dominant strictures reported that dilation alone provides outcomes
similar to dilation with PS indwelling for three months. In this study the PSs were
associated with more complications, but, on the other hand, all the stents were inserted
Endoscopic Management of Benign Biliary Strictures
51
in patients in whom dilation alone was not believed to improve biliary drainage
sufficiently (Kaya et al. 2001).
Stricture dilation with or without stent insertion resulted in perforation in 2–5% of
cases (Kaya et al. 2001; Ponsioen et al. 1999). A recent large study reported the incidence
of perforation to be up to 6% in any ERCP performed for PSC (von Seth et al. 2015).
Consequently, after a fragile PSC-related stricture is balloon-dilated with a risk of
contrast extravasation, a clinical practice of a short-term stent therapy may be reasonable
to ensure bile flow downstream from the potential leak site. The rate of cholangitis is
elevated after the dominant stricture is managed by intrabiliary interventions such as
brushing, dilation and stent insertion to provide biliary drainage. In narrow strictures
associated with PSC it is sometimes impossible to use stents larger than 7F. It has been
noted that the lower the diameter of the PS, the higher the incidence of cholangitis. The
infrequent use of multiple PSs in PSC-related dominant strictures was not associated
with different complication profile than in the rest of the patients (Navaneethan et
al. 2015b). The use of FCSEMSs is far from routine in PSC-related strictures due to
the stent diameter and high radial force usually inappropriate to narrow bile ducts;
FCSEMSs have occasionally been used in some studies, but no subgroup analysis of
PSC has been published (Irani et al. 2014; Mahajan et al. 2009; Tarantino et al. 2012b).
Taken together, the optimal treatment strategy for PSC-related strictures is not
evidence based (Eaton et al. 2013). It should include routine brush samples used for
cytology and advanced analyses, followed by cautious balloon dilation and possibly a
short-term (two weeks) PS therapy to ensure biliary drainage (Baron and Davee 2013).
Forthcoming RCTs assessing the rationale of dilation and stent insertion in PSC will
hopefully clarify optimal stent management in PSC. Prognostic models to predict the
timing of LT during the life-long surveillance of PSC patients have been proposed,
based on annual radiologic imaging with serum CA19-9 assessment and endoscopic
sampling (cytology, FISH, DIA, flow cytometry). However, their use in individual
patients has been questioned due to significant variation in disease course and lack
of consensus and evidence of an optimal model (Chapman et al. 2010; Eaton et al.
2013; Ehlken and Schramm 2013). The protocol is aimed to detect dysplasia before the
development of CCA to ensure a timely LT. The thoroughness of national surveillance
is affected by the availability of liver transplants, which is generally good in the Nordic
countries. The surveillance protocol of PSC developed in Helsinki University Hospital
is presented in Figure 4 (Boyd et al. 2014).
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Antti Siiki
Figure 4. Algorithm for diagnosis and surveillance of PSC (primary sclerosing cholangitis) developed
by Färkkilä and co-workers in Helsinki University Hospital (Boyd et al. 2014). ERC: endoscopic
retrograde cholangigraphy, m-Amsterdam: modified Amsterdam scale of intra- and extrahepatic
severity of PSC, CT: computed tomography, MRI: magnetic resonance imaging, R: cytology grade,
LT: liver transplantation. Presented with permission from Professor Färkkilä, University of Helsinki,
Finland.
2.9.5 Autoimmune cholangitis
There are no publications comparing different endoscopic treatment methods of IgG4related biliary obstruction. Considering the indeterminate nature of a stricture at the
time of ERCP, tissue sampling with a single plastic stent insertion is usually sufficient
to provide biliary drainage during steroid therapy. In case of an early treatment failure,
re-evaluating the diagnosis has to be contemplated, after which stent exchange - with or
without increase in the number of PSs or exchange to FCSEMSs - remain as options. In
IAC and IAP short-term endoscopic management is aimed to support the corticosteroid
therapy by relieving the obstruction caused by primary biliary inflammation or external
mass (Chan and Telford 2012).
Endoscopic Management of Benign Biliary Strictures
53
2.9.6 Other causes of BBS
Several other infrequent aetiologies of BBS have been described in the literature without
studies evaluating the treatment methods (Table1). In most cases, endoscopy is the
intervention of choice with similar general principles as in more common aetiologies.
Selective biliary guide wire cannulation is the prequisite for safe procedures, followed
by cholangiography, balloon dilation using 4–12 mm balloon advanced across the
stricture under fluoroscopic guidance and inflated to facilitate the insertion of initially
1–2 PSs (Baron and Davee 2013). Adequate tissue sampling and radiologic imaging for
the differential diagnosis of occult malignancy are warranted (Chan and Telford 2012).
When the diagnosis becomes obvious, the initial PS may be followed by the insertion of
tri-monthly exchanged and gradually increased number of PSs to reshape the stricture
or insertion of FCSEMSs in selected cases (Baron and Davee 2013; Costamagna and
Boškoski 2013).
2.10 Treatment with endoscopic stents
The development of stents has led to situation in which FCSEMSs are replacing
multiple PS therapy in CBD strictures in clinical work, despite the lack of strong
evidence (Deviere et al. 2014). There are currently only two RCTs on this issue, one of
post-LT strictures and another of CP -related strictures (Haapamaki et al. 2015; Kaffes
et al. 2014). The plastic stents are used in cases where FCSEMSs are not practical, such
as in strictures in the intrahepatic ducts or at the biliary confluence (Costamagna and
Boškoski 2013; Dumonceau et al. 2011; Larghi et al. 2008). The dilation of a BBS is
seldom enough for long-term treatment (Zoepf et al. 2006). In the early years of ERCP
practice the dilation balloon may have been one of the few instruments to fit the narrow
working channel of early duodenoscopes. However, it still has its place in facilitating PS
insertion across a narrow stricture (Costamagna and Boškoski 2013).
BDBSs could potentially be the next generation of biliary stents that could overcome
disadvantages related to traditional stents (Lorenzo-Zuniga et al. 2014). BDBSs
have been successfully used percutaneously in BBS (Mauri et al. 2013). However, no
endoscopic implantation device has been available for BDBS.
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Figure 5. Three types of biliary stents. Left: 10 F x 7 cm polyethylene plastic stent (Advanix,
Boston Sci, MA, USA). Centre: Nitinol braided silicone covered self-expanding 10 mm x 60 mm
FCSEMS (SX-Ella, Nitinol Plus, Ella, Czech Republic). Right: Braided self-expanding polydixanone
biodegradable 8 mm x 60 mm BDBS (Ella, Czech Rep)
2.10.1Plastic stents
Plastic stents are the most inexpensive and simplest types of endoscopically inserted
stents, prototypes of which were introduced in the late 1970s (Soehendra and
Reynders-Frederix 1980). Currently several different designs of polyethylene stents
are commercially available. They usually have anchoring flaps at both ends, and most
commonly have a calibre of 7, 8.5 or 10 F and length of 5–15 cm. A single PS may be
used to treat a BBS, as a bridge to definitive treatment in an icteric patient and in postCCY bile leaks (Perri et al. 2011). Multiple plastic stents have been shown to be superior
to single plastic stents or UCSEMSs in the long-term treatment of BBS (Van Boeckel
et al. 2009). Single, small bore (diameter 7–8.5 F) PSs especially have a very limited
dilation effect and failures in the treatment with episodes of acute cholangitis occur in
up to 30–50% of patients (Perri et al. 2011; Van Boeckel et al. 2009). According to a
Swedish nationwide ERCP study, the stents used are plastic in 79%, and single in 87%
of cases (Enochsson et al. 2010).
BBS therapy with tri-monthly ERCPs where increasing numbers of mPSs are placed
side-by-side across the stricture facilitated by balloon dilation has been supported
as a treatment of choice especially in post-operative cases (Baron and Davee 2013;
Costamagna et al. 2001). Most of the study protocols have all the stents removed at
12–14 months (Costamagna et al. 2001; Draganov et al. 2002). Short stent exchange
interval of two weeks (Morelli et al. 2008) and extended indwelling up to six months
(Lawrence et al. 2010) have been successfully tried out to shorten treatment duration
Endoscopic Management of Benign Biliary Strictures
55
and to reduce the number of ERCPs required. The major advantages of mPS therapy
are the gradually increasing continuous dilation effect and the possibility to treat even
strictures at the biliary confluence with insertion of PSs going up to the intrahepatic
branches (Costamagna et al. 2001; Dumonceau et al. 2011). In addition, stent
displacement, migration or poor response can be managed at the time of any stent
exchange (Costamagna and Boškoski 2013). The main disadvantage is the number of
ERCP sessions needed; typically a minimum of four per patient (Costamagna et al.
2010; Tabibian et al. 2010). The mPS therapy is demanding for both endoscopist and
patient compliance. Such a BBS treatment method is a fairly infrequent procedure,
and only few centres or endoscopists have extensive experience of it (Costamagna and
Boškoski 2013; Enochsson et al. 2010).
While the adverse events related to mPS insertion are usually mild, occurring at a
rate of 1–9%, stent occlusion and cholangitis necessitate early stent exchange in 7–18%
(Costamagna et al. 2001; Draganov et al. 2002; Sakai et al. 2009). Stent clogging is
thought to result from the accumulation of bacterial biofilm and sludge inside the stent
(Donelli et al. 2007). While in all BBSs the clinical success rate is up to 80%, the poorest
outcomes are associated with complex post-operative hilar strictures and strictures
secondary to calcifying CP, which are associated with success rates of 25% and 8–44%
respectively (Draganov et al. 2002; Sakai et al. 2009). Thus the main problems of mPS
therapy are failure to achieve stricture resolution or a relapse of the stricture soon after
treatment (Perri et al. 2011).
2.10.2Covered self-expandable stents
Self-expanding metal stents (SEMS) were first used in the 1980s in malignant CBD
strictures to provide adequate radial strength and patency in tight strictures secondary
to tumours in e.g. the head of the pancreas (Neuhaus, Hagenmuller, Classen 1989). At
that time UCSEMSs were the only option available. For benign indications, UCSEMSs
were first used in chronic pancreatitis related tight strictures in patients unfit for surgery
(van Berkel et al. 2004). With stent development, interest has since turned to CSEMSs,
in which the covering prevents tissue ingrowth and allows eventual removal (Cahen et
al. 2008; Vakil 2011).
Today FCSEMSs are entirely silicone covered nitinol stents, with 10 mm postdeployment diameter, allowing flexion during implantation, patency and later removal
(Baron TH and Davee 2013; Dumonceau et al. 2011; Vakil 2011). FCSEMS are best
suited to CBD strictures or post-LT anastomotic strictures. If a FCSEMS is placed
in the proximal CHD or over the biliary confluence, the plastic cover obstructs the
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Antti Siiki
contralateral main intrahepatic branch (Dumonceau et al. 2011). In most cases, a
FCSEMS is implanted so that the lower end remains visible from the duodenum to
facilitate removal. Another option is to implant a special design FCSEMS up in the bile
duct with only removal threads dangling visible in the duodenal lumen. This technique
is used to avoid too long stents, e.g. in CHD or post-LT strictures (Haapamaki et al.
2012; Kaffes et al. 2014; Poley et al. 2012). The potential of the uncovered part of the
stent to embed and integrate into the biliary wall and consequent problematic removal
inhibits the use of PCSEMSs in the treatment of BBS (Kawakubo et al. 2012; Vakil
2011).
Several large studies on the usage of FCSEMSs in BBS have been published during
the last few years (Deviere et al. 2014; Irani et al. 2014; Kahaleh et al. 2013; Perri et
al. 2012; Tarantino et al. 2012b; Wagh et al. 2013). The current evidence on FCSEMS
use in BBS is based on these, and on a few earlier cohort studies (Cahen et al. 2008;
Garcia-Pajares et al. 2010; Hu et al. 2011; Mahajan et al. 2009; Traina et al. 2009). The
first RCT on endoscopic treatment of BBS to compare FCSEMSs with multiple PSs
in patients with post-LT strictures showed similar treatment success with a reduced
number of ERCPs and fewer adverse events in the FCSEMS group (Kaffes et al. 2014).
Another recent RCT addressing treatment of strictures secondary to CP reported
that six-month treatment with either mPS or single FCSEMS resulted in similar 90%
clinical success rate in two-year follow-up (Haapamaki et al. 2015)
The main advantage of FCSEMSs is the good bile flow because of a large, 10 mm
post-deployment diameter with a radial force to press the stricture open (Baron TH and
Davee 2013). In addition, stent insertion devices function quite smoothly and usually
no previous balloon dilation is necessary (Deviere et al. 2014). Clinical experience has
supported the encouraging results gained from FCSEMS studies; up to 10–12 months
of indwelling time has been unproblematic with a good, 76–90% stricture resolution
when stent therapy has ranged from 6-12 months (Deviere et al. 2014; Kahaleh et al.
2013; Tarantino et al. 2012b; Wagh et al. 2013). Even though a single FCSEMS is
currently ten times more expensive than a single PS, FCSEMS therapy was still costeffective due to fewer endoscopy sessions and shorter hospital stay in the only study so
far to include a cost-analysis (Kaffes et al. 2014).
The possible drawbacks of FCSEMS include migration and difficult removal
as well as complications such as acute cholangitis. The rate of overall adverse events
has been up to 25–27% during the course of treatment with FCSEMSs (Deviere et
al. 2014; Kahaleh et al. 2013). Biliary cannulation and EST, with associated risk of
haemorrhage and pancreatitis, are usually required for diagnostic procedures before
stent implantation, even if the FCSEMS itself can be placed endoscopically without
EST (Deviere et al. 2014; Haapamaki et al. 2012). Cholangitis has been reportedly
Endoscopic Management of Benign Biliary Strictures
57
associated with FCSEMS in 10-14% and pancreatitis in 3% (Deviere et al. 2014;
Irani et al. 2014). Although not supported in all studies, it has been postulated that
FCSEMSs placed in the distal CBD could potentially predispose to PEP by obstructing
the pancreatic duct orifice due to covering membrane or the high radial force during
stent expansion (Kahaleh et al. 2013).
One of the largest recent studies with FCSEMSs reported migration rates as high
as 24–29% (Deviere et al. 2014), while a low risk of migration of 2–10% has also been
presented (Haapamaki et al. 2015; Irani et al. 2014; Kahaleh et al. 2013). Regardless of
the type of stent, migration is associated with a lower rate of stricture resolution (Deviere
et al. 2014; Kahaleh et al. 2013). However, not all migrations result in treatment failure
or necessitate additional procedures (Deviere et al. 2014; Irani et al. 2014; Tarantino et
al. 2012b). In most cases, migration occurs distally or downwards and may potentially
lead to treatment failure, obstruction of the bile duct or bowel or perforation (Baron
and Davee 2013; Deviere et al. 2014; Kaffes and Liu 2013). Proximal migration, on the
other hand, results in difficult removal (Baron and Davee 2013; Deviere et al. 2014;
Kaffes and Liu 2013). To overcome migration, stents with convex shape and anchoring
flaps or flares at the ends have been tested (Moon et al. 2012; Park et al. 2011a; Perri et
al. 2012).
In recent studies with modern FCSEMSs without specific anti-migration features
and with indwelling time of up to 12 months, eventual endoscopic stent removal has
been achievable in all cases with only occasional use of e.g. stent-in-stent technique in
difficult proximal migration (Deviere et al. 2014). The cases of impossible removal have
occurred in patients with CP-related strictures with poor compliance to participate in
the follow-up and consequent inadvertently long indwelling (Irani et al. 2014). However,
the optimal stent indwelling time is still debated because shorter indwelling of only six
months seems to provide over 90% stricture resolution rate in CP (Haapamaki et al.
2015).
Acute cholecystitis, thought to result from obstruction of the cystic duct, may occur
in nil to 3% of all cases (Deviere et al. 2014). A higher incidence of up to 33% has been
associated with narrow CBD with intact gallbladder and CSEMS inserted above the
level of the cystic duct junction (Irani et al. 2014). Post-deployment pain occuring in
2–6% of cases is presumably caused by stent expansion to the maximum diameter in
24–48 hours, and seldom requires hospitalisation or stent removal (Deviere et al. 2014;
Irani et al. 2014; Kahaleh et al. 2013).
An alarming tendency of late de-novo strictures, which were not secondary to the
disease progression or recurrence, was observed in some of the early studies evaluating
FCSEMSs. The incidence of these secondary strictures has ranged 2–8% (Irani et al.
2014; Kasher et al. 2011; Sauer et al. 2012) to up to 35% (Phillips et al. 2011). The
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highest incidence of strictures occuring at the proximal end of the stent was observed in
post-LT strictures with stents with exceptional radial force, suggesting that ischaemic
factors and atypical stent design were the principal causes (Phillips et al. 2011).
A similar observation was made more recently when 2% of patients, none of whom
had a post-LT stricture, treated with CSEMSs developed a new stricture requiring
endoscopic treatment. It was hypothesized that the discrepancy between stent diameter
and bile duct diameter could lead to a pressure necrosis, circumferential ischaemia
and ulceration causing a de-novo stricture. Thus the authors recommended avoiding
CSEMSs with diameter greater than the bile duct where the proximal end of the stent
would reside (Irani et al. 2014). It is interesting that the molecular level changes in
response to modern FCSEMSs that may be associated with stricture resolution, late restricturing or difficult removal have not been extensively researched (Vakil 2011). In a
single study, FCSEMSs appeared to induce only mild inflammation, fibrosis or epithelial
injury in histologic examination after indwelling of only three months in an animal
model (Bakhru et al. 2011). In a second animal study an incidental de-novo stricture
was present in 42% of autopsies after FCSEMS therapy (Lee et al. 2014). While the
most severe epithelial hyperplasia was noted when the silicone covering of a FCSEMS
was damaged and strictures most commonly occurred when a stent had been in place
for more than six months, the authors hypothesised that the small calibre of bile duct
comparing to stent diameter may predispose to de-novo stricture formation. The role
of tissue response towards stents and covering materials is unclear in the development
of de-novo strictures and warrants further attention in future studies (Lee et al. 2014).
The use of FCSEMS in biliary strictures below the biliary confluence is both
technically feasible and has been associated with a good resolution rate. The current
evidence supporting their use is based on several cohort studies, and only recently in
terms of the post-LT strictures and CP on two RCTs (Haapamaki et al. 2015; Kaffes
et al. 2014).
2.10.3Biodegradable stents
In BBS therapy, BDBSs could potentially offer a radial expansion force and patency
similar to FCSEMSs without the costs and morbidity associated with repeat ERCP
procedures (Lorenzo-Zuniga et al. 2014). BDBSs could also overcome other limitations
of current stents, such as difficult removal. In addition, they would not require
removal even if they migrated (Tokar et al. 2011). The most promising biodegradable
materials in stent design are synthetic polymers such as polylactid acid (PLA) and
polydioxanone (PDX), the degradation and behaviour of which in the human body are
Endoscopic Management of Benign Biliary Strictures
59
well documented (Freudenberg et al. 2004). PDX has been widely used in absorbable
PDS surgical sutures from 1980s (Ray et al. 1981) and has been proven to be a durable
material in the environment of the human biliary duct (Freudenberg et al. 2004). The
degradation characteristics of PLA resemble material used in Vicryl (Ethicon EndoSurgery, Ohio, US) sutures (Freudenberg et al. 2004). A single experiment has been
published on the endoscopic implantation of a non-radiopaque poly-capro-lactone
BDBS, a material close to that used in Monocryl (Ethicon) sutures (Itoi et al. 2011).
PDX is the only biodegradale material from which BDBSs are currently manufactured
and commercially available.
The first experimental PLA biodegradable stents were inserted into rabbit ureters in
Finland (Kemppainen et al. 1993). This was followed by a variety of studies on their use
in human pancreato-biliary tract surgery and in animal models (Ginsberg et al. 2003;
Laukkarinen et al. 2007a; Laukkarinen et al. 2008; Nordback et al. 2008; Nordback et
al. 2012) . The endoscopically inserted Finnish designed, braided, self-reinforcing PLA
stents with 10 mm diameter and 50 mm length showed encouraging characteristics of
expansion and patency in the CBDs of pigs (Ginsberg et al. 2003). Further studies on
experimental pig models have confirmed their predictable degradation in three to six
months of a PLA BDBS in securing a HJ anastomosis (Laukkarinen et al. 2007b) and
in the CBD for the treatment of a cystic duct leak (Laukkarinen et al. 2007a).
Subsequent studies have concentrated on the percutaneous insertion of BDBSs
made of PDX in the absence of an endoscopic insertion device (Petrtyl et al. 2010).
In percutaneous use in humans PDX stents have reportedly been associated with
immediate radial expansion, good patency and complete degradation in six months
(Mauri et al. 2013; Petrtyl et al. 2010). These findings have been substantiated by a
recent study on PDX biliary stents inserted in an animal model (Grolich et al. 2015).
In the largest human study so far, 10 patients were treated for post-operative and CPrelated BBS with percutaneosly inserted BDBSs. The 16-month follow-up witnessed
no relapses or re-stricturing, indicating adequate radial expansion strength to treat the
BBS, but a 30% incidence of transient episodes of cholangitis (Mauri et al. 2013). It has
been postulated that PDX has a higher flexibility, degrades more slowly by hydrolysis
and potentially retains its mechanical properties longer than other biodegradable
polymers such as polyglycolide or PLA (Sabino, Márquez, Feijoo 2000). Although PLA
and PDX stents have not been compared, as a suture material PDX appears to have an
optimal degeneration pattern in human bile environment (Freudenberg et al. 2004).
PDX is expected to degrade by hydrolysis in 3-6 months (Sabino, Márquez and Feijoo
2000), which finding concurs with clinical results on the radiologic disappearance of
braided PDX stents and absence of re-stricture in six months (Mauri et al. 2013) as well
as with the results from an animal study of PDX biliary stents (Grolich et al. 2015).
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One concern about BDBSs has been the possible epithelial hyperplasia which may
develop after stent therapy, occasionally observed after the use of oesophageal PDX stents
(Hair and Devonshire 2010; Lorenzo-Zuniga et al. 2014). In biliary PLA stent studies
on animals there have been no changes similar to those associated with SEMSs, i.e. no
epithelial hyperplasia, inflammation or proliferation after stent therapy; (Ginsberg et
al. 2003; Laukkarinen et al. 2007a). In the study on pigs with an experimental cystic
duct leak a blinded histologic analysis excluded any signs of residual stent material,
scar formation and granulation after BDBS therapy of six months (Laukkarinen et al.
2007a). It has been suggested that the unexpected finding of neglible tissue reaction
is not solely attributable to the lower radial expansion force than in SEMS, but to the
material itself (Ginsberg et al. 2003). These findings were supported by the results from
an animal experiment where the intensity of inflammatory foreign-body reaction to
PDX stents decreased over the duration of stent therapy and was considered temporary
with no clinical consequences (Grolich et al. 2015). The potential problems arising
in the endoscopic use of biliary PDX stents are yet to be discovered; the feasibility of
implantation in more widespread use, the predictability of stent expansion, sufficient
radial force for stricture remodelling and possible migration risk remain uncharted.
Before BDBS insertion, EST is often necessary but correspondingly to FCSEMSs, preimplantation dilation of a stricture is not (Mauri et al. 2013).
Consequently, there is a clear need for more studies comparing mPSs and
CSEMSs as well as evaluating the emerging role of endoscopically inserted BDBSs
in the management of BBS. Although some animal studies and experiences from
percutaneous use are encouraging, the lack of an endoscopic implantation device for
BDBSs has so far prevented their clinical use (Mauri et al. 2013; Grolich et al. 2015).
Furthermore, molecular level pathogenesis and tissue response to biliary stents remains
largely unstudied (Bakhru et al. 2011; Lee et al. 2014).
Endoscopic Management of Benign Biliary Strictures
61
3 AIMS OF THE STUDY
The aim of this thesis was to review the current endoscopic diagnostics and treatment
of relatively infrequent benign biliary strictures.
The detailed aims of the studies were as follows:
I)
To describe the rate of complications and success rate of ERCP in a Finnish
central hospital.
II)
To evaluate the usefulness of single operator peroral SpyGlass cholangioscopy
in the diagnostics of BBS, especially in PSC, which is still one of the most
difficult and least published entities in BBS.
III) To compare the two methods of endoscopic BBS treatment currently in use
in terms of clinical success and complication rate: a traditional method with
insertion of mPSs and increasingly used therapy with CSEMSs.
IV) To examine the differences in protein expression in an experimental animal
model between: a) intact bile duct and an ischaemic biliary stricture and b)
between strictures treated with FCSEMSs or BDBSs.
V)
62
To assess the feasibility of a novel endosopically inserted biodegradable stent
and its implantation device in post-operative biliary leak.
Antti Siiki
4 MATERIALS AND METHODS
4.1 Study I: ERCP success rates and complications
in a Finnish central hospital
The database of Kanta-Häme Central Hospital (KHKS) was searched for all ERCPs
performed from 2002 to 2009 as specified by the procedure codes. A retrospective
chart review was continued for up to 30 days after the procedure or to the end of
longer hospitalisation at KHKS or local district hospitals. The primary method of
cannulation was to use a sphincterotome or to cannulate over a guide wire. In the early
years, contrast medium injection was sometimes used to facilitate cannulation. When
necessary, a needle-knife precut sphincterotomy was performed. In the last few years of
the period in question the double-guide-wire technique or pancreatic sphincterotomy
were used selectively.
During the last two to three years of the study period a routine antibiotic prophylaxis
was administered. Before this, antibiotics were given if a stent insertion was planned or
if a patient had a bile duct obstruction or an acute infection. Pre-ERCP rectal diclofenac
was not routinely administered. In the last few years of the study period ERCPs were
performed under general anaesthesia supervised by an anaesthesist. In the earlier years,
the endoscopy team managed and monitored sedation. Routine serum WBC count,
haemoglobin, CRP and amylase were measured after 6–10 hours. Each patient was
followed up in the hospital for at least 24 hours after ERCP.
Complications were classified using the standardised criteria presented in Table 3
(Cotton et al. 1991).
4.2 Study II: Initial experience of SpyGlass cholangioscopy in
biliary strictures secondary to sclerosing cholangitis
The first 11 consecutive patients undergoing ERC and SOC for intrahepatic or
combined PSC from March to August 2012 in Tampere University Hospital were
included. The diagnosis of PSC was based on the typical cholangiographic findings in
Endoscopic Management of Benign Biliary Strictures
63
MRI and in nine cases (82%) also on earlier ERC. MRI was performed using standard
imaging protocols including heavily T2-weighted 2D thin-section and thick sequences
in coronal plane to visualise all biliary ductal structures. Additionally, gadolinium
enhanced sequences were routinely used to estimate inflammatory and neoplastic
changes. An experienced endoscopist performed all the endoscopies with standard
ERC and Spyglass SOC instrumentation (Boston Scientific) with air insufflation.
Tissue samples were harvested by endoscopic brushing for cytology and flow cytometry
as well as by visually controlled Spybite (Boston Scientific) biopsy forceps for histology.
The number of histological biopsies ranged from four to six for each patient. A routine
single-dose prophylactic intravenous cefuroxime and diclofenac suppository was
administered to all patients before ERC. The endoscopy team managed the patient’s
sedation. Duodenal peristalsis was reduced by giving, i.v. hyoscine butylbromide or i.v.
glugacon.
ERC- and cholangioscopy-related findings were recorded prospectively. Patient
history, serum LFT and tumour marker CA19-9, brush cytology and flow cytometric
analysis as well as pathological analysis of the biopsies were recorded. Post-ERC
complications were graded and prospectively recorded for 30 days after the procedure
according to their severity and length of the associated hospital stay as in Study I (Table
3).
An experienced abdominal radiologist re-analysed the patients’ MRI and
cholangiography images. The intra- and extrahepatic PSC findings were graded
according to the Amsterdam classification (Majoie et al. 1991) presented in Table 2.
Data on patients’ later treatment and follow-up, including the need for any further
procedures, was recorded.
The endpoints were technical success and complication rate of ERC with SOC
and the adequacy of biopsies obtained. The effect on clinical decision-making was also
subjectively assessed in terms of additional benefit obtained by the direct stricture
visualisation and biopsies. Moreover, to assess the need for repeated endoscopy
procedures or later events, e.g. disease progression, a prospective follow-up was carried
out from the hospital records until March 2014.
4.3 Study III: Meta-analysis comparing covered self-expanding metal
stents and multiple plasic stents in benign biliary strictures
A literature search of the Medline and Embase and Scopus databases was conducted for
studies published in English and completed by a manual search of the reference lists of key
studies. The titles and abstracts of the studies identified were screened and the full texts
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of potentially relevant publications were obtained. Studies on endoscopic treatment of
BBS with PSs or CSEMSs and with adequate data about stent type, stricture aetiology,
complications and outcome were considered to meet the inclusion criteria. The search
strategy, resulting in 13 PS studies and 10 CSEMS studies, is presented in Figure 6.
Data extracted from the selected studies included: study details, characteristics of study
population and strictures treated, technical success, complications related to stent
insertion and removal, complications and other adverse events such as stent migration
in follow-up, duration of stent therapy and clinical success at stent removal after six and
12 months and at the end of follow-up. The definitions are presented in Table 6.
To assess the outcome of the stent therapy, three aetiology groups were formed:
chronic pancreatitis (CP), post-liver transplantation (LT) and others (Other Strictures).
The aetiology-specific outcome was available from most of the studies. Five CSEMS
studies reported the results of single stricture aetiology and seven studies of multiple
stricture aetiologies. Eleven PS studies addressed single stricture aetiology and two
studies multiple stricture aetiologies. When it was only possible to extract data on the
majority of the study population, and not aetiology-specific data; these results were
grouped according to the majority. In the strictures related e.g. to CCY or bile duct
stones, case numbers were insufficient for subgroup analysis. Therefore all strictures
except those due to chronic pancreatitis and liver transplant were combined into a
single group of other aetiologies for outcome. Case numbers in the aetiology groups
were as follows: CP: 128 CSEMS and 90 PS, LT: 118 CSEMS and 190 PS, and other
aetiologies: 130 CSEMS and 290 PS.
The primary outcome was sustained clinical success defined as stricture resolution
without unscheduled endoscopic interventions or treatment failure during follow-up.
Secondary outcome parameters were technical success rate and complications.
Endoscopic Management of Benign Biliary Strictures
65
Records identified through Medline
database search (n=3558)
Records identified through Cochrane
database search (n=420)
Records excluded after review of title and abstracts (n=3899)
Full text articles assessed for eligibility (n=79)
Additional articles after handsearching of reference lists (n=20)
Studies of potential relevance (n=99)
Included in meta-analysis (n=23)
Plastic stent n=13, cSEMSn n=10
Excluded with reasons (n=76)
Insufficient data
or otherwise not relevant n=30
Single plastic stent n=28
Uncovered or unremoved stent n=7
Percutaneous treatment n=3
Abstract only n=3
Case report n=3
Dilation only n=2
Post sphincterotomy stricture n=1
Figure 6. Flow chart of the search strategy for meta-analysis and systematic review
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Table 6. Definitions of BBS, treatment methods, outcome measures, complications and follow-up in
Study III
Expression
Definition
Benign biliary stricture
A non-malignant stricture of common bile duct secondary to chronic pancreatitis, orthotopic-liver transplantation, cholecystectomy or other cause.
Multiple plastic stents
A treatment strategy of tri-monthly plastic stent exchange with insertion
of a gradually increasing number of plastic stents across the stricture and
eventual stent removal at 12 months
CSEMS
A BBS treatment with PCSEMSs or FCSEMSs covered self-expandable
metal stent with eventual stent removal
Clinical success
A successful clinical stricture resolution at a given time point without
unscheduled interventions or a change of treatment strategy.
Procedure related complications
ERCP or stent exchange related complications, such as pancreatitis,
cholangitis, haemorrhage, perforation and post-insertion pain requiring
hospital admission.
Other adverse events
Infections, stent migration or stent occlusion in the follow-up period
Early complications
Occurring during the first 30 days from initial stent insertion
Late complications
Occurring during follow-up until stent removal
Follow-up
The data on treatment success was collected at one or more time points;
at stent removal, at 6 and 12 months and at the end of follow-up.
4.4 Study IV: Protein expression in benign biliary strictures before
and after treatment with metal and biodegradable biliary stents
BBS was induced surgically in 14 pigs in laparotomy by subtotal ligation of the CBD
with absorbable sutures causing controlled ischaemia. Two months after induction of
BBS, the CBD was cannulated under duodenoscopy. In ERC a tight BBS, estimated
length of median 10 mm (range 9–11 mm) was confirmed in all animals.
The groups compared are shown in Figure 7. Five animals had no treatment of the
stricture (untreated). From these animals, BBS samples were harvested at two months
after the induction of BBS. Nine animals received endoscopic treatment of BBS; in
the BDBS group four with a braided self-expandable polylactide BDBS (diameter 7
mm, length 50 mm; custom-made at the Institute of Biomaterials, Tampere University
of Technology, Finland) and in the CSEMS group five with an FCSEMS (diameter
10 mm, length 80 mm; Wallstent, Boston Sci, USA). Control samples were harvested
from the intact part of the bile duct. During follow-up, stent patency, function and
location were confirmed by repeated serum liver function tests and native x-ray. At six
months tissue samples were harvested from the stent-treated BBSs and the animals
were exsanguinated. All procedures were performed in at the University of Kuopio,
Endoscopic Management of Benign Biliary Strictures
67
Finland (now part of the University of Eastern Finland) under general anaesthesia
with intubation. The animals received antibiotics for infection profylaxis i.v. cefuroxim
before operations and peroral cefalexin for three days afterwards. The animals were fed
with standard pig chow and were allowed free access to water and free movement in
their pens. Adequate intra- and postoperative analgesia was provided.
The management of protein samples and identification of expression patterns took
place entirely in the University of Heidelberg, Mannheim, Germany. The proteins were
subjected to a fractionated extraction protocol as described previously (Lohr et al. 2010).
After protein labelling for 2-dimensional gel electrophoresis (DIGE), the separated
proteins in DIGE gels were visualised using image analysis software. Gel staining,
digestion, protein extraction and identification of protein sequences were performed
according to earlier published methods (Hellman et al. 1995; Mortz et al. 2001).
Figure 7. Protocol of Study IV. In 14 Yorkshire pigs, an ischaemic stricture was induced by subtotal
ligation of the CBD. Five animals formed a control group (Intact BD) and five were left untreated
(BBS). At two months ERC was performed and polylactide BDBS or FCSEMS was implanted across
the stricture in four (BDBS) and five pigs (CSEMS) respectively. The drawing is from the archives of
Docent Johanna Laukkarinen, and presented with her permission.
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Antti Siiki
4.5 Study V: Biodegradable biliary stent in the endoscopic
treatment of cystic duct leak after cholecystectomy.
The first patient enrolled in the prospective study of endoscopic BDBS use in cystic duct
leak was a previously healthy 64 year-old male admitted two days after an elective open
CCY with elevated temperature and CRP and upper abdominal pain. Trans-abdominal
ultrasound and CT scan revealed a 6 cm fluid accumulation in the gallbladder bed
without signs of biliary obstruction or concomitant vascular injury. The MRCP did
not show any CBD stones, but failed to accurately identify the site of the bile leak. A
radiologist inserted a percutaneous 8F pigtail drain under ultrasonic guidance into the
fluid accumulation, from which elevated bilirubin confirmed a post-operative bile leak.
As the bile flow into the drain continued for eight days after surgery, ERCP was
performed under conscious sedation. An anti-inflammatory suppository of diclofenac
was given an hour before ERC. Duodenal peristalsis was reduced with buscopan i.v.
The patient was receiving i.v. meropenem treatment. A standard duodenoscope with air
insufflation was used. The cholangiography revealed a slight leakage of contrast in the
vicinity of the cystic duct stump (Figure 8).
Before stent implantation, a long stiff guidewire was replaced. A custom made
braided non-covered self-expandable biodegradable PDX stent with golden radiopaque
markers at both ends and 40 mm in length with a post-deployment diameter of 8 mm
(Ella CS, Czech Republic) was then inserted (Figure 8 and 9).
Endoscopic Management of Benign Biliary Strictures
69
Figure 8. BDBS insertion. A. Cholangiography image from ERCP showing a suspected leak of bile
from the stump of the cystic duct just below the surgical clips (arrow). A percutaneous pigtail drain is
visible on the left and the implantation device on the right side of the duodenoscope. B. Insertion of
BDBS. The arrows indicate the radiopaque markers at both ends of the stent. C. Endoscopy image
of insertion of BDBS. D. Endoscope image of the implanted BDBS. The distal end of the stent is
visible from the duodenum and the guidewire is still inside the stent. Re-printed with permission of the
copyright holder, published in J Laparoendosc Adv Surg Tech 2015; 25(5): 419–22, Siiki et al.
70
Antti Siiki
Figure 9. The braided self-expandable biodegradable polydioxanone (PDX) non-covered biliary stent
with golden radiopaque markers at both ends with a post-deployment diameter of 8 mm and the
endoscopic implantation device with the compression tool for stent loading (Ella CS, Czech Republic).
Re-printed with permission of the copyright holder, published in J Laparoendosc Adv Surg Tech 2015;
25(5): 419–22, Siiki et al.
Endoscopic Management of Benign Biliary Strictures
71
5 STATISTICS
In Study I statistical analysis was performed using IBM SPSS Statistics 19.0 (IBM
Computer Software, USA). Categorial variables were compared using Chi-square test
and calculating odds ratios and their 95% confidence intervals. In Study IV, variables
were compared using 2-tailed Student’s t-test. In both of these, a probability of <0.05
was regarded as significant. In Studies II and V no statistical analyses were performed
due to the nature of the study settings (small cohort in Study II, case report in Study V)).
In Study III an analysis of the systematic review and a meta-analysis were performed
by a statistician. The statistical analysis of the review comparing two methods was
performed using metaprop function in Meta Package for R (Software environment
for statistical computing and graphics, version 2.13.0, The R Foundation for Statistical
Computing, Austria). Arcsine transformation was applied for comparisons where either
of the groups (CSEMS or PS) contained at least one study with a proportion of 100%,
otherwise untransformed proportions were used. Using the proportion estimates and
confidence intervals obtained from the systematic review, the statistical significances
for the differences between the groups were evaluated using unpaired, 2-tailed Student’s
t-test, and an association was considered significant when the exact significance level of
the test was p < 0.05.
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Antti Siiki
6 ETHICAL ASPECTS
All studies were carried out in accordance with the Helsinki Declaration. In Study I
the protocol was approved by the Ethics Committee of KHKS and in Study V by the
Regional Ethics Committee of Pirkanmaa Hospital District. For Study V informed
consent was acquired from the patient for the research use of a biodegradable stent.
In Study IV the protocol was reviewed and approved by the Provincial Government
of Eastern Finland and the Animal Ethics Committee of the University of Kuopio,
Finland (now part of University of Eastern Finland). Studies II and III involved no
ethical issues because the use of SOC in Study II was part of regular patient care and
Study III consisted of a literature review only.
Endoscopic Management of Benign Biliary Strictures
73
7RESULTS
7.1 Study I: ERCP success rates and complications
in a Finnish central hospital
Demographics, indications and success rate
A total of 1,207 consecutive ERCPs were performed on 809 patients. Of all procedures,
79% were planned electively and 21% were acute cases where ERCP was perfomed less
than 72 hours after admission. Of the procedures 8.7% were planned second attempt
procedures, taking place 2–14 days after either a failed or intentionally aborted initial
ERCP, The most common initial working diagnosis or indication for ERCPs was
CBD stone in 28%, unspecified icterus in 24%, suspected malignancy in 19%, acute
pancreatitis in 6%, chronic pancreatitis in 5% and benign pancreto-biliary disease in
6% of the cases. A biliary stent exchange was performed in 7.6%. Any kind of biliary
stent was inserted in 14% of the cases: for malignant stricture in 11% and for other
reasons in 3.3% of these 1,207 ERCPs.
The papilla was intact i.e. no earlier sphincterotomy had been performed in 68% of
the procedures (n=825, 61% females, median age 70 years). Data on cases with intact
papilla was considered the most relevant in terms of the success rate of cannulation and
incidence of complications. In the cases with the papilla intact, CBD stone was the
most common working diagnosis or indication at the time of ERCP (32%), followed by
malignant biliary obstruction (21%) and icterus with unspecific diagnosis at the time
of the procedure (21%). Benign pancreato-biliary indications accounted for 5% of the
cases (Table 7).
Cannulation of the desired duct was achieved in 89% of the procedures. With intact
papilla complete stone extraction was successful in 91% and bile duct obstruction was
relieved completely in 80% of procedures with an intact papilla.
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Antti Siiki
Table 7. Indications or working diagnoses of the 825 ERCPs with intact papilla, amounting to 68% of
all cases. Re-printed with permission of copyright holder, Siiki et al. Scand J Surg 2012;101:45–50
n
%
CBD stone
Indication or work-up diagnosis
266
32 %
Malignancy
173
21 %
Bile duct obstruction or jaundice without accurate diagnosis
172
21 %
Acute biliary pancreatitis
64
7.8%
Acute cholangitis
59
7.2%
Chronic pancreatitis
35
4.2%
Dysfunction of sphincter of Oddi
10
1.2%
Bile leak after cholecystectomy
7
0.8%
Other benign pancreato-biliary disease
39
4.7%
Total
825
100%
Complications
Overall complication rate was 11% in ERCPs with intact papilla (Table 8). The
majority of the complications (77 %) were mild or moderate, i.e. they were managed
conservatively and necessitated less than ten days of hospitalisation. Two of the 16 (1.9%)
cases of PEP were severe and required surgery, but the patients recovered. Haemorrhage
occurred after 16 (1.9%) of the procedures. Perforations caused by EST or guidewire
were observed in eight (1.0%) patients, three of whom required surgery. Most of the
cases were retroperitoneal and were noticed during the same endoscopy. Seventeen
(2.1%) patients developed cholangitis, none of which was related to mortality. One of
the cholangitis patients was laparotomised for suspected duodenal perforation after
referral to another hospital.
Other adverse events occurred in 4.2% of ERCPs with intact papilla. The most
common cases were pneumonia, infection of unknown origin, cerebral infarction,
cardiac event and urinary retention or urinary tract infection. Additionally two patients
(0.2%) with cholecystitis were operated on. The overall complication rate was 9.8% in
the entire study population of 1,207 procedures.
Risk factors of complications
Precut sphincterotomy was a risk factor for moderate or severe PEP (OR 3.8, 95 %
CI 1.1–12.8, p 0.022). Age over 60 years was a risk factor for other complications
(e.g. cardiac event, pneumonia) graded moderate or severe (OR 3.6, 95% CI 1.1–12.0,
Endoscopic Management of Benign Biliary Strictures
75
p 0.027). There was a slight trend towards increased incidence of PEP, haemorrhage and
perforation after precut as well as towards more frequent PEP in patients less than 50
years of age, but the differences were not statistically significant.
Table 8. Complications, adverse events and ERCP-related mortality in 825 ERCPs with intact
papilla and their severity grades based on the need for interventions and the length of associated
hospitalisation. Age: median (interquartile range); PEP: post-ERCP pancreatitis (Re-printed with
permission of copyright holder, Siiki et al. Scand J Surg 2012;101:45–50)
Complication
Severity
Pancreatitis
Mild
Moderate
Severe
Haemorrhage
Mild
Moderate
Severe
Cholangitis
Mild
Moderate
Severe
Perforation
Mild
Moderate
Severe
Other
Mild
Moderate
Severe
Overall complications
Age (years)
Total
Total
Total
Total
Total
63 (44–74)
74 (53–83)
77 (58–83)
72 (68–81)
79 (68–88)
75 (63–83)
n (%)
ERCP related
mortality
4 (0.5%)
10 (1.2%)
2 (0.2%)
16 (1.9%)
0
0
0
0
16 (1.9%)
0
0
2
2
17 (2.1%)
0
0
0
0
8 (1.0%)
0
0
0
0
35 (4.2%)
0
0
0
0
1 (0.1%)
9 (1.1%)
6 (0.7%)
3 (0.3%)
12 (1.5%)
2 (0.2%)
5 (0.6%)
–
3 (0.4%)
5 (0.6%)
20 (2.4%)
10 (1.2%)
91 (11%)
2 (0.2%)
Mortality
In the procedures with the papilla intact, the ERCP related mortality was 0.2% (n=2).
Both of these cases resulted from haemorrhage in patients with severe co-morbidities.
Overall mortality in 30 days was 3.3% (n=27). Eighteen (2.2%) of these were caused
by cancer and seven (0.8%) by other, non-ERCP-related events, such as pneumonia or
cardiac disease.
In all 1,207 procedures ERCP related mortality was was 0.4% (n=5). The details of
these cases are presented in Table 9. In addition to the abovementioned two cases of
haemorrhage, two patients died after perforation and the death of a one patient nine
days after biliary stent insertion was considered ERCP-related.
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Antti Siiki
Table 9. ERCP -related 30-day mortality after 1,207 procedures. Details of the five patients who died
of complications are presented. The two uppermost cases had an intact papilla i.e. had not undergone
previous EST
Cause of
death
Age/
Sex
Co-morbidities
Intact
papilla
ERCP indication
Haemorrhage,
acute myocardial infarction
83/F
Hypertension, coronary heart disease,
acute myocardial
infarction
Yes
CBD stones in percuta- EST, stone
neous cholangiography extraction
(T-tube)
Severe bleeding
at 7 days
Haemorrhage
88/F
Dementia, hypertension, congestive
heart disease, atrial
fibrillation, sick sinus
syndrome
Yes
Inoperable pancreatic
carcinoma, bile duct
obstruction, PTD
removed by patient
ERCP and precut
sphincterotomy,
no access to
biliary duct
Severe early
bleeding
Perforation
76/F
None
No
Inoperable pancreatic
carcinoma, bile duct
obstruction
EST, dilation of
CBD stricture,
stent insertion
Laparotomy
for duodenal
perforation
Perforation
82/F
None
No
Inoperable pancreatic
carcinoma, bile duct
obstruction
Replacement of
obstructed biliary
duct stent
Managed
non-operatively
Unclear biliary duct
obstruction
EST, biliary stent
insertion
Intensive care
for multi-organ
failure for 9 days
Multi-organ fail- 68/M
ure of unknown
origin
Atrial fibrillation,
No
chronic pancreatitis,
congestive heart
disease, mechanical
aortic valve, anticoagulation therapy
ERCP procedure Comment
7.2 Study II: Initial experience of SpyGlass cholangioscopy in
biliary strictures secondary to sclerosing cholangitis
Eleven patients (5 female, median age 45, range 24–66) underwent ERC with SOC
for PSC. The baseline characteristics of the study population are presented in Table
10. The median time from the diagnosis of PSC was eight years (range 1–28 years). All
but one patient were on ursodeoxycholic acid treatment for PSC and all patients had
ulcerative colitis. In nine patients (82%) a previous ERC, and in six (55%) a previous
sphincterotomy had been performed. One patient had had an earlier temporary biliary
stent therapy for CBD stricture years before the current endoscopy. Another patient
had undergone conservative treatment for a mild post-ERC perforation years earlier.
Serum tumour markers CA19-9 and CEA were within normal range in all patients.
The progression of PSC was classified according to Amsterdam criteria (Table 2, Table
10). Both intra- and extrahepatic changes were present in eight (73%) patients; the rest
had intrahepatic disease.
Endoscopic Management of Benign Biliary Strictures
77
Table 10. Details of ERC and results of tissue analysis in patients of Study II. PSC; primary sclerosing
cholangitis, MRI; magnetic resonance cholagiopancreatography, LFT; liver function tests. ERC;
endoscopic retrograde cholangiography, Stricture classification: intra and extrahepatic disease
according to Amsterdam classification; Cytology: cytology class. Inadeq: Sample inadequate. Reprinted with permission of copyright holder, published in Scand J Gastroenterol 2014; 49:1385–90,
Siiki et al.
Stricture classification
No
Age/sex
Indication
Intrahep
Extrahep
1
43/M
Progression in MRI
III
IV
2
28/M
Progression in MRI,
elevated LFT
I
Normal
3
44/F
“
II
II
Cytology
DNA
index
S-phase
Histology
2
1
1.8
Inadequate
2
1.2
7.2
Inflammation
2
1
2.1
Normal
4
41/M
“
III
II
1
1
NA
Inflammation
5
45/F
Elevated LFT, no
previous ERC
II
I
2
1
1.2
Inflammaton
6
54/F
Elevated LFT
II
II
NA
Regenerative
atypia
7
51/M
More than 5 year
from ERC
I
IV
NA
Fibrosis
Fibrosis
Inadeq.
2
Inadeq
1
8
50/F
Progression in MRI
III
I
2
1
0
9
49/F
“
III
II
2
1
6.8
10
66/M
“
I
Normal
11
24/M
Over 5 years from
ERC
I
Normal
Inadeq.
1
Inadeq
1
Inlammation
NA
Fibrosis
0
Fibrosis
Under ERCP, EST was performed in 90% of patients. Both brush samples for cytology
and flow-cytometry were successfully obtained from desired locations in all patients as
well as direct visualisation of the epithelium by SOC and guided biopsy. The stricture
could be completely traversed with a cholangioscope in six cases (55%). In others, a
tight impassable dominant stricture was located intrahepatically, except in one patient,
with a narrow class IV extrahepatic stenosis. Bile duct stones, initially unidentified in
MRCP and cholangiography, were detected in SOC in one patient and removed by
extraction balloon.
Out of nine patients (82%) with adequate brush samples for cytologic analysis, the
result was Amsterdam class 2 in seven and class 1 in two. The flow-cytometric analysis
showed normal diploidic DNA content in all but one patient, who had an elevated
DNA index of 1.21 and normal S-phase of 7.2%, which were considered suspicious for
malignancy. The biopsy specimens were adequate for successful histological analysis in
ten (91%) patients; one normal bile duct epithelium and seven regenerative, fibrotic or
chronic inflammatory changes (Table 10). Most of the histologic specimens consisted
of stromal cells and only a small amount of epithelial tissue.
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Antti Siiki
Two patients developed immediate complications from which they all recovered
uneventfully; one 28 year-old male and one 43 year-old male developed a moderate PEP
within three days after ERC. In addition, one 41 year-old male was observed for mild
post-ERC pain without pancreatitis.
The follow-up of PSC patients was planned individually in accordance with the
guideline of our institution, which is essentially similar to that used in the Endoscopy
Unit of Helsinki University Hospital and is presented in Figure 4 (Boyd et al. 2014).
The median length of follow-up at the time of analysing the data was 22 months
(range 16–24 months). Patient #1 with severe cholangiography changes and rapid
PSC progression was referred to the liver-transplantation unit of Helsinki University
Hospital after the SOC-ERCP procedure, but LT has not so far been necessary. He
has later undergone endoscopic stenting and stent removal. Patient #2 with initially
aneuploidic flow cytometry was scheduled for re-ERC at six months with normalised
results. Other patients were scheduled for outpatient follow-up, during which none of
them had progression of PSC or episodes of acute cholangitis. The patient with CBD
stones removed has been asymptomatic ever since.
7.3 Study III: Meta-analysis comparing covered self-expanding metal
stents and multiple plasic stents in benign biliary stricture
Twenty-five studies met the final inclusion criteria for the review: 13 studies on mPSs
with 570 patients and 12 studies on CSEMSs with 376 patients. The CSEMS and PS
groups were comparable in terms of age and sex.
All 13 PS studies reported an endoscopic technique with gradually increasing
number of polyethylene 7-10 F plastic stents inserted and exchanged tri-monthly for up
to 12 months. Three of the CSEMS studies used partially covered stents (Behm et al.
2009; Chaput et al. 2010; Kahaleh et al. 2008). The median duration of stent therapy
was shorter in the CSEMS (4.5 months) than in the PS group (11 months) (p=0.001).
Fewer ERCP sessions were needed in the CSEMS than in the PS group (median 1.5
and 3.9, p=0.002). When cases of CP were analysed separately, the difference in the
duration of stent therapy (median 4.8 vs. 16 months, p=0.1) or in the number of ERCPs
(2.0 vs. 4.2, p=1.0) was statistically insignificant. The primary stent insertion and the
eventual stent removal were equally successful in the CSEMS and PS groups.
In 83% of CSEMS studies and 100% of PS studies adequate data at 12 months of
follow-up was obtained, and was used in the final analysis. The results at the end of the
total follow-up time were not comparable, as the length of follow-up was shorter in the
CSEMS group (14 vs. 49 months, p=0.003).
Endoscopic Management of Benign Biliary Strictures
79
There was no difference in the early complications (pancreatitis, cholangitis,
perforation and haemorrhage) between the CSEMS and PS groups in all stricture
aetiologies. However, late complications or any adverse events (pain, infection, stent
occlusion and stent migration) occurred less often with CSEMS than in PS (5% vs 14%,
p=0.006) when all aetiologies were combined (95% CI 2–7% and 9–19% respectively).
There were fewer late complications in the CSEMS (3 vs. 67%) than in the PS group in
CP aetiology (95% CI 0–13% vs. 17–99%, p=0.02). No statistical difference was found
in the complication figures of other aetiology groups.
The clinical success of treatment according to stricture aetiology at the end of the
stent therapy and at six and 12 months after stent removal is presented in Figure 10.
In CP strictures there was tendency for better clinical success in CSEMS treatment at
12 months after stent removal: 77% vs. 33% (95% CI 61–94% vs. 4–63%, p=0.06) in
CSEMS and PS respectively. At other time points of follow-up the difference was also
observable: at stent removal 80% vs. 38% (95% CI 62–93% vs. 12–68%, p=0.02) and
at six months 74% vs. 33% (61–86% vs. 4–63%, p=0.02). In other aetiologies except CP
there was no difference in the success rate. The overall clinical success of CSEMS and
PS in all aetiologies at stent removal was 87% vs. 85% (p=0.8) and at 12 months 79%
vs. 77% (p=0.9).
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Antti Siiki
%
100
A. Chronic pancreatitis
80
74
77
%
100
B. Post-liver transplantation
91
88
50
85
76
72
6 mo
12 mo
50
38
33
33
6 mo
12 mo
0
0
Immediate
%
100
85
Immediate
C. Other aetiology
92
88
85
86
84
85
6 mo
12 mo
50
0
Immediate
Figure 10. Success rate of CSEMS and PS therapy in strictures by aetiology (A) chronic pancreatitis
(CP), (B) post-liver transplant (LT), and (C) other aetiologies immediately after primary stent insertion
and after 6 and 12 months (mo) in Study III. *p<0.05, overlapping confidence intervals, see text for
details on statistical significance. Re-printed with permission of copyright holder, published in J Clin
Gastroenterology 2014; 48:653–453, Siiki et al.
7.4 Study IV: Protein expression in benign biliary strictures before
and after treatment with metal and biodegradable biliary stents
Proteins potentially associated with tissue damage and healing, apolipoprotein-A1,
annexin-A4, galectin-2, transgelin, myosin light polypeptide-6 (MLP-6), albumin,
superoxide dismutase-1, heat-shock protein beta-6, peroxiredoxin-5 and muscle creatine
kinase were screened for. Expression pattern of annexin-A4, galectin-2, transgelin and
MLP-6 from an intact BD, untreated BBS and after treatment with BDBS or CSEMS
is presented in Figure 11. For other proteins no differences were found.
Tissue samples were analysed from pigs with intact bile duct (intact BD, n=5),
untreated BBS (n=5) and after six months of therapy with BDBS (n=4) or CSEMS
(n=5). In BBS, expression of annexin-A4 was reduced to 37% and expression of
galectin-2 was reduced to 14% (p=0.03) compared to the intact BD. Fragmented
transgelin expression was increased by 190% compared to the intact BD. No difference
in myosin light polypeptide-6 (MLP-6) expression was observed (Figure 11).
Endoscopic Management of Benign Biliary Strictures
81
After BDBS and CSEMS treatment the expression of annexin A4 remained at the
level seen in BBS. After BDBS treatment the expression of galectin-2 returned to the
level of intact BD, whereas after CSEMS treatment the expression remained at the
low level seen in the BBS (p=0.02). Transgelin expression, being zero in intact BD,
was increased to 450% in CSEMS-treated animals compared to BDBS. Expression of
fragmented transgelin remained at the elevated level of untreated BBS after both BDBS
(p=0.03) and CSEMS treatment. MLP-6 expression was increased to 300% after BDBS
treatment, but remained unchanged after CSEMS treatment (Figure 11).
Figure 11. Expression of annexin A4 (A), galectin-2 (B), transgelin (C) and myosin light polypeptide-6
(D) proteins based on immunohistochemical analysis. Four samples (columns from left to right) were
compared: intact bile duct (BD), BBS at two months (BBS 2 mo) from stricture induction and after six
months treatment with either BDBS or CSEMS. In figure B p<0.05 in BBS 2 mo compared to intact
duct, CSEMS compared to intact duct and CSEMS compared to BBS 2 mo. In figure C, p<0.05 in
BDBS compared to intact duct. Re-printed with permission of copyright holder, under review in BMC
Gastroenterolgy 2015, Siiki et al.
82
Antti Siiki
7.5 Study V: Biodegradable biliary stent in the endoscopic
treatment of cystic duct leak after cholecystectomy
Endoscopic insertion of the BDBS was successful for the treatment of the post-CCY
biliary leak. The stent was adjusted to the proper location in the CBD with its distal end
visible inside the duodenum (Figure 7). The external drain was removed on day 7 after
ERC at an outpatient visit. Although complications related to ERCP or stent did not
occur during the first 30 days, the patient had been treated with peroral antibiotics for
an episode of acute infection, presumably acute cholangitis, at 1.5 months from ERC.
At three-month follow-up MRI the stent was patent and in the right location (Figure
12), whereas at six months it was no longer visible.
Figure 12. MRI image at three months after BDBS insertion. BDBS is visible fully expanded in the
distal CBD (arrow). Re-printed with permission of the copyright holder, published in J Laparoendosc
Adv Surg Tech 2015; 25(5): 419–22, Siiki et al.
Endoscopic Management of Benign Biliary Strictures
83
8 DISCUSSION
This thesis summarises current endoscopic BBS management based on a literature review
and five original publications. In indeterminate biliary strictures, the primary goal is
to exclude malignancy and set at least a temporary diagnosis. While patient history,
serum samples, radiologic imaging and ERCP with brush samples are often sufficient
in the primary evaluation of indeterminate strictures, repeated ERCP or advanced
endoscopic methods such as cholangioscopy with guided biopsies may be necessary
in unclear cases. After a diagnosis of BBS, an appropriate treatment strategy may be
selected; this may include insertion of a single plastic or multiple plastic stents, which is
often the case in post-operative strictures affecting the biliary confluence, or FCSEMSs
that are most appropriate for strictures in the CBD and CHD. Biodegradable stents
are a convincing alternative of which clinical experience is needed before embarking on
widespread clinical use.
The impact of this thesis on the literature is in providing data on ERCP practice in
a Finnish central hospital as well as substantiating and complementing the findings of
earlier studies on SOC diagnostics in PSC patients. In addition, the thesis clarifies the
issue of the optimal stent therapy in benign CBD strictures. Furthermore, it introduces
possibilities of proteomic research that could perhaps lead to better comprehension
of BBS pathogenesis and improved stent development and stent therapy. Lastly,
a pioneering endoscopic therapy with BDBS is reported, which may have further
applications as more experience accumulates.
The first publication evaluating ERCP practice in a Finnish central hospital showed
that even in a low-volume centre it is possible to achieve an appropriate success rate in
cannulations (Colton and Curran 2009; Enochsson et al. 2010; Kapral et al. 2008) and
an acceptable incidence of post-ERCP complications (Andriulli et al. 2007; Christensen
et al. 2004; Colton and Curran 2009; Testoni et al. 2010). The case-mix reported in
our study was close to what has been reported from other non-university hospitals
(Colton and Curran 2009; Garcia-Cano Lizcano et al. 2004), and, as expected, differed
considerably from that of academic centres in terms of numbers of complex procedures
(Enochsson et al. 2010). Basic ERCP such as CBD stone removal, carrying the lowest
risks is more common in low-volume centres than in specialised units (Enochsson et
al. 2010; Garcia-Cano Lizcano et al. 2004; Testoni et al. 2010). This needs to be kept
84
Antti Siiki
in mind when complication figures are compared. The risk factors for PEP are known
to be cumulative (Freeman 2012), including e.g. female sex, young age and challenging
cannulation (Cotton et al. 2009; Halttunen et al. 2014; Testoni et al. 2010; Williams
et al. 2007). The trend seen in our paper is consistent with earlier findings.
Reviewing own complications is crucial in the process of continous improvement of
quality and education, and is also needed in balancing the risk for future complications
(Anderson et al. 2012). The value of a nationwide register in quality control and
acquiring the “big picture” of ERCP practice, indications, complication rate and
differences in patient mix between centres and adequate referral pattern of complex
cases has been demonstrated in the large Swedish Gallriks -studies (Enochsson et al.
2010; Enochsson et al. 2013). Unfortunately no such national registry so far exists in
Finland. This makes it even more important to run investigations like that reported
in Study 1, where the advantages were the careful inclusion of over 1,000 consecutive
ERCPs in a single domestic central hospital in a quality control setting, and a separate
analysis of the procedures with intact papilla. A retrospective study may obviously
include errors in terms of data collection and interpretation. The study concluded that
ERCP quality is at an appropriate level in a Finnish non-university centre, at least when
the procedures are assigned to a few endoscopists and the standards of practice are
critically monitored, as was the case here.
According to the second study, Spyglass cholangioscopy is safe and feasible in the
evaluation of PSC with an acceptable rate of successful biopsies. The findings confirm
the usefulness of SOC in indeterminate biliary strictures and the diagnostics of BBS as
well as in PSC (Awadallah et al. 2006; Chen and Pleskow 2007; Draganov et al. 2011;
Kalaitzakis et al. 2012; Manta et al. 2013; Rey et al. 2014; Tischendorf et al. 2006). A
similar finding was recently published from Sweden, encouraging SOC use in selected
cases of PSC (Arnelo et al. 2015). In our study the rate of PEP was 18%, which, being
partly attributable to the learning curve with SOC in our institution, is consistent with
rates reported in other studies (Awadallah et al. 2006; Tischendorf et al. 2006; Arnelo
et al. 2015). Because the complication risk is elevated both in PSC (Ismail et al. 2012;
von Seth et al. 2015) and for performing SOC (Draganov et al. 2011; Lubbe et al. 2015,
Arnelo et al. 2015), the indications and true role of SOC in the surveillance of PSC
have to be carefully analysed. Study II was the first report from Finland on SOC use in
PSC, and one of the first papers on SOC safety in PSC in general. Rare PSC cases were
deliberately collected into this consecutive series. It can be argued that the number of
patients is insufficient to demonstrate the true rate of complications and the follow-up
is short for the diagnostic yield. A large multicentre study with long follow-up is called
having as its end-points the influence of SOC on surveillance as well as diagnosing
dysplasia and exlusion of CCA. As a conclusion from Study II, the complication risk
Endoscopic Management of Benign Biliary Strictures
85
of SOC is tolerable and provides additional diagnostic information in PSC patients.
We suggest that SOC should be a second-line option in conjunction with MRI,
cytology and flow cytometry as a part of the multi-disciplinary surveillance of PSC in
experienced centres, e.g. in cases with suspicious cytologic findings or aneuploidy. The
next generation of SOC instruments will without doubt change our thinking on SOC
possibilities as the quality of the image and thus diagnostics improve (Parsi et al. 2014).
The third study showed that treatment with CSEMSs is more successful with
comparable complications and smaller numbers of ERCP sessions than multiple PS in
CP related CBD strictures. The findings were compatible with the clinical expectations
and the recently published pioneering Finnish RCT (Haapamaki et al. 2015). The
results were also in accordance with other recent studies reporting long-term success
rates of 80–90% with FCSEMS in CP (Deviere et al. 2014; Kahaleh et al. 2013). In
the studies included in the meta-analysis, a very short stent indwelling time of 4–6
months was used; however, modern FCSEMSs may be safely kept in place much longer
in CP-related strictures, presumably further improving the stricture remodelling and
long-term effect (Deviere et al. 2014). The migration rate remains a problem even with
the current FCSEMSs, although it does not automatically lead to treatment failure
(Deviere et al. 2014). In LT or other post-operative strictures, where later studies have
shown encouraging results (Deviere et al. 2014; Kaffes et al. 2014; Kahaleh et al. 2013)
the meta-analysis was inconclusive. Further studies with adequate follow-up are needed
to ascertain the long-term recurrence rate of FCSEMS-treated strictures, as well as the
cost-efectiveness in comparison to mPSs or surgery. It can be summarised, however,
that up to 12 months indwelling time with modern FCSEMSs is feasible and yields
impressive clinical results in selected BBS. Particularly strictures secondary to CP,
which are typically treatment resistant and located in the distal CBD, as well as LTrelated anastomotic strictures are best suited for FCSEMS therapy (Deviere et al. 2014;
Kaffes et al. 2014; Haapamäki et al. 2015). A single PS has and will continue to have
a role as a bridge to surgery and e.g. in PSC related dominant strictures. The strategy
of gradual stricture remodelling with mPS therapy remains relevant in hilar strictures
or multifocal strictures arising from previous surgery, which are different entities than
calcifying CP affecting the distal CBD. The main drawback of mPS therapy in postoperative strictures is the need for repeated ERCP sessions with associated burden
on the patient and costs (Costamagna and Boškoski 2013). To give a perspective in
the Finnish health care system, the cost of an ERCP procedure varies between 800
and 1200 euros, a FCSEMS costs approximately 800 euros and a PS around 80 euros.
Thus a year’s treatment with mPSs consisting of at least four ERCPs with progressive
insertion of up to seven PSs is over twice as expensive as therapy with a single FCSEMS
necessitating ERCP procedures only twice: for insertion and removal.
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The strength of Study III was a meticulous literature search and careful selection
of studies for inclusion. The meta-analysis was designed with and performed with the
help of a statistician. However, all the studies included were uncontrolled low-quality
studies, with confounding factors due to heterogenity, making it hard to draw solid
conclusions on comparison of treatment groups even after meta-analysis. Furthermore,
the number of cases was relatively small in aetiology-specific subgroups. In addition,
the variation in the definition of clinical success and relatively short follow-up times
were the major limitations. At the time of the preparation of Study III, no high-quality
papers on FCSEMS with a long follow-up had been published. Thus our results, already
updated by a recent multi-centre RCT, lend support to the clinical use of FCSEMS in
CP related CBD strictures.
The fourth paper concluded that the expression of proteins related to tissue healing,
such as galectin-2 and annexin-A4, have a different expression pattern in ischaemic
BBS than in intact bile duct. Furthermore, a difference was noted after treatment with
either BDBSs or FCSEMSs. The proteomic response to BDBS resembling intact bile
duct may suggest a beneficial effect of BDBSs over FCSEMSs in BBS. However, in the
absence of similar research of BBS proteomics, it remains unknown which benefits BBS
healing most, change towards intact bile duct or no such change. The potentially more
beneficial effect does not contradict with earlier findings, where BDBS stents did not
cause scar formation or histologic changes that could potentially precede re-stricturing
or damaging biliary epithelium (Ginsberg et al. 2003; Laukkarinen et al. 2007a). The
physiology and potential clinical applications of variation in tissue response and lack
of epithelial hyperplasia warrant additional studies. When FCSEMSs are increasingly
used in BBS with long indwelling times, our findings constitute an interesting point of
comparison to recent reports of de-novo strictures after FCSEMSs due to late epithelial
response, which has been thought to result from the forceful radial expansion of metal
stents and at least partly from covering materials (Ginsberg et al. 2003; Irani et al. 2014;
Phillips et al. 2011). The differences in protein expression imply that the optimal result
of endoscopic therapy also depends on the molecular level mechanisms of stricture
pathogenesis, scar formation and response to stent of the biliary epithelium. Study IV
was the first to investigate the pathogenesis of BBS and to compare the tissue response
to CSEMSs and BDBSs in terms of protein expression pattern in a carefully performed
and documented experimental ischaemic large animal model. The BDBS was made of
PLA, which is a slightly different co-polymer from PDX used in the BDBSs currently
commercially available. The future prospects in the endoscopic management of BBS
include diagnostic and prognostic biomarkers, possible target molecules for therapy
and improved stent design to reduce tissue damage. Furthermore, the biodegradable
Endoscopic Management of Benign Biliary Strictures
87
polymers used for drug release are presumably among the next technological advances
in stent design (Lorenzo-Zuniga et al. 2014; Tokar et al. 2011).
The fifth study demonstrated the feasibility of the novel endoscopic implantation
device of BDBSs in the treatment of post-operative bile leak as an alternative to
traditional PS therapy. The degradation and predictable behaviour of PDX BDBS is
also well documented in human BBS (Freudenberg et al. 2004; Lorenzo-Zuniga et
al. 2014; Mauri et al. 2013). The lack of an endoscopic insertion device has prevented
endoscopic use until this experience. It is reasonable to conclude that an 8mm diameter
BDBS provides better bile flow than a smaller diameter PS (Laukkarinen et al. 2007a).
The usefulness of BDBSs in the leak of a cystic duct may be extrapolated to BBS of
the CBD, since the implantation device may be easier to introduce into a dilated duct
above the stenosis. It is still unknown whether the radial expansion effect of the current
BDBS, reportedly up to 30% less than in CSEMS in the early PLA stent experiments
(Ginsberg et al. 2003) and 10% less in 8mm bore BDBS made of PDX (Grolich et al.
2015) is sufficient for successful stricture remodelling, prevention of migration and
long-term success. In this sense, the results from its percutaneous use are encouraging,
but the numbers are small, consisting mostly of post-operative strictures (Mauri et al.
2013). The cost of BDBSs may be justified by rendering unnecessary repeated endoscopy
either for CSEMS removal or multiple PS insertion. This may be particularly important
in patients with alcohol-related CP, often associated with poor compliance (Kiehne,
Folsch, Nitsche 2000), which may lead to difficult removal or septic cholangitis if the
stents are inadvertently left in situ (Irani et al. 2014). The episodes of acute cholangitis
during the stent therapy, noted in our case report and in up to 30% of the cases during
percutaneous BDBS therapy warrant attention in future studies (Mauri et al. 2013).
Study V was the first report of a successful endoscopic insertion of PDX BDBS in a
single patient with thorough follow-up. The feasibility of BDBS implantation and
the excellent results during six-month follow-up encourage us to continue with the
prospective cohort trial of endoscopic BDBS use in BBS and in bile leaks.
During the past decade extensive research has been conducted on endoscopic BBS
management and the medical technology has rapidly developed. Earlier studies have
shown that the diagnosis of BBS is often complex and the treatment strategy of BBS has
to be chosen according to the stricture aetiology. The diagnostics of biliary strictures
may be safely improved by selective use of SOC even in PSC patients. In addition, the
clinical use of CSEMSs is encouraged in benign CBD strictures, especially in CP. This
thesis also supports the usefulness of BDBSs, based both on our results from the animal
model and on the feasibility demonstrated in the first case report of endoscopic use in
humans. As in any invasive procedure, the indications for ERCP and the endoscopic
approach to BBS management need to be weighed up against the complication risks.
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9 SUMMARY AND CONCLUSIONS
The present thesis provides data to support the following conclusions and summary:
1) ERCP success rates and complications were for the first time evaluated in a Finnish central hospital, showing that high quality level can be achieved in a lowvolume ERCP unit.
2) SpyGlass single-operator peroral cholangioscopy is a safe and useful method in
diagnostics and surveillance of primary sclerosing cholangitis, and it´s role is still
evolving.
3) Covered self-expanding metal stents may well be used in selected cases of benign
biliary strictures, especially in strictures secondary to chronic pancreatitis. Although cases of stent migration and cholangitis do occur, the main advantages are
the good stricture resolution rate with fewer procedures.
4) The novel biodegradable biliary stents has a different and potentially beneficial
effect on biliary epithelium compared to covered self-expanding metal stents according to the analysis of protein expression in a pig model. Additionally, an
ischaemic biliary stricture has a different protein expression pattern than an
intact bile duct, and this information may also be beneficial for future clinical
applications.
5) Endoscopic insertion of biodegradable biliary stent was successful and without
significant complications during the six-month follow-up in the first published
case report on the treatment of a post-cholecystectomy bile leak. Even though
more experience and more research on the endoscopic use of biodegradable biliary stents are needed, they appear to be promising option for the future treatment
of benign biliary strictures.
Endoscopic Management of Benign Biliary Strictures
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10 FUTURE PERSPECTIVES
The future of endoscopic diagnostics of indeterminate biliary strictures may develop
in the direction of combining advanced samples such as FISH, DIA or flow-cytometry
with standard ERCP with cytologic samples (Barr Fritcher et al. 2014; Halme et al.
2012). Additionally, the analysis of bile juice for diagnostic markers such as pyruvate
kinase may offer interesting prospects in evaluation of indeterminate strictures
(Navaneethan et al. 2015a). The stepwise approach with additional radiologic
modalities, such as contrast enhanced MRI and FDG PET in selected cases will
hopefully be of help in unclear cases (Katabathina et al. 2014; Sangfelt et al. 2014).
Potential further investigations when standard procedures are non-diagnostic, includes
peroral cholangioscopy, preferably with high-definition digital image quality, which
enables an impressive view of the ductal lumen and mucosa as well as superior accuracy
(Parsi et al. 2014). Additional techniques such as staining could augment the visual
diagnostics of SOC (Chen et al. 2011). In SOC the adequacy of biopsies continues
to be an issue; the diagnostic accuracy is improved if more biopsies with more tissue
are available for analysis (Kalaitzakis et al. 2012). While in recent studies the range of
median number of biopsies has been from three to four (Chen et al. 2011; Kalaitzakis
et al. 2012), perhaps even more and up to ten biopsies per lesion should be taken
(Draganov et al. 2011). The true diagnostic yield of SOC, optimal timing and relation
to radiologic imaging in different clinical scenarios require further studies despite the
present promising results. Interesting prospects of immediate cytopathologic staining
and interpretation in the endocopy suite may provide more accurate diagnosis and help
in intraprocedural decisions (Wright et al. 2011).
Future research may eventually show the true diagnostic predictive value and
accuracy of SOC-cholangioscopy and targeted biopsies, also in the evaluation of PSC
progression and in the exclusion of CCA that remains one of the most difficult problems
in BBS management (Eaton et al. 2013). In PSC, narrow-band imaging, also aimed
to better visualize mucosal surface abnormalities such as dysplasia by filtering light in
the green and blue spectra has already been used experimentally in conjunction with
cholangioscopy. Although the first use of this promising method enabled definition of
tumour margins in patients with CCA and increased number of biopsies, it did not in
a single report increase the detection of dysplasia (Azeem et al. 2014). FDG PET may
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Antti Siiki
also serve as a more accurate tool than cytologic samples in the exclusion of malignancy
in PSC (Sangfelt et al. 2014).
In addition, further research on the molecular basis of stricture formation and
response to stents to possibly verify our findings, is eagerly anticipated (Bakhru et al.
2011; Lee et al. 2014).
In the treatment of BBS, recently published randomised studies and others already
ongoing studies may modify our thinking on optimal stent selection and perhaps
confirm the ideas on the superiority of FCSEMSs over plastic stents in selected cases of
BBS (Deviere et al. 2014; Kaffes et al. 2014; Haapamaki et al. 2015). The optimal and
safe indwelling time is yet to be defined; it probably varies between six and 12 months
(Deviere et al. 2014; Haapamaki et al. 2015). The issue of optimal dilation with or
without PS in the dominant strictures associated with PSC will hopefully be clarified
in future studies (Ehlken and Schramm 2013). Furthermore, possible benefits of early
surgery in CP to manage not only biliary obstruction but also pain and pancreatic
insufficiency are currently being investigated (Ahmed Ali et al. 2013). Finally, clinical
studies on the endoscopic use of BDBSs in BBS have already been undertaken to gain
experience of this promising technology.
While the ever-evolving technology and instrumentation will provide even more
advanced diagnostic and therapeutic methods, the risk of complications and patient
safety has to be critically considered in all future studies.
Endoscopic Management of Benign Biliary Strictures
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ACKNOWLEDGEMENTS
This thesis was carried out at the Department of Gastroenterology and Alimentary
Tract Surgery, Tampere University Hospital, at the Department of Surgery, KantaHäme Central Hospital and at the School of Medicine, University of Tampere, during
the years 2010–2015.
I warmly thank Head of Department of Surgery, Professor Teuvo Tammela for
supporting me to finish my work.
I owe my deepest gratitude both to supervisor, Chief of Alimentary Tract Surgery,
Docent Johanna Laukkarinen, and co-supervisor Head of Division, Docent Juhani Sand,
for the opportunity to work under their expert guidance in Tampere Pancreas Group.
I wish especially to thank Johanna for endless support and optimism throughout the
process and Juhani for encouraging feedback and constructive revision of manuscripts.
Despite of all your duties, both of you always had time and energy for me and this work.
I would also like to express my thanks to Chief of Surgery Pekka Kuusanmäki, MD,
PhD for convincing me to begin scientific research on ERCP in Kanta-Häme Central
Hospital and for mentoring the first original publication. I am also grateful to Head
of Gastroenterology, Professor Pekka Collin and Head of Radiology, Docent Irina
Rinta-Kiikka, the follow-up members of this work, for their excellent collaboration
and helpful comment on the manuscripts and the thesis. I am also indebted to other
co-authors, especially Heidi Gröhn, MSc, Mika Helminen, MSc, Ralf Jesenofsky, MSc,
Professor Minna Kellomäki, Tarmo Koivisto, MD, Professor Matthias Löhr, Joonas
Mikkonen, MSc, Docent Isto Nordback, Antti Tamminen, MD, Timo Tomminen,
MD and Kaija Vasama, MD for their highly proficient contribution to the publications.
I am thankful to research coordinator Mrs. Taina Ahlgren and research nurse Mrs.
Satu Järvinen for all their help. I owe special thanks to Chief of Alimentary Tract
Surgery, Docent Petri Aitola, who together with the supervisors and Professor Collin,
facilitated the completion of the thesis beside my clinical work at the Department of
Gastroenterology and Alimentary Tract Surgery.
I wish to sincerely thank Docent Jorma Halttunen and Docent Sari Venesmaa, the
official reviewers of the thesis, for providing with excellent comments and criticism
to improve the manuscript. I also thank Virginia Mattila, MA, for her expertise in
revising the English language.
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Antti Siiki
I would like to acknowledge all colleagues I have had priviledge to work with and
learn from during the years of surgical training. I am particularly grateful to Head
of Endoscopic Surgery, Docent Urban Arnelo, for the ERCP fellowship in 2013 in
the Karolinska University Hospital, Stockholm, Sweden. Special thanks go to the
participants and mentors of the sixth course of international Pancreas 2000 -program
as well as the members of Tampere Pancreas Group.
This study was financially supported by Competitive State Research Financing
of the Expert Responsibility area of Tampere University Hospital, The Pirkanmaa
regional Fund of the Finnish Cultural Foundation, The Finnish Medical Foundation,
Mary and Georg Ehrnrooth Foundation, The Finnish-Norwegian Medical Foundation
and The City of Tampere.
I express my warmest gratitude to my parents Ritva and Pertti for their kind support.
I also wish to thank my brother Johannes, my aunt Marja and my grandparents for
believing in me. I am thankful to my friends, especially Ilkka Kivekäs, MD, PhD and
Kari Ranta, MD, and all the others that cannot be thanked by name here: friendship
with you is extremely valuable in reminding me that there is life outside. Finally, I want
to dedicate this thesis to my beloved wife Piia, MD, PhD. Together with our wonderful
daughter, you are the best fan club I can ever wish for.
Tampereella 18.5.2015
Endoscopic Management of Benign Biliary Strictures
93
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ORIGINAL COMMUNICATIONS
Endoscopic Management of Benign Biliary Strictures
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Scandinavian Journal of Surgery 101: 1–6, 2012
ERCP PROCEDURES IN A FINNISH COMMUNITY HOSPITAL:
A RETROSPECTIVE ANALYSIS OF 1207 CASES
A. Siiki, A. Tamminen, T. Tomminen, P. Kuusanmäki
Department of Surgery, Kanta-Häme Central Hospital, Hämeenlinna, Finland
ABSTRACT
Background and Aims: Endoscopic retrograde cholangiopancreatography (ERCP) is a
procedure with a risk of serious and life-threatening complications. The most common
complications are pancreatitis, haemorrhage, perforation and cholangitis. The aim of this
study was to determine indications, success rates and complications in a low-volume
ERCP unit in Kanta-Häme Central Hospital (KHCH).
Material and Methods: Data on 1207 consecutive ERCPs performed in KHCH between
2002 and 2009 was collected retrospectively from patient histories. Complications were
classified according to need for intervention and length of hospitalisation.
Results: Cannulation of the desired duct was successful in 89.2% of 825 ERCPs with
no earlier sphincterotomy. Complete stone removal was achieved in 91.3% of procedures.
Standard biliary sphincterotomy was performed in 73.8% and precut sphincterotomy in
12.0 % of cases. Cholangitis developed in 2.1%, bleeding in 1.9%, pancreatitis in 1.9%,
perforation in 1.0% and cardio-pulmonary or miscellaneous complications in 4.2% of
cases. The majority of complications could be managed conservatively. In procedures
with no earlier sphincterotomy ERCP-related 30-day mortality was 0.2% (n = 2) and overall 30-day mortality was 3.3% (n = 27).
Conclusions: ERCP indications and success rates, as well as morbidity and mortality
were comparable to those reported earlier. Although the success rate of cannulation and
thereby ERCP procedures seem to be somewhat lower than in tertiary referral centres,
ERCP procedures can be safely performed in a low-volume ERCP unit by concentrating
procedures on a few experienced endoscopists. The success rates may be further improved with the latest cannulation techniques, used selectively in the last years of the
study period.
Key words: ERCP; complications; sphincterotomy; precut sphincterotomy; pancreatitis; cholangitis;
perforation; haemorrhage
INTRODUCTION
Endoscopic retrograde cholangiopancreatography
(ERCP) is used in the treatment of benign and malignant pancreatic and biliary diseases. It is a demandCorrespondence:
Antti Siiki, M.D.
Kanta-Häme Central Hospital
Ahvenistontie 10,
FI - 13530 Hämeenlinna, Finland
Email: [email protected]
ing procedure with a long learning curve and a risk
of serious and life-threatening complications. The
most common indications of ERCP are removal of
common bile duct (CBD) stones and relieving bile
duct obstruction by stent insertion. Diagnostic procedures should be avoided, because they can be mostly
replaced by non-invasive magnetic resonance imaging (MRI) or endoscopic ultrasound. The main complications are pancreatitis, haemorrhage, cholangitis
and perforation of the CBD or duodenum (1, 2). Several studies, most from large academic centres have
reported a low incidence of complications (3–17). In
A. Siiki, A. Tamminen, T. Tomminen, P. Kuusanmäki
2
Finland ERCPs are also widely performed in lowvolume community hospitals. The quality indicators
of ERCP practice include adequate indications and
low complication figures as well as success rate of
cannulation (18). The cannulation of the desired duct
should be successful in over 85% of ERCPs (18), but
success rates as high as 98% have been reported (19,
20, 21). In this study, our aim was to retrospectively
investigate indications, success rates and complications of ERCPs in a low-volume community hospital.
MATERIAL AND METHODS
The hospital database was searched for ERCPs performed
between 1 January 2002 and 31 December 2009 in the endoscopy unit of Kanta-Häme Central Hospital (KHCH) in
Hämeenlinna. KHCH is a medium-sized community hospital in southern Finland serving a population of 173.000.
All procedures were performed by two experienced endoscopists. All complications were managed in our hospital
except one patient with cholangitis and suspected duodenal perforation. Thirty-three procedures were excluded
because papilla Vateri could not be reached (for reasons
related e.g. to duodenal obstruction or inadequate sedation). Retrospective chart review was continued for up to
30 days after the procedure or to the end of longer hospitalisation. Patient status after 30 days could be confirmed
in 91.5% of ERCPs. Olympus duodenoscopes were used in
all ERCPs. The cannulation techniques evolved during the
study period. A primary method of entering the bile duct
was to use sphincterotome or to cannulate over guide wire
inserted in the CBD. In the early years of the study period,
the guide wire cannulation was not routinely used and
some cannulations had to be done with a little contrast
medium injection to the pancreatic duct as access to CBD
was attempted. When necessary, a precut sphincterotomy
was performed with a needle knife towards 11–12 o´clock
TABLE 1
Indications or work-up diagnosis of 825 ERCPs with intact papilla
Indication or work-up diagnosis
CBD stone
n
%
266
32.2%
173
20.9%
172
20.8%
Acute biliary pancreatitis
64
7.8%
Acute cholangitis
59
7.2%
Chronic pancreatitis
35
4.2%
Dysfunction of sphincter of Oddi
10
1.2%
7
0.8%
Malignancy
1
Bile duct obstruction or jaundice
without accurate diagnosis
Bile leak after cholecystectomy
Other benign biliary disease
Total
1
2
2
39
4.7%
825
100.0%
Pancreatic cancer or papillary cancer 114 (13.8%), liver metastasis
or hepatocellular cancer 32 (3.9%), cancer of biliary tract or gallbladder 18 (2.2%), other (e.g. lymphoma or malignancy of unknown origin) 9 (1.1%)
Cases of benign stricture of CBD, primary sclerosing cholangitis,
papillary tumor or polyp, bile duct obstruction after cholecystectomy, primary biliary cirrhosis, cyst of CBD and pancreatic duct
stone or stricture.
to expose the CBD. Selectively, in the last few years a pancreatic sphincterotomy technique was used in which precut
was directed towards pancreatic duct. Some of the CBD
cannulations were performed with a double-guide-wire
technique (i.e. an another guide wire inside the pancreatic
duct). CBD stones were extracted by balloon catheter or
basket.
During the last two years of the study period, a routine
antibiotic prophylaxis (i.v. cefuroxime 1.5 g) was administered. Before this, antibiotics were given selectively if a
stent insertion was planned or if a patient had a bile duct
obstruction or an acute infection. The patients were given
i.v. sedation (midatsolame or propofol) in the last three
years of the study period administered mainly by an anaesthetist. In the earlier years, sedation and monitoring were
managed by the endoscopy team and only i.v. midatsolame
was used. Duodenal peristalsis was reduced by i.v. hyoscine butylbromide or i.v. glucagon. Procedures were classified as therapeutic when sphincterotomy, stone removal,
stent insertion or removal, brush cytology or dilatation was
performed. Routine serum blood samples after 6–10 hours
included WBC count, haemoglobin, CRP and amylase. Each
patient was followed up in our hospital for at least 24 hours
after ERCP.
Complications were classified using the standardised
criteria proposed by Cotton et al. (22). A complication was
defined as any adverse event occurring during the 30-day
period after ERCP requiring more than one night of hospitalisation. Severe complications required more than ten
days of hospitalisation, necessitated surgical or invasive
radiologic intervention, required admission to the intensive
care unit (ICU) or caused patient’s death. We compared
the age, sex, history of diabetes, use of anticoagulation
treatment, long-term corticosteroid use and the procedure
related factors (e.g. precut) to mortality and morbidity to
find significant risk factors. The grade of procedure difficulty and complexity was defined by the criteria published
earlier (23).
Statistical analysis was performed using IBM SPSS Statistics 19.0. Categorial variables were compared using
Chi-square test and calculating odds ratios and their 95 %
confidence intervals. A probability of < 0.05 was regarded
as significant. The study protocol was approved by ethics
committee of KHCH.
RESULTS
A total of 1207 consecutive ERCPs were performed to
809 patients. Papilla was intact i.e. no earlier sphincterotomy had been performed in 68.4% (n = 825) of
procedures. In these procedures 61.1% of patients
were females and the median age was 70 years (range
17–101). The cannulation of the desired duct was
achieved in 89.2% (n = 736) of the procedures with
intact papilla in the first ERCP session of the study
period. Complete stone extraction was successful in
91.3% and bile duct obstruction could be relieved
completely in 80.1% of procedures with intact papilla.
Of all 1207 ERCPs performed, 80.9% were therapeutic, 11.7% diagnostic or without therapeutic interventions and in 7.4% cannulation was unsuccessful.
The most common indications were CBD stones or
bile duct obstruction caused by malignancy (Table 1).
Of ERCPs with intact papilla, precut was performed
in 12%, standard sphincterotomy in 73.8%, CBD stone
removal in 33.7%, brush cytology in 11.8% and stricture dilation in 8.1% of procedures. A biliary stent
ERCP procedures in a Finnish community hospital: a retrospective analysis of 1207 cases
3
TABLE 2
Complications and ERCP related mortality in 825 ERCPs with intact papilla (i.e. no earlier sphincterotomy).
Age: median (interquartile range)
Complication
Difficulty grade
Pancreatitis
Mild
Moderate
Severe
Total
Haemorrhage
Mild
Moderate
Severe
Total
Cholangitis
Mild
Moderate
Severe
Total
Perforation
Mild
Moderate
Severe
Total
Other
Mild
Moderate
Severe
Total
All complications
Age (years)
n (%)
ERCP-related death n (%)
63 (44–74)
04
10
02
16
(0.5%)
(1.2%)
(0.2%)
(1.9%)
0
0
0
0
74 (53–83)
01
09
06
16
(0.1%)
(1.1%)
(0.7%)
(1.9%)
0
0
2
2
77 (58–83)
03
12
02
17
(0.3%)
(1.5%)
(0.2%)
(2.1%)
0
0
0
0
72 (68–81)
05 (0.6%)
0–
03 (0.4%)
08 (1.0%)
0
0
0
0
79 (68–88)
05
20
10
35
0
0
0
0
75 (63–83)
91 (11.1%)
(0.6%)
(2.4%)
(1.2%)
(4.2%)
2 (0.2%)
was inserted for malignant stricture in 11.4% and for
other reasons in 3.3% of ERCPs. A pancreatic stent
was inserted in 0.6% and pancreatic stone was extracted in 0.5% of primary procedures. Pancreatography was performed or contrast medium was observed
in the pancreatic duct in 47.8% of ERCPs with intact
papilla and in 38.8% of all procedures. Of all 1207
procedures a biliary stent exchange was performed
in 7.6% of ERCPs.
The complexity and difficulty level of completed
ERCP procedures were graded by a three-step classification. ERCPs with intact papilla fell into categories I, II and III respectively as 79%, 19% and 2%. No
connection between the level of difficulty and complications was found.
Of all ERCPs, 8.7% were planned second attempt
procedures 2–14 days after an incomplete or failed
procedure. These included cases where an earlier attempted ERCP had failed or had been intentionally
aborted after performing precut sphincterotomy in a
difficult cannulation.
Overall complication rate was 11.1% in procedures
with intact papilla (Table 2) and 9.8% in all ERCPs.
The majority of the complications (77 %) were mild
or moderate i.e. they were managed conservatively
and necessitated less than ten days of hospitalisation.
No statistically significant risk factors for overall
complications were found.
After precut sphincterotomy, pancreatitis of any degree was noted in six (5.6%) cases and after standard
sphincterotomy in 11 (1.8%) cases, but the difference
was not statistically significant (NS). Precut was a
risk factor of moderate or severe pancreatitis (OR 3.8,
95% CI 1.1–12.8, p 0.022). Patient´s sex, diabetes,
medication or contrast injection to pancreatic duct
during ERCP did not affect the risk of pancreatitis. In
patients under 50 years of age pancreatitis developed
in five cases (3.4%) and in 11 cases (1.6%) in older
patients (NS).
PANCREATITIS
Seventeen (2.1%) patients developed cholangitis after
ERCPs with intact papilla. One patient was treated
surgically for a suspected duodenal perforation. Both
cases of severe cholangitis developed after therapeutic procedures. No risk factors for cholangitis were
found.
Pancreatitis occurred after 16 (1.9%) of procedures
with intact papilla. Two of these were severe and required operation. Both were caused by a therapeutic
procedure. None of the patients died of pancreatitis.
HAEMORRHAGE
Haemorrhage was present after 16 (1.9%) ERCPs with
intact papilla. Half of these (50%) were treated with
re-duodenoscopy to achieve haemostasis. Two patients died of ERCP-related haemorrhage. Bleeding
resulted after four (4.0%) procedures with precut
sphincterotomy and after 13 (2.1%) of those with
standard sphincterotomy (NS). All ERCPs that caused
moderate or severe bleeding were therapeutic. None
of the patient or procedure related factors (e.g. age,
use of anticoagulation treatment, sphincterotomy,
precut) were related to the incidence of hemorrhage.
CHOLANGITIS
4
A. Siiki, A. Tamminen, T. Tomminen, P. Kuusanmäki
PERFORATION
Perforation was observed in eight (1.0%) patients.
Most of the perforations (75%) were retroperitoneal
and were noticed during the endoscopy (75%). None
of the cases were caused by a duodenoscope. Three
patients required surgery. All cases of moderate or
severe perforations were preceded by a therapeutic
ERCP. Perforation occurred in two (2.0%) procedures
with precut sphincterotomy and in four procedures
(0.7%) with standard sphincterotomy (NS). Patient or
procedure related factors were not related to risk of
perforation. Two patients of all of the 1207 ERCPs
died after perforation.
OTHER COMPLICATIONS
Other morbidity or complications developed in 35
(4.2%) of ERCPs with intact papilla. These included
seven (0.8%) patients with pneumonia, seven (0.8%)
infections of unknown origin, six (0.7%) cerebral infarctions, four (0.5%) cardiac events and four (0.5%)
cases with urinary retention or urinary tract infection.
Two (0.2%) patients with cholecystitis were operated
on. In addition, one case (0.1%) of each of the following events occurred: acute colitis, gastroenteritis,
deep venous thrombosis, suspected pulmonary embolism, and haemorrhage from oesophageal varices.
Age over 60 years was a risk factor of other complications graded moderate or severe (OR 3.6, 95% CI
1.1–12.0, p 0.027).
MORTALITY
The ERCP-related mortality in procedures with intact
papilla was 0.2% (n = 2). Both cases resulted from
hemorrhage. Overall mortality in 30 days was 3.3%
(n = 27). Eighteen (2.2%) of these were caused by cancer and seven (0.8%) by other, non-ERCP-related adverse events. These seven deaths consisted of two
cases of pneumonia, three cardiac events, a septic
infection after insertion of a percutaneous transhepatic biliary drain and a haemorrhage from esophageal varices in a patient with severe liver cirrhosis.
Age over 60 years was a risk factor of overall 30-day
mortality (OR 11.8, 95% CI 1.6–87.4, p 0.002).
In all of the 1207 procedures, ERCP-related mortality was 0.4% (n = 5). Two patients died after perforation. In addition, the death of a 68-year old male in
the ICU nine days after biliary stent insertion was
considered ERCP-related. In autopsy, the cause of
death was multi-organ failure of unknown origin.
DISCUSSION
Given that ERCP is a technically demanding invasive
procedure with a risk of complications, ERCP practice should be critically evaluated in terms of indications, success rates and complications (18). Most of
the earlier studies come from university clinics,
whereas there are only few reports of complications
in low-volume centres (10). Our objective was to describe ERCP-practice in a community hospital and to
report success rates and complication figures that
could be compared to earlier studies.
In our material 80.9% of all ERCPs were therapeutic and 11.7% were diagnostic or without need for
intervention. In the earlier studies, the proportion of
therapeutic ERCPs has ranged from 54.7% to 97.7%
(7, 8, 10, 12, 13). Both the indications of ERCPs and
the proportions of different biliary procedures were
essentially similar to those described in earlier reports (6, 8–12). The number of pancreatographies
seems high, because it was defined as any amount of
contrast medium in the pancreatic duct and not only
as an intentional diagnostic filling of the duct. In the
early years of the study period, as CBD was cannulated without a guide wire, a careful injection of contrast medium to pancreatic duct was sometimes unavoidable. In our study a pancreatic stent was inserted in 1.8% of all procedures and in 0.6% of ERCPs
with intact papilla. No complications occurred after
pancreatic procedures. In the earlier studies the proportion of pancreatic procedures varied widely, which
may indicate differences in patient mix between centres. In the study by Williams et al. (9) pancreatic
procedures accounted for 1.6% of ERCPs. In other
reports, the proportion of pancreatic stent insertions
has ranged from 5.5 to 9.2% of procedures (10, 11).
A three-step classification of procedure complexity
has been used in a few earlier studies to control the
effect of patient mix to complications (10, 11). More
complex and more difficult procedures (grade III)
have resulted more often in severe complications or
mortality (11). The proportion of the most complex
procedures was expectedly slightly lower than in
larger centres (10, 11). In a retrospective setting, defining ERCP complexity may be unreliable. In our
material, five patients were referred to the endoscopy
unit of Helsinki University Hospital (HUS) because
demanding pancreatic interventions were needed
and in our unit even repeated attempts had not been
successful.
We used precut sphincterotomy in 12% of ERCPs
with intact papilla. This is slightly more than 8.5–
10.0% in earlier studies (5, 6, 19, 21). In our material
precut was a significant risk factor for moderate or
severe pancreatitis. This concurs with findings showing both difficult cannulation and precut sphincterotomy to be risk factors of ERCP-related complications
(5, 7, 8, 9, 12). On the other hand, properly timed
precut sphincterotomy performed by an expert endoscopist makes it possible to complete the procedure
endoscopically without risk of operative or percutaneous interventions (3, 4, 19, 20, 21). It has been suggested, that precut sphincterotomy should be used
early enough in a difficult cannulation to avoid numerous cannulation attempts and unnecessary injury
to the papilla or to the pancreatic duct. Early use of
precut sphincterotomy may reduce the risk of pancreatitis (24, 25). The second cannulation attempt a
few days after precut is usually easier (13, 19, 20).
In the last two years of the study period, we selectively used pancreatic sphincterotomy in difficult bile
duct cannulation (21, 26, 27). This technique has been
shown to enable bile duct cannulation relatively
safely in up to 98.1% of cases (20). We did not use
ERCP procedures in a Finnish community hospital: a retrospective analysis of 1207 cases
temporary pancreatic stenting to prevent ERCP-related pancreatitis (12, 27, 28, 29).
The success rate of cannulation and complication
figures are usually reported from ERCPs with no earlier sphincterotomy. The cannulation of the papilla is
easier and less risky if a sphincterotomy has already
been done. In the present study the success rate of
cannulation was 89.2% of ERCPs in which the papilla
was intact and 92.6% of all ERCPs. Studies from academic centres have reported successful bile duct cannulation in 85.6–98.1% of cases (8, 9, 10, 12, 13, 19, 20,
21). However, in our study the proportion of planned
second attempt ERCPs 2–14 days after aborted or
failed procedure was 8.7% of all procedures. As far as
we know, this figure has seldom been reported in
other studies; in the study by Palm et al., the proportion of second attempt ERCPs was 3.0% (20). We have
tried to avoid complications by converting a difficult
cannulation attempt early enough into a precut
sphincterotomy, followed by a planned second attempt ERCP a few days later. As our figures are per
procedure, the definitive success rate per patient after
repeated ERCPs remains unknown. In the other studies, repeat ERCP after precut sphincterotomy has
been shown to enable successful cannulation ultimately in up to 96.0–98.2% of cases (19, 20). The success rates for extraction of CBD stone or relieving bile
duct obstruction were similar to the results of Colton
et al. in a community setting and to the published
guideline (10, 18).
In our study the incidence of pancreatitis (1.9%)
was lower than 2.6–7.2% reported earlier (3, 4, 6–12,
21). According to the prospective studies, younger
patients and patients under 60 years of age have been
in increased risk of pancreatitis (4, 9, 12). In the earlier studies, the incidence of haemorrhage and cholangitis has been 0.3–2.0% and 0.3–1.4%, respectively
(3, 4, 6–12). The highest incidence of cholangitis has
reportedly been up to 5% (8). Our results substantiate
this. Some cases of haemorrhage could have been
avoided, as some of the procedures were performed
to extremely high risk patients as a palliative attempt
to relieve e.g. malignant biliary obstruction. Perforation has occured in 0.1–1.1% of cases (3, 4, 6–12). Our
incidence was 1.0%. Other, e.g. cardio-pulmonary
complications were slightly more frequent than 0.2–
1.5% in recent reports (7–12). On the other hand, in a
large prospective Danish study with a thorough follow-up, the incidence of other complications was
5.1% with an overall complication rate of 15.9% (8).
As noted in the earlier studies (7–12), the majority of
the complications was mild or moderate and could
be managed non-operatively with a short hospitalisation.
The most of the mortality was caused by cancer or
non-ERCP-related diseases. ERCP-related mortality
in procedures with intact papilla (0.2%) was similar
to figures of 0–1.0% of the earlier studies (8, 10, 11).
In the reports from Finnish academic centres, ERCPrelated mortality has been 0.1–0.3% (13, 14, 20). Overall mortality usually ranges from 1.4% to 5.8% (8, 10,
11), but this figure, as well as rate of overall morbidity, may be influenced to some extent by differences
in patient follow-up and study design. Both non-ER-
5
CP-related complications and overall mortality were
expectedly related to patient´s age of over 60 years.
This study describes ERCP practice in a low-volume community hospital. The indications and success rates as well as morbidity and mortality are acceptable compared to those in earlier reports and
published guidelines. Although the success rate of
cannulation and thereby ERCP procedures seem to be
somewhat lower than in tertiary referral centres, our
results confirm that ERCP procedures can be safely
performed in a low-volume ERCP unit. Adequate indications of ERCP and good procedure routine can be
maintained, at least when procedures are concentrated on a few experienced endoscopists. Cannulation success rates reported from academic centers
may be achieved using techniques, such as pancreatic
sphincterotomy and cannulation with the double
guide wire technique, that were used only in the last
years of the study period.
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Received: February 25, 2011
Accepted: June 18, 2011
Scandinavian Journal of Gastroenterology. 2014; 49: 1385–1390
ORIGINAL ARTICLE
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Spyglass single-operator peroral cholangioscopy seems promising in the
evaluation of primary sclerosing cholangitis-related biliary strictures
ANTTI SIIKI1, IRINA RINTA-KIIKKA2, TARMO KOIVISTO1, KAIJA VASAMA3,
JUHANI SAND1 & JOHANNA LAUKKARINEN1
1
Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland,
Department of Clinical Radiology, Tampere University Hospital, Tampere, Finland, and 3Department of Pathology,
Fimlab Laboratories, Tampere University Hospital, Tampere, Finland
2
Abstract
Early diagnosis of dysplastic changes and exclusion of cholangiocarcinoma (CCA) in patients with primary sclerosing
cholangitis (PSC) remain a major clinical challenge. Although SpyGlass single-operator cholangioscopy (SOC) appears
effective in diagnostics of indeterminate biliary strictures, there are only few studies on its safety in PSC-related strictures.
Objective. The aim of this study was to assess the clinical feasibility of SOC and directed biopsies, flow cytometry, and brush
cytology in PSC patients. Materials and methods. Eleven consecutive patients (median age 45 years, 5 females) undergoing
SOC for progression of PSC in a single tertiary center were included in a prospective observational study. Results. Brush
sample and directed biopsies were successfully acquired from strictures in all cases. Samples were adequate for cytological and
histological diagnosis in 9 (82%) and 10 patients (91%), respectively. There were two cases of pancreatitis. In one patient, flow
cytometry showed aneuploidy, which resulted in closer follow-up. Conclusions. SpyGlass SOC and directed biopsies seem to
offer a feasible and promising method in evaluation of PSC-related strictures. However, the long-term prognostic value it adds
to cytology and flow cytometry remains to be assessed in future trials.
Key Words: Benign biliary strictures, cholangioscopy, endoscopic retrograde cholangio-pancretography, primary sclerosing
cholangitis
Introduction
Early diagnosis of dysplastic changes and exclusion
of cholangiocarcinoma (CCA) in patients with
primary sclerosing cholangitis (PSC) remain a major
clinical challenge. Although single operator peroral
cholangioscopy (SOC) appears effective in diagnostics of indeterminate biliary strictures, there are only
few studies of its safety and feasibility on PSC-related
strictures [1–9]. Combination of cholangiography,
brush cytology, analysis of serum tumor markers
(CA19-9, CEA) and flow cytometry (DNA ploidity)
provide only relatively accurate differentiation
between benign and malignant strictures in PSC
[9,10].
The objective was to characterize the initial experience and clinical feasibility of SOC in PSC patients
in a tertiary endoscopy unit and to evaluate the
combined diagnostic yield of SOC and directed
biopsies, flow cytometry and brush cytology.
Methods
All consecutive patients who underwent endoscopic
retrograde cholangiopancreatography (ERC) and
SOC between March and August 2012 for progression of PSC in a single tertiary center (Tampere
University Hospital, Finland) were included. The
case series was carried out in accordance with
Declaration of Helsinki.
Correspondence: Johanna Laukkarinen, MD PhD, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35,
P.O. Box 2000, 33521 Tampere, Finland. Tel: +358 3 311 64314, + 358 50 358 6556. Fax: + 358 3 311 64358. E-mail: johanna.laukkarinen@fimnet.fi
(Received 4 February 2014; revised 5 April 2014; accepted 24 June 2014)
ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare
DOI: 10.3109/00365521.2014.940376
1386
A. Siiki et al.
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A
B
Figure 1A-B. Cholangiography image of a 49-year-old female (patient no 9) with PSC duration of 23 years. Intrahepatic findings (*) and
SpyGlass cholangioscope (**) in the common hepatic duct.
The diagnosis of PSC was based on the typical
findings in MRCP (magnetic resonance cholangiopancreatography) and previous ERC. MRCP was
performed using standard imaging protocols including heavily T2-weighted two-dimensional thinsection and thick sequences in coronal plane to
visualize all biliary ductal structures. Additionally,
gadolinium-enhanced sequences were routinely
used to estimate inflammatory and possible neoplastic
changes.
SOC procedures were performed by SpyGlass
Direct Visualization Equipment (Boston Scientific
Corp, USA) according to the methods described in
detail by Chen et al. [1]. The number of directed
biopsies (Figures 1, 2 and 3) ranged from four to six
and they were obtained with SpyBite biopsy forceps
(Boston Scientific Corp). For both cytology [11] and
flow cytometric analysis [10], brush sampling (RX
Cytology Brush, Boston Scientific Corp) was
performed. A single dose of intravenous antibiotics
(i.v. cefuroxime 1.5 g) and anti-inflammatory suppository (diclofenac 100 mg) was given to all patients
before ERC. Patient sedation (i.v. midatsolame and
oxycodone) was administered and monitored by an
endoscopy team. To reduce duodenal peristalsis, i.v.
hyoscine butylbromide (20–40 mg) or i.v. glugacon
(0.3 mg) was given. PatientsMRCP and cholangiography images were carefully reanalyzed by an experienced abdominal radiologist to classify the PSC
findings according to the well-established method
of Majoie et al. [12] presented in Table I. Procedures
were performed in outpatient setting, except in 4 cases
with 24 hours of in-patient observation for deep
Figure 2. A hematoxylin-eosin–stained specimen taken by a
SpyBite biopsy forceps from bile duct of a 49-year-old patient
(no 9) presenting active chronic inflammation, regenerative atypia,
and no dysplasia.
Figure 3. Typical appearance of primary sclerosing cholangitis in
extrahepatic bile duct of a 51-year-old male (no 7). Images acquired
by SpyGlass single-operator peroral cholangioscopy; note SpyBite
biopsy forceps in the lower right-hand image.
Spyglass cholangioscopy in sclerosing cholangitis
Table I. Classification of cholangiographic findings in primary
sclerosing cholangitis [12].
Type of duct
involvement/classification
Intrahepatic
I
Multiple strictures; normal caliber of
bile ducts or minimal dilation
Multiple strictures, saccular dilations,
decreased arborization
Only central branches filled despite
adequate filling pressure, severe
pruning
II
III
Extrahepatic
I
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Cholangiographic abnormalities
Slight irregularities of duct contour, no
stenosis
Segmental stenosis
Stenosis of almost entire length of duct
Extremely irregular margin;
diverticulum-like out-pouchings
II
III
IV
sedation or patient logistics. ERC complications
were classified according to Cotton et al. [13], and
were prospectively recorded for 30 days after the
procedure.
Study endpoints were technical success, frequency
of adequate biopsies obtained and complication rate.
For PSC progression, prospective follow-up from
hospital records was carried out until March 2014.
Results
A total of 11 patients (5 female) underwent ERC with
SOC. The baseline characteristics of the study
1387
population are presented in Table II. The median
age was 45 years (range 24–66). The median time
from the diagnosis of PSC was 8 years (range 1–28
years).
In nine patients (82%) a previous ERC, and in
six (55%) a previous sphincterotomy had been
performed. None of the patients had previous postERC pancreatitis. Pre-procedural serum tumor
markers (CA19-9 and CEA) were within normal
range in all patients.
After successful wire-guided biliary cannulation,
endoscopic sphincterotomy was performed on all
but one patient (90%), for whom earlier sphincterotomy was adequate.
The radiologic grade of PSC changes is presented
in Table I. Both intra- and extrahepatic changes were
present in eight (73%) patients; the other three had
intrahepatic disease.
Brush samples for cytology and flow cytometry
were successfully obtained from extrahepatic and/or
intrahepatic dominating strictures in all cases. Direct
visualization of the epithelium at the site of the
dominant stricture as well as acquiring SOC-guided
biopsies was successful in all cases (Figure 3). The
stricture could be completely traversed with a cholangiosope in six cases (55%). In others, a tight
impassable dominant stricture was located intrahepatically, except in one patient, with a narrow class IV
extrahepatic stenosis. Bile duct stones were unexpectedly detected in cholangioscopy in one patient (9%)
and successfully removed by balloon. Stricture
Table II. Patient demographics, indication for and findings of ERC, results of cytological and flow cytometric analysis, and histological
findings of SpyGlass biopsies.
Classification (Majoie)
N
Age
Sex
Indication (PSC)
Intrahepatic
Extrahepatic
Cytology
DNA index
S-phase
Histology
1
2
43
28
M
M
III
I
IV
Normal
2
2
1
1.21
1,8
7.2
Inadequate
Inflammation
3
44
F
II
II
2
1
2.1
Normal
4
41
M
III
II
1
1
NA
Inflammation
5
45
F
II
I
2
1
1.2
Inflammation
6
54
F
Progression in MRI
Progression in MRI,
elevated LFT
Progression in MRI,
elevated LFT
Progression in MRI,
elevated LFT
Elevated LFT,
no previous ERC
Elevated LFT
II
II
Inadeq.
Inadeq.
NA
7
51
M
I
IV
2
1
NA
Regenerative
atypia
Fibrosis
8
9
10
11
50
49
66
24
F
F
M
M
III
III
I
I
I
II
Normal
Normal
2
2
Inadeq.
1
1
1
Inadeq.
1
0
6.8
NA
0
Fibrosis
Inflammation
Fibrosis
Fibrosis
More than 5 years
rom ERC
Progression in MRI
Progression in MRI
Progression in MRI
Over 5 years from
ERC
Abbreviations: Age (years); PSC = primary sclerosing cholangitis; MRI = magnetic resonance cholagiopancreatography; LFT = liver function
tests; ERC = Endoscopic retrograde cholangiography; Stricture classification = Majoie; Cytology = Papa classification. Inadeq = Sample
inadequate for diagnosis.
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1388
A. Siiki et al.
dilatation or stenting was not necessary in any of
the procedures.
Out of nine patients (82%) with adequate brush
sample for cytological analysis, the result was
class 2 in seven and class 1 in two. The flow cytometric analysis showed normal diploidic DNA in all
but one patient, who had a marginally elevated DNA
index of 1.21 and normal S-phase of 7.2%. The
specimens were adequate for successful histological
analysis in 10 (91%) patients; one normal bile duct
epithelium and seven regenerative, fibrotic or chronic
inflammatory changes (Table II).
Two patients developed immediate post-ERC complications from which they recovered uneventfully
without need for interventions or intensive care; a
28-year-old male and a 43-year-old male both developed a moderate pancreatitis within a few days after
ERC.
The follow-up of PSC patients was planned according to guidelines of our institution. The median length
of follow-up was 22 months (range 16–24 months).
Patient 1 with severe cholangiography changes and
rapid PSC progression at first referred to the livertransplantation unit of Helsinki University Hospital,
Finland, has undergone endoscopic stenting and stent
removal. Without episodes of acute cholangitis or
disease progression, liver transplantation has not yet
been performed. Patient 2 with initially aneuploidic
flow cytometry was scheduled for re-ERC at 6 months
with normalized results. Next surveillance ERCP is
going to take place at 18 months. Other patients were
scheduled for outpatient follow-up (liver enzymes,
CA19-9, MRCP, colonoscopy for ulcerative colitis)
and for re-ERC at 12 months (patients 3, 4, 6, 7 and
8) or at 36–48 months (patients 5, 9, 10 and 11).
None of the patients have unexpected disease
progression or episodes of acute cholangitis. Patient
8 with a common bile duct stone has been asymptomatic ever since the stone removal.
Discussion
SOC has been reported to increase the sensitivity and
specificity in the detection of malignant biliary strictures [1–5]. It may also be beneficial in PSC patients
[6,7], where cholangiography (ERC) and MRCP have
traditionally been the foundation of diagnostics. To
the best of our knowledge, no reports on the results of
combined diagnostic yield of SOC, directed biopsies,
flow cytometry and brush cytology in PSC have been
presented. We found that direct visualization SOC
seems feasible and it, thus, may be promising in terms
of even better stricture evaluation and diagnostics
when compared to methods such as cholangiography,
flow cytometry and brush cytology. The true safety,
diagnostic value of SOC and guided biopsies in the
long term remain to be assessed in future trials.
The most important clinical problem with PSCrelated stricture is the prompt diagnosis of biliary
dysplasia and exclusion or early detection of cholangiocarcinoma, potentially associated with poor
prognosis [8].
In PSC, the combination of brush cytology, flow
cytometry and serum tumor markers (CEA, CA19-9)
has been found to yield the most accurate results in
predicting malignancy; sensitivity of 100% and specificity of 85%, positive predictive value of 78% and
negative predictive value of 100% were reported by
Lindberg et al. in 24 months of follow-up [9]. Combining flow cytometry and cytology in predicting liver
transplantation or a diagnosis of CCA or dysplasia in
PSC has produced sensitivity and specificity of 72%
and 82%, respectively [10]. Brush cytology has a high
specificity but sensitivity is low, which is similar to
flow cytometry with sensitivity of 29% and specificity
of up to 100% [9].
In the earlier studies, direct SOC visualization
without biopsies has been found misleading and
unreliable in PSC setting due to the inflammatory
and fibrotic appearance of the stricture [6]. Prediction
of malignancy in PSC with multiple strictures may be
more challenging than in patients with non-PSC
stenosis, who usually have otherwise normal morphology of the biliary tree [7].
In unselected biliary strictures, the suspicious
findings can usually be confirmed by SOC-directed
biopsies [1]. In indeterminate strictures the accuracy
of biopsies was 87% in distinguishing malignant from
benign stricture [4]. In a multicenter study by
Chen et al., SOC was found to be decidedly more
accurate than cholangiography in the diagnostics of
malignancy; sensitivity and specificity were 78% and
82% to 51% and 54%, respectively [2]. SOC and
directed biopsies have been found to alter clinical
management in 64% of patients in indeterminate
strictures [2]. Although the sensitivity, accuracy and
negative predictive value of mini-forceps biopsies have
reportedly been superior to those of brush cytology or
cholangiography-guided biopsies, the negative predictive value being of mini-forceps biopsy has been as low
as 69% [3]. It has been suggested that in patients with
suspected malignancy but benign tissue samples,
a repeated cholangioscopy with biopsies should be
carried out [7].
In the present study, all procedures were technically
successful. The cannulation of the papilla has reportedly been more difficult in PSC patients than in
unselected patients with an indeterminate biliary
stricture [4]. Very narrow intrahepatic or hilar stricture may sometimes prevent safe passing with a
Scand J Gastroenterol Downloaded from informahealthcare.com by Tampere University on 12/08/14
For personal use only.
Spyglass cholangioscopy in sclerosing cholangitis
cholangioscope [6]. In these cases, tissue samples
could still be obtained from the stricture area by
SOC-directed biopsies, which is clinically more
important than completely traversing an intrahepatic
stricture with a cholangioscope.
Our findings support the excellent rate (91%) of
obtaining adequate biopsies for histological analysis.
In the literature the rate of sufficient biopsies acquired
has been up to 98% in PSC [6]. However, determining epithelial dysplasia from tiny amount of tissue
obtained by mini-forceps for histologic samples may
be unreliable, since the biopsy bites seem to consist of
mostly stroma and only small amount of epithelial
tissue. We thus recommend acquiring more than four
to six directed biopsies per stricture. Moreover, the
cytology, flow cytometry and histology samples from
each case should all be analyzed simultaneously and
complementary to each other by experienced and
highly specialized pathologists.
SOC was considered useful in evaluation of PSC.
There was no discrepancy between information from
SOC image, cytology, flow cytometry and histology.
However, our sample size is small for any conclusion
of additional clinical value provided by SOC. In the
study by Tischendorf et al. on 53 PSC patients, SOC
was found to significantly increase the ability to distinguish malignant from benign strictures compared
to cholangiography or brush cytology [7]. An SOC
sensitivity of 92%, specificity of 93%, accuracy of
93%, positive predictive value of 79% and negative
predictive value of 97% in the evaluation of dominant
PSC strictures were reportedly achieved in the
median follow-up of 47 months [7].
There was one case of biliary stones undiagnosed in
MRCP or cholangiography, but found and removed
by SOC. In the study of Awadallah et al., cholangioscopy revealed in 30% of PSC patients bile duct
stones missed in cholangiography, the removal of
which resulted in clinical improvement in up to
77% [6].
Two complications occurred, neither with severe
clinical consequences. These patients were among the
first four SOCs performed for PSC in our institution,
which may be attributable to learning curve. The rate
of post-ERC pancreatitis has reportedly been 7% in
PSC patients when SOC is not performed, with
female sex and difficult cannulation increasing and
earlier sphincterotomy decreasing the risk [14], The
most common complications related to SOC are
episodes of cholangitis and pancreatitis [1,4,5,15].
Total overall ERC complications have been reported
to be twice, and cholangitis nearly five times as
frequent when concomitant SOC is performed [15].
In conclusion, SOC and directed biopsies seem
to offer a feasible and promising method in evaluation
1389
of PSC-related strictures, especially in extrahepatic
disease. The additional information SOC provides
when combined with flow cytometry, brush cytology
and serum tumor markers is a subject for future trials.
Moreover, further studies on PSC patients are needed
to assess the predictive value and long-term effect on
clinical decision-making of this novel technology.
Acknowledgments
This work was financially supported by the Sigrid
Jusélius Foundation, Finland, and the competitive
research found of Pirkanmaa Hospital District,
Finland.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
References
[1] Chen Y, Pleskow D. SpyGlass single-operator peroral
cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with
video). Gastrointest Endosc 2007;65:832–41.
[2] Chen Y, Parsi M, Binmoeller K, Hawes R, Pleskow D,
Slivka A, et al. Single-operator cholangioscopy in patients
requiring evaluation of bile duct disease or therapy of biliary
stones (with videos). Gastrointest Endosc 2011;74:805–14.
[3] Draganov P, Chauhan S, Wagh M, Gupte A, Lin T,
Hou W, et al. Diagnostic accuracy of conventional and
cholangioscopy-guided sampling of indeterminate biliary
lesions at the time of ERCP: a prospective, long-term
follow-up study. Gastrointest Endosc 2012;75:347–53.
[4] Kalaitzakis E, Webster G, Oppong K, Kallis Y, Vlavianos P,
Huggett M, et al. Diagnostic and therapeutic utility of singleoperator peroral cholangioscopy for indeterminate biliary
lesions and bile duct stones. Eur J Gastroenterol Hepatol
2012;24:656–64.
[5] Ramchandani M, Reddy N, Gupta R, Lakhtakia S,
Tandan S, Darisetty S, et al. Role of single-operator peroral
cholangioscopy in the diagnosis of indeterminate biliary
lesions: a single-center, prospective study. Gastrointest
Endosc 2011;74:511–19.
[6] Awadallah N, Chen Y, Piraka C, Antillon M, Shah R. Is there
a role for cholangioscopy in patients with primary sclerosing
cholangitis. Am J Gastroenterol 2006;101:284–91.
[7] Tischendorf J, Krüger M, Trautwein C, Duckstein N,
Schneider A, Manns M, et al. Cholangioscopic characterization of dominant bile duct stenosis in patients with primary
sclerosing cholangitis. Endoscopy 2006;38:665–9.
[8] Chapman R, Fevery J, Kalloo A, Nagorney D, Boberg K,
Schneider BM, et al. Diagnosis and management of primary
sclerosing cholangitis. Hepatology 2010;51:660–78.
[9] Lindberg B, Arnelo U, Bergquist A, Thörne A, Hjerpe A,
Grandqvist S, et al. Diagnosis of biliary strictures in
conjunction with endoscopic retrograde cholangiopancreaticography,with special reference to patients with primary
sclerosing cholangitis. Endoscopy 2002;34:909–16.
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[10] Halme L, Arola J, Numminen K, Krogerus L, Mäkisalo H,
Färkkilä M. Biliary dysplasia in patients with primary sclerosing cholangitis: additional value of DNA ploidity. Liver
Int 2012;32:783–9.
[11] Boberg K, Jebsen P, Clausen O, Foss A, Aabakken L,
Scrumpf E. Diagnostic benefit of biliary cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol
2006;45:568–74.
[12] Majoie C, Reeders J, Sanders J, Huibregtse K, Jansen P.
Primary sclerosing cholangitis: a modified classification of
cholangiographic findings. AJR Am J Roentgenol 1991;157:
495–7.
[13] Cotton P, Lehman G, Vennes A, Geenen J, Russell L,
Meyers W, et al. Endoscopic sphincterotomy omplications
and their management: an attempt at consensus. Gastrointest
Endosc 1991;37:383–93.
[14] Ismail S, Kylänpää L, Mustonen H, Halttunen J,
Lindström O, Jokelainen K, et al. Risk factors for complications of ERCP in primary sclerosing cholangitis. Endoscopy
2012;44:1133–8.
[15] Sethi A, Chen Y, AustinG,Brown W,BrauerB,Fukami N,etal.
ERCP with cholangiopancreatoscopy may be associated
with higher rates of complications than ERCP alone: a single
center experience. Gastrointest Endosc 2011;73:251–6.
ORIGINAL ARTICLE
Covered Self-expanding Metal Stents May be Preferable
to Plastic Stents in the Treatment of Chronic
Pancreatitis-related Biliary Strictures
A Systematic Review Comparing 2 Methods of Stent Therapy
in Benign Biliary Strictures
Antti Siiki, MD,* Mika Helminen, MSc,wz Juhani Sand, MD, PhD,*
and Johanna Laukkarinen, MD, PhD*
Background: Covered self-expanding metal stents (CSEMS) are
being increasingly used in the endoscopic treatment of benign
biliary strictures (BBS). There is no solid evidence yet to support
their routine use.
Goals: To evaluate feasibility, success rate, and complications of
CSEMS compared with multiple plastic stents (PS) in BBS in a
systematic review.
Study: A systematic search of electronic databases (Medline,
Scopus, and Embase) for studies published from 2000 to 2012
combined to hand-search of reference lists resulted 4977 articles.
Out of 99 potentially relevant studies selected for full-text review,
12 CSEMS (376 patients) and 13 PS studies (570 patients) met the
final inclusion criteria. A systematic review comparing the 2
methods was made using proportion meta-analysis.
Results: A tendency to successful use of CSEMS in strictures
related to chronic pancreatitis (CP) was shown: clinical success of
77% and 33% [95% confidence interval (CI), 61%-94% vs. 4%63%, P = 0.06] was achieved with CSEMS and PS at 12 months
follow-up, respectively. There were no differences in the success
rates of other etiologies except CP or in the early complications. In
CSEMS, incidence of late adverse events was lower in CP-related
strictures (3% vs. 67%, 95% CI, 0%-13% vs. 17%-99%,
P = 0.02). The median number of endoscopic retrograde cholangiopancreatographies was lower with CSEMSs: 1.5 versus 3.9
(P = 0.002).
Conclusions: Improved clinical success with fewer endoscopic sessions and corresponding complication rate may be achieved with
CSEMS treatment compared with PS in BBS secondary to CP. In
other BBS etiologies, this systematic review remains inconclusive.
Key Words: endoscopy, benign biliary strictures, stents, chronic
pancreatitis, postoperative biliary stricture
(J Clin Gastroenterol 2014;48:635–643)
Received for publication March 25, 2013; accepted October 8, 2013.
From the *Department of Gastroenterology and Alimentary Tract
Surgery, Tampere University Hospital; wScience Center, Pirkanmaa
Hospital District; and zSchool of Health Sciences, University of
Tampere, Tampere, Finland.
Supported by Sigrid Jusélius Foundation, Finland and the competitive
research fund of Pirkanmaa Hospital District, Finland.
The authors declare that they have nothing to disclose.
Reprints: Johanna Laukkarinen, MD, PhD, Tampere Pancreas Laboratory, Department of Gastroenterology and Alimentary Tract
Surgery, Tampere University Hospital, Teiskontie 35, FIN-33521
Tampere, Finland (e-mail: johanna.laukkarinen@fimnet.fi).
Copyright r 2013 by Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Number 7, August 2014
I
n the endoscopic treatment of benign biliary strictures
(BBS), the use of multiple plastic stents (PS) has a widely
recognized role as a primary therapy.1–4 Relatively high
stricture recurrence rate and a tendency to stent clogging
necessitating frequent stent exchanges in PSs has generated
a growing interest of use of covered self-expanding metal
stents (CSEMS) in BBS.1,2,5–8 Although a single randomized controlled trial (RCT) comparing PS and CSEMS in
postoperative strictures supports,9 as well as several recent
non-comparative studies show promising results, strong
evidence justifying their routine use is limited.
BACKGROUND
The etiology of BBS ranges from postoperative
[postorthotopic liver transplant (LT) or postcholecystectomy] to stenosis caused by chronic pancreatitis (CP),
common bile duct (CBD) stones, sclerosing cholangitis,
previous endoscopic sphincterotomy, and abdominal
trauma.1,6 The optimal treatment strategy and expected
outcome depend on stricture etiology.3 Percutaneous
transhepatic and surgical methods are associated with significant morbidity and a considerable recurrence rate.10–12
If endoscopy fails, the long-term results of operative
approach in refractory BBS are relatively good.12,13 However, surgical hepaticojejunal anastomosis makes later
endoscopic treatment challenging if restricturing of anastomosis occurs. Especially in CP, patient comorbidities
and hostile conditions due to chronic inflammation may
complicate the surgical approach.
The well-established endoscopic treatment method of
PS includes tri-monthly insertion of increasing number of
10 F PS across the stricture for 12 months.2,14 PS therapy
has produced good long-term results in BBS,14–17 especially
in postcholecystectomy BBS14,17–20 and duct-to-duct anastomotic strictures after LT.16,21–24 Strictures secondary to
CP respond least well to PS treatment25–29 because of the
fibrotic nature of the strictures in calcifying CP. The main
drawbacks of PS therapy are the need for frequent endoscopic stent exchanges, either scheduled tri-monthly or
unscheduled for stent obstruction, and relatively challenging insertion of multiple stents side-by-side across the
stricture.6
CSEMS offer potential advantages over PS: fewer
endoscopic sessions and improved patency with fewer stent
occlusions due to postdeployment diameter equivalent of
three 10 F PS.1,6 Possible drawbacks include complicated
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635
J Clin Gastroenterol
Siiki et al
removal secondary to tissue embedding or proximal
migration,30–32 cholecystitis due to occlusion of the cystic
duct,33 de novo strictures after stent removal,34–36 stent
migration,8,34,37,38 postdeployment pain possibly due to
stent,8,32 limited usefulness in hilar strictures,39 and insufficient evidence of optimal stent design and of adequate
stent indwelling time. One single study has reported a costanalysis of stent therapy in BBS, supporting the use of
CSEMS in CP-related strictures.40 Studies on CSEMS
report promising results in postoperative strictures9,30,41–47
and in CP.8,32,37,48–52 The only RCT available up to date
reported feasibility and better long-term patency of
CSEMS compared with multiple PS in 31 cases of postoperative strictures, with success rates up to 82% with
CSEMS during 5 to 6 years of follow-up.9 However,
because of heterogeneity of studies and relative lack of
RCTs, CSEMS use, at least as a first-line treatment, cannot
yet be universally recommended in BBS.5,6
OBJECTIVES
The aim of this systematic review was to compare
the outcomes of CSEMS and PS in the endoscopic treatment of BBS.
METHODS
Search Strategy
A literature search of the Medline and Embase and
Scopus databases was conducted for studies assessing
endoscopic treatment of BBS. To perform a highly sensitive
database query, an information specialist with expertise on
medical search strategy was involved (Mervi Ahola of
Department of Health Sciences of Tampere University
Library). The query was limited to studies on adults published in English between January 1, 2000 and December
31, 2012. The search was performed with the following
keywords combined with appropriate Medical Subject
Headings terms: “biliary stricture, stenosis or constriction,
bile duct diseases, cholestasis, jaundice, chronic pancreatitis, postoperative complications of liver transplantation and cholecystectomy or sclerosing cholangitis”
and “endoscopy, cholangiopancreatography, or stents.”
The analysis was based on published results, and no additional data were obtained from any original authors.
The titles and abstracts of studies identified were
screened and the full texts of potentially relevant publications were obtained. Studies on endoscopic treatment of
BBS with PS or CSEMS and with reported adequate data
about stent type, stricture etiology, complications, and
outcome were considered to meet the inclusion criteria. The
selection process was carried out by 2 independent
reviewers (A.S., J.L.). In addition, the reference lists of key
studies were hand searched to identify further relevant
studies.
Case reports, publications about percutaneous, operative, or vascular approaches, intestinal stenting, malignant
strictures, pancreatic duct strictures and bile leaks, as well
as strictures treated with only balloon dilatation or
sphincterotomy were excluded. Whenever it was not
possible to exclude cases with neoplasm, biliary fistula
(leakage) or combined operative and percutaneous treatment, the entire study was excluded.
Data extracted from the selected studies included:
primary author, year of publication, country of origin,
636 | www.jcge.com
Volume 48, Number 7, August 2014
characteristics of study population (age, sex, stricture etiology, previous treatment), study design, number of
patients, technical success, complications related to stent
insertion and removal, complications and other adverse
events (such as stent migration) in the follow-up, duration
of stent therapy, and clinical success at stent removal, after
6 and 12 months and at the end of follow-up. Complications were divided to early [related to stent insertion and
post–endoscopic retrograde cholangiopancreatography
(ERCP) period of 30 d] and late (during the follow-up until
stent removal).
Definitions
BBS: It is a nonmalignant stricture of CBD. Multiple
PS: It is a treatment strategy of tri-monthly plastic stent
exchange with insertion of a gradually increasing number of
PS across the stricture and an eventual stent removal at
12 months.18,20–24,26,29,53–57 CSEMS: It is used in BBS
treatment with a partially or fully (FCSEMS) covered
self-expandable metal stent with eventual stent
removal30,37,41,46–48,50,51,58–60 or exchange of FCSEMS
every 2 months32 until removal. Clinical success: It is
defined as a successful clinical stricture resolution at a given
time point without unscheduled interventions or a change
of treatment strategy. Complications: ERCP-related or stent
exchange–related complications, such as pancreatitis,
cholangitis, hemorrhage, perforation, and postinsertion
pain, requiring hospital admission (Figs. 2A, B, procedurerelated) as well as other adverse events like infections, stent
migration, or stent occlusion in the follow-up period
(Figs. 2A , B, other adverse events). Complications were
defined as early, when they occurred during the first 30 days
from initial stent insertion. Follow-up: The data on treatment success was collected at one or more time points; at
stent removal, at 6 and 12 months, and at the end of followup.
Outcome Measures
The primary outcome was sustained clinical success
defined as stricture resolution without unscheduled endoscopic interventions or treatment failure during follow-up.
Secondary outcome parameters were technical success rate
and complications.
Study Quality
The review consisted of 9 retrospective and 16 prospective studies. No controlled studies comparing plastic
and CSEMS treatment could be included. As the quality of
the included studies was assessed using the NewcastleOttawa scale (NOS),61 all 25 studies received 4 or 5 in the
classifications of maximum 9 points.
Statistical Analysis
As controlled studies were unavailable, a systematic
review was made by means of proportion meta-analysis.
Statistical analysis of the review comparing the 2 methods
was performed using metaprop function in meta package
for R (Software environment for statistical computing and
graphics, version 2.13.0, The R Foundation for Statistical
Computing). Arcsine transformation was applied for comparisons where either of the groups (CSEMS or PS)
contained at least one study with a proportion of 100%,
otherwise untransformed proportions were used. Using the
proportion estimates and confidence intervals obtained
from the systematic review, the statistical significances for
r
2013 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Number 7, August 2014
the differences between CSEMS and PS groups were evaluated using the unpaired, 2-tailed Student t test, and an
association was considered significant when the exact significance level of the test was P < 0.05.
RESULTS
Selected Studies
The search retrieved 99 studies of possible relevance. A
flowchart of the search strategy is presented in Figure 1.
Twenty-five studies met the final inclusion criteria for
the review: 13 studies on multiple PS18,20–24,26,29,53–57 and 12
studies on CSEMS30,32,37,41,46–51,58–60 (Table 1). The quality
assessment provided relatively low NOS scores in all
selected studies, mainly because of lack of control groups
and also for the length of follow-up that may have been too
short for outcomes, for example, treatment failure to occur.
The most of the excluded studies reported other
treatment modalities than those to be addressed in this
review (eg, single PS or unremoved or uncovered SEMS),
or included cases with biliary fistulas, or provided insufficient data on follow-up or complications. To produce
results as valid and as clinically generalizable as possible,
several otherwise excellent studies, among them 11 studies
CSEMS in the Treatment of Biliary Strictures
of CSEMS,8,9,34,36,38,42–45,49,61 were excluded from the
analysis because of data that were noncomparable with
other articles in terms of study end-points.
In the excluded CSEMS studies, the results were
mainly in line with the included studies. A better long-term
patency of CSEMS in postoperative strictures compared
with PS has been proposed.9 In cohort studies of wide
variety of benign biliary conditions, including fistulas and
refractory strictures, the clinical success of CSEMS therapy
has been 70% to 100%8,45,49,61 with migrations occurring in
9% to 10%8,45 and secondary strictures or relapses in 13%
to 18%.36,61 A recent multicenter study showed stricture
resolution rate at stent removal of up to 81% in CP compared with 92% in postsurgical strictures.8 In treatment of
postorthotopic liver transplantation complications,
CSEMS success rate has reportedly been up to 61% to
95%8,34,38,43 with 14% to 31% of migrations.8,41
Patient Characteristics
Of the 25 studies, a total of 946 patients were included
in the review: 376 underwent treatment with CSEMS and
570 with multiple PS. The summary of study characteristics
and patient demographics is presented in Table 1. The
groups were well comparable for age and sex. Mean age
FIGURE 1. Search strategy for systematic review.CSEMS indicates covered self-expanding metal stents.
r
2013 Lippincott Williams & Wilkins
www.jcge.com |
637
638 | www.jcge.com
Group
Stent
R
R
P
P
R
R
P
P
R
R
R
R
R
P
P
P
P
P
P
P
P
P
P
P
P
4
5
4
5
5
5
4
5
5
5
5
5
5
5
5
5
5
5
5
5
4
5
4
5
4
Design NOS
USA
Japan
Germany
UK
NL
USA
Slovak Rep
Hungary
Hungary
USA
Italy
USA
Germany
Italy
Italy
NL
Italy
Korea
China
Korea
Korea
France
USA
USA
USA
Country
52.5w
58.9
52.8
48.5
49
46.7
50.4
61.3
50.8
48
46
51.4
54.7
52
57
57
59.1
61.7
51.2
69
61.5
49.7
53.5w
51
55
65.2
78.8
73.3
39.6
28.2
80
90
10
72.4
64
22.5
55.2
82.1
94
65
52.2
66.7
61.9
76.9
58.8
53.5
81.8
63.6
90
68.4
69
33
15
53
110
25
43
20
29
25
80
29
39
17
62
23
15
21
13
17
43
22
44
20
79
0
13
0
0
0
0
0
0
29
0
0
9
39
17
4
13
0
6
0
10
11
0
19
20
32
69
0
15
53
0
25
0
0
0
25
0
3
0
0
38
0
15
3
13
0
2
22
9
0
16
0
20
0
0
110
0
43
20
0
0
80
16
0
0
20
10
0
12
0
7
30
0
16
0
31
11
100.7
16.8
18
91.2
21.5
16
14.5
12.9
54
70.8
48
58
24
15.9
15
14.4
13.8
12.1
15
4
12
3.8
22
12
94.2
57.6
73.3
71.7
73.6
100
100
100
62.1
95.7
68.6
93.1
46.2
70.5
90.3
65.2
100
95.2
92.3
70.6
90.7
86.4
82.9
95
91.1
92.8
57.6
73.3
69.8
73.6
81.8
100
95
62.1
95.7
61.4
69
30.8
64.7
87.0
65.2
46.7
95.2
92.3
70.6
83.7
45.5
82.9
90
87.3
Patients
Success rate (%)
Age (Mean)
Sex
Follow-up (Mean)
(y)
(Male %) All CP OLT Other
(mo)
Removal (Stent Removal) 12 mo*
J Clin Gastroenterol
r
*Follow-up: at 12 mo or at the end of shorter follow-up.
wMedian values.
zPartially covered.
CP indicates chronic pancreatitis; CSEMS, covered self-expanding metal stents; NOS, Newcastle-Ottawa Scale (range 1-9); OLT, orthotopic liver transplantation; Other, postcholecystectomy, other postoperative,
bile duct stone, trauma, sphincterotomy stricture, other; P, prospective; R, retrospective.
Tabibian et al21
PS
Plastic
PS
Plastic
Sakai et al18
PS
Plastic
Kulaksiz et al22
24
PS
Plastic
Holt et al
PS
Plastic
DeReuver et al53
PS
Plastic
Pasha et al23
PS
Plastic
Kuzela et al20
54
PS
Plastic
Pozsar
PS
Plastic
Pozsar et al29
PS
Plastic
Morelli et al55
PS
Plastic
DePalma et al56
26
PS
Plastic
Dragonov et al
PS
Plastic
Eickhoff et al57
CSEMS
Niti-S
Perri et al51
Niti-S-ComVi
Tarantino et al46 CSEMS
32
CSEMS
Hanaro
Poley et al
Niti-S-Comvi
Tarantino et al58 CSEMS
CSEMS
Bonastent
Moon et al41
CSEMS
MicroTech
Hu et al47
59
CSEMS
S&G Biotech
Park J
CSEMS MI Tech/Std ST
Park et al60
CSEMSz
Wallstent
Chaput et al29
CSEMS
Viabil
Mahajan et al50
48
CSEMSz
Wallstent
Behm et al
CSEMSz
Wallstent
Kahaleh et al37
References
TABLE 1. Study Characteristics, Patient Demographics, Case Numbers in Different Stricture Etiologies, Length of Follow-up, and Clinical Success Rate
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was 57 years in the CSEMS group and 51 years in the PS
group (P = 0.06). There were 67% men in the CSEMS
group and 55% in the PS group (P = 0.5). The frequency of
previous endoscopic treatment attempts was reported in
8 studies30,32,41,46,48,51,59 in the CSEMS group and in 1 PS
study.53
Stricture Etiology
Five CSEMS studies30,47,48,51,58 reported the results of
single stricture etiology and 7 studies32,37,41,46,50,59,60 of
multiple stricture etiologies. Eleven PS studies20–24,29,53–57
were on single stricture etiology and 2 studies18,26 on multiple stricture etiologies.
Case numbers of different stricture etiologies are presented in Table 1. To assess the outcome, 3 groups were
formed: CP, post–liver transplantation (LT), and other
strictures (OS). The etiology-specific data of outcome was
available from most of the studies. In few studies, it was
only possible to pull out data that presented the majority of
the study population, and these studies were grouped
according to this majority etiology. In strictures related to
postcholecystectomy or bile duct stones, case numbers were
insufficient for subgroup analysis. Therefore, all strictures
except CP and liver transplant were combined into a single
group (OS) for etiological outcome analysis. Case numbers
in the etiology groups were as follows: CP, 128 CSEMS and
90 PS; LT, 118 CSEMS and 190 PS; and other etiologies,
130 CSEMS and 290 PS.
Stent Design
There were slight differences in CSEMS stent designs,
the trademarks and types of which are presented in Table 1.
The populations of the studies by Park et al60 and Perri
et al51 comparing stents with and without anchoring fins
were pooled for analysis. All 13 PS studies had comparable
endoscopic technique with a gradually increasing number
of polyethylene PS inserted and exchanged at tri-monthly
intervals up to 12 months. Three of the CSEMS
studies30,37,48 used partially covered stents and
932,41,46,47,50,51,58–60 used fully covered stents.
Technical Success and Stent Indwelling Time
Technical success of primary stent insertion was similar in the study groups: 100% in CSEMS and 98% in PS
(P = 0.8). The median duration of stent therapy was
shorter in the CSEMS (4.5 mo) than in the PS group
(11 mo) (P = 0.001). Significantly fewer ERCP sessions
were required in the CSEMS group than in the PS group
(median 1.5 and 3.9, P = 0.002). When cases of CP were
analyzed separately, neither duration of stent therapy
(median 4.8 vs. 16 mo, P = 0.1) nor number of ERCPs (2.0
vs. 4.2, P = 1.0) were statistically different between CSEMS
and PSs. Stent removal was equally successful in CSEMS
and PS groups, respectively (99.8% and 100% of cases;
P = 0.8).
Follow-up
In 83% of CSEMS studies and 100% of PS studies,
adequate data at 12 months of follow-up were obtained and
were used in the final analysis (Table 1). In two CSEMS
studies,50,60 the mean follow-up time was <6 months. The
results at the end of the total follow-up time were not
comparable, as the length of follow-up was shorter in the
CSEMS group (14 vs. 49 mo, P = 0.003).
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Complications
There was no difference in the early complications
(pancreatitis, cholangitis, perforation, hemorrhage)
between the CSEMS and PS groups [13% vs. 14%, 95%
confidence interval (CI), 7%-19% vs. 8.1%-19%, P = 0.9)
in all stricture etiologies. However, late complications or
any adverse events (pain, infection, stent occlusion and
stent migration) occurred less often in CSEMS than in PS
(4.6% vs. 14%, P = 0.006) when all etiologies were combined (95% CI, 2%-7% and 9%-19%, respectively)
(Figs. 2A, B). The complication figures according to treatment group and stricture etiology are presented in Figures
2A and B; there were less late complications in the CSEMS
group (3% vs. 67%) than in the PS group in CP etiology
(95% CI, 0%-13% vs. 17%-99%, P = 0.02). No statistical
difference in complication figures of other etiology groups
was found (P = 0.06-0.9). Severity grade of complications
was not systematically reported in the studies.
Clinical Success
In CP strictures, there was tendency to better clinical
success in CSEMS treatment at 12 months after stent
removal: 77% versus 33% (95% CI, 61%-94% vs. 4%63%, P = 0.06) in CSEMS and PS, respectively. In other
time points of follow-up, the difference was also observable:
at stent removal, 80% versus 38% (95% CI, 62%-93% vs.
12%-68%, P = 0.02) and at 6 months, 74% versus 33%
(61%-86% vs. 4%-63%, P = 0.02); however, the P-values
might not be reliable because of the small numbers of
studies in comparisons. In other etiologies except CP there
was no difference (P = 0.08-0.9) in the success rate. The
overall clinical success of CSEMS and PS in all etiologies at
stent removal was 87% versus 85% (P = 0.8) and at 12
months 79% versus 77% (P = 0.9). Clinical success
according to stricture etiology is presented in Figures 3A–C
at the end of the stent therapy and at 6 and 12 months after
stent removal.
DISCUSSION
Besides PS, CSEMS are today widely used in the
endoscopic treatment of BBS. However, there is only one
single RCT on the subject comparing CSEMS to PS in
postoperative strictures.9 Present systematic review of
studies published in the 2000s sheds light on the controversial issue about the decision between these treatment
modalities. CSEMS seemed to be a more effective and safe
treatment method in strictures caused by CP. In other
stricture etiologies, such as LT, no difference between the 2
methods was found.
Treatment of BBS with multiple PS has been considered to be a relatively safe method with few complications.14 The review by VanBoeckel et al suggested that
multiple PS treatment was safer than single plastic stent or
uncovered SEMS.4 In the postoperative series by Costamagna et al,14 the early complication rate was 9% and
distal displacement occurred in 11% of cases. In the treatment of CP, the rate of acute pancreatitis has been up to
3.4% to 5.0%,18,26 the rate of cholangitis up to 7%,26 and
the rate of stent migration up to 2.5% to 9%.27,57 In PS
therapy, frequent stent exchange and stent clogging seem to
be the major drawbacks, truly complicated cases being
merely occasional and with mild clinical consequences.
The clinical success of multiple plastic stent treatment
has been shown to be superior to single plastic stent
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FIGURE 2. Early (A) and late (B) complications and other adverse events after stricture treatment with covered self-expanding metal
stents (CSEMS) or plastic stents (PS). By etiology, complications include chronic pancreatitis (CP), post–liver transplant (LT), and other
etiologies (Other). Procedure-related complications include pancreatitis, cholangitis, perforation, and hemorrhage. Other adverse
events include pain, infection, stent occlusion, and stent migration. *P < 0.05.
treatment in BBS.4,27 The use of a single PS may be seen as
a “bridge to decision” in newly diagnosed cases and in
indeterminate strictures.2,51 Treatment with multiple PS has
been feasible in postcholecystectomy strictures, with a
success rate of 70% to 90%14,15,17,19,26,53–56 and with 14%
stent clogging and up to 33% pain after simultaneous
insertion of multiple PS.53 In post-LT anastomotic strictures, the reported success rate has been 69% to 91% in
multiple PS.16,21–24 However, in CP, the results of PS
therapy have been mostly disappointing; success rates as
low as 24% to 38% in median follow-up of 45 months25
and treatment failure rate of up to 83% in follow-up of 48
months26 have been reported. In contrast, in the study by
Catalano et al,27 the prognosis was better with the insertion
of up to 5 simultaneous PS; only 8% failure rate in followup of 3.9 years was reported. The presence of calcifications
in the pancreatic head secondary to CP is related to poorer
outcome with PS therapy, probably due to the fibrotic
nature of the strictures.25,27,28,51 Temporary biliary
obstruction due to acute pancreatic inflammation is associated to success rate of up to 92% in PS.25
In CSEMS, complications such as cholangitis, pancreatitis, and cholecystitis occur at the rate of about
14%37,50 and stent migrations at the rate of 5%37 to 10%8
to up to 38%38 with wide variation in their clinical consequences. The difference in migration rate may reflect the
variation stent indwelling time and in the CSEMS design;
fully covered stents with or without anchoring fins, stents
with different coating materials, and partially covered stents
with uncovered ends have been used. It is logical to assume
that the fully covered stents may be more prone to migration but less problematic to remove than the partially
covered ones. However, these stent designs are yet to be
compared in clinical study and also our material proved
inadequate to reliably assess the difference. The optimal
duration of CSEMS therapy allowing safe removal and
stricture resolution remains unknown. As the present
studies report results after 2 to 6 months of stent indwelling,
the recent multicenter study of Kahaleh et al8 using
CSEMS with anchoring fins proposed that the stent
indwelling time of >90 days was associated with increased
likelihood of stricture resolution at stent removal. The
FIGURE 3. Success rate of covered self-expanding metal stents (CSEMS) and plastic stents (PS) in strictures with different etiologies: (A)
chronic pancreatitis (CP), (B) post–liver transplant (LT), and (C) other etiologies (other). *P < 0.05.
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forceful radial expansion of CSEMS is likely to cause some
discomfort immediately after stent insertion: Poley et al32
reported transient abdominal pain in up to 56% of cases
after stent insertion, only a few cases resulting in admission.8 The clinical significance of de novo strictures occasionally associated with CSEMS in a few recent studies,34–36 remains a subject for further research.
Our study showed that CSEMS treatment was at least
as safe as PS in terms of complication rate, both in all cases
and in the etiological subgroup analyses. The tendency to
slightly higher prevalence of late adverse events in PS can
be explained by the high frequency of late stent clogging, a
known problem of multiple PS therapy. The postinsertional
pain, a complication typical of CSEMS and presumably
actively reported in first pilot studies, seems to cause a
remarkable part of CSEMS early complications. Although
infrequent, clinically significant proximal migrations and
problems with removal of CSEMS should be considered as
a potential and serious risk of CSEMS therapy. If endoscopic removal fails, surgical operation may be inevitable.
Previous results with CSEMS have been encouraging
in BBS.8,37,41,45,47,48,50 Long-term success rates range from
53%30 to 96% to 100%34,42,43,46,47 in postorthotopic liver
transplantation strictures. In strictures secondary to postendoscopic sphincterotomy, a resolution rate of 90% at
14.5-month follow-up has been achieved.54 The studies by
Mahajan et al50 and Moon et al41 with FCSEMS have
reported treatment success rates of 83% to 95% on followup of 3.8 to 13.8 months in populations with a variety of
stricture etiologies including postoperative and CP cases.
Similar promising outcomes were reported by Kahaleh
et al37 and Park et al60 in studies including multiple etiologies, as well as in studies of Tarantino et al46 and
Mangiavillano et al49 with FCSEMS at 1 year of follow-up.
The long-term resolution rate with FCSEMS, solely in CPrelated strictures, has been around 66%.31 In the recent
study of Perri et al,51 the 2-year treatment success of
FCSEMS in CP was 47%, with most of the failures caused
by migrations of unflared-end stents used in the beginning
of the study. In contrast, the success rate with FCSEMS on
follow-up of 15 months has been 80% for all patients but
only 46% for patients with CP.32 The fibrotic strictures
secondary to CP appear the most difficult to treat effectively
in the long term, irrespective of the type of stent. Achieving
necessary dilatation and stricture remodeling effect14,27,31,53
with fewer endoscopic interventions compared with an
increasing number of PS appear the main benefits of
CSEMS therapy.
The only study up to date directly comparing PS to
CSEMS by Artifon et al9 of 15 patients managed with
multiple PS and 16 cases treated with CSEMS, proposed
feasibility and safety of FCSEMS use in postoperative
strictures with clinical success in 5-year follow-up of 82%
and 72% in FCSEMS and multiple PS, respectively.
Present study proposes a better success rate of CSEMS
treatment in strictures secondary to CP: the success rate
defined as resolution without unscheduled reinterventions
was 77% with CSEMS compared with 33% in the PS group
at 12 month after stent removal. Parallel results at stent
removal and after 6 months seem to support this finding in
CP. The results may reflect better dilating force of CSEMS
than PS treatment in strictures secondary to calcifying CP.
However, this review did not find any difference between
the 2 treatment methods in other BBS etiologies, such as
postoperative, CBD stone or postsphincterotomy-related
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biliary strictures. This is explained by heterogeneity and the
small number of studies, making it difficult to prove any
difference significant. Although the unit cost of CSEMS
stent is 10 times as high as that of PS, the number of
endoscopic interventions to produce equivalent clinical
effect is considerably less in CSEMS therapy. This is consistent with the reported cost-effectiveness of CSEMS
therapy in strictures secondary to CP.40
The strength of this systematic review was a meticulous literature search to include all relevant articles and a
careful selection process to pick out studies with comparable data. However, the lack of RCTs weakens the
systematic review. The definition of success rate differed
slightly between studies and in some papers comparable
success rates needed to be deduced from the data presented.
Several studies on postoperative strictures had to be
excluded as fistula-free data was not provided; evaluating
the outcome of strictures with biliary fistulas was considered noncomparable with pure biliary strictures. The only
RCT of postoperative strictures had to be omitted because
of inadequate follow-up data. The most important drawbacks of the studies included are the short follow-up of
CSEMS studies, insufficient data on previous unsuccessful
treatment, and often-unknown prevalence of calcifying
pancreatitis. In most of CSEMS studies (72%), a previously
failed treatment attempt with PS had been made. A previous treatment attempt with PS may be associated with
inferior resolution rate with subsequent CSEMS treatment.8 As studies on CP did not systematically report the
prevalence of calcifying pancreatitis, it remains unknown
whether the strictures of CSEMS and PS groups are truly
comparable in CP.
According to earlier studies with PS, an optimal follow-up time would be 12 to 24 months after stent removal,
by which time most restrictures appear.14,17,25,26,53,56 When
successful endoscopic outcome is not achieved within 12
months, surgical treatment of CP-related stricture should
be considered.25 As the number of CSEMS studies is low
and some of them report follow-up of <12 months, the
results of long-term stricture patency have to be interpreted
with caution until more trials with longer follow-up times.
Whether CSEMS therapy actually prevents, or merely
delays the need for definitive surgical treatment in unresponsive cases of CP strictures remains unknown. Further
studies with a clear definition of complications, treatment
success, and follow-up of at least 12 to 24 months are
recommended to compare CSEMS with PS.
In conclusion, this systematic review of the treatment
of BBS demonstrates a better success rate with an equivalent complication rate for CSEMS compared with PS
when the BBS is caused by CP. With regard to other BBS
etiologies, this systematic review remains inconclusive. A
randomized, controlled trial comparing CSEMS and PS in
the treatment of different BBSs is warranted: not only to
study stricture resolution and treatment-associated complications but also to clarify indications and optimal stent
design.
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Biodegradable biliary stents have a different effect than covered metal stents on the expression of proteins associated with tissue healing in benign biliary strictures Antti Siiki1, Ralf Jesenofsky2, Matthias Löhr3, Isto Nordback1, Minna Kellomäki4, Heidi Gröhn5, Joonas Mikkonen4, Juhani Sand1, Johanna Laukkarinen1 1Dept. of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland 2Dept. of Medicine II,
University of Heidelberg, Mannheim, Germany 3Gastrocentrum, Karolinska University Hospital, Huddinge, Sweden 4Biomaterials and Tissue Engineering Group, BioMediTech and Department of Electronics and Communications Engineering, Tampere University of Technology, Tampere, Finland 5Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland Background: Benign biliary strictures (BBS) are primarily treated endoscopically, increasingly with covered self-­‐expandable metal stents (CSEMS). Biodegradable biliary stents (BDBS) have shown promising results in animal models and may be the future of endoscopic therapy of BBS. Tissue response in BBS to different stents is largely unknown. The aim was to assess the expression of proteins related to tissue healing in BBS compared to the intact bile duct (BD), and to study the protein expression after therapy with CSEMS or BDBS. Methods: Swine with ischemic BBS were endoscopically treated either with BDBS or CSEMS. Tissue samples were harvested from swine with intact BD (n=5), untreated BBS (n=5) and after six months of therapy with BDBS (n=4) or CSEMS (n=5). Two-­‐dimensional electrophoresis with protein identification was performed to evaluate protein expression patterns at these stages. Results: Compared to the intact BD, in BBS the expression of proteins Galectin-­‐2 and Annexin-­‐A4 decreased. BDBS treatment normalized Galectin-­‐2 level, but with CSEMS therapy it remained low. Annexin-­‐A4 expression remained low after both treatments. Transgelin expression, which was low in intact BD and in the BBS, remained low after BDBS treatment but increased after CSEMS therapy. Conclusion: The expression of proteins related to tissue healing in BBS is different after treatment with BDBS and CSEMS. Treatment with BDBS may bring the protein expression towards what is seen in the intact BD. These findings suggest future therapeutic implications and warrant further research. Key words: biliary, stricture, stent, biodegradable, bioabsorbable, ERCP (endoscopic retrograde cholangio-­‐pancreatography) 1
Background Endoscopic stent insertion has a well-­‐established role as a primary therapy for benign biliary strictures (BBS) [1]. The traditional use of plastic stents (PS) [2-­‐4] has been challenged due to the need of frequent endoscopic stent exchanges and relatively high rate of stricture recurrence with consequent burden to patient. Increasingly used covered self-­‐expandable metal stents (CSEMS) may offer potential advantages over PS: fewer endoscopic sessions and improved patency with fewer stent occlusions due to larger post-­‐deployment diameter [5, 6]. However, only few studies comparing plastic stents to CSEMS in benign strictures exist and the optimal duration of CSEMS therapy to ensure stricture resolution with safe stent removal is yet to be determined [1]. A biodegradable self-­‐expanding, large-­‐bore stent (BDBS) with no need for stent removal offers a seemingly ideal solution to overcome the drawbacks of previous methods [7-­‐9]. As the device for endoscopic application of these stents has been only recently available, those few clinical studies published on human biliary strictures are from percutaneous use [10]. The protein-­‐level mechanism of development of BBS as well as the details of tissue response caused by CSEMS or BDBS are largely unknown. Understanding pathogenesis of a BBS and tissue response to CSEMS and BDBS are factors that may prove critical in determining the optimal strategy of stent therapy in BBS. In the present study we analyzed proteins, which according to the previous findings may play a role in the gastrointestinal stricture formation [11-­‐17]. The aim of this study was 1) to determine protein expression pattern of BBS and 2) to specify the proteomic response to BDBS and CSEMS in biliary duct in the swine. Methods BBS was induced as previously described [18] in 14 Yorkshire swine (weight median 50 kg, range 48-­‐
52 kg). BBS was induced in laparotomy by subtotal ligation of the common bile duct (CBD) with absorbable sutures resulting in controlled ischemia. Two months after induction of BBS, CBD was cannulated under duodenoscopy (Olympus 145 series, Tokyo, Japan). In endoscopic retrograde cholangiography (ERC) with iohexol contrast medium (Omnipaque 180 mg I/ml; Amersham Health AS, Oslo, Norway) a tight BBS, median length of 10 mm (range 9-­‐11 mm) was confirmed in all of the animals. 2
Five animals had no treatment of the stricture (BBS group). From these animals, samples were harvested at two months after the induction of BBS and the animals were sacrificed. Nine animals received an endoscopic treatment of BBS; in BDBS group four with a braided self-­‐expandable poly-­‐
lactide BDBS (diameter 7 mm, length 50 mm; custom-­‐made at the Institute of Biomaterials, Tampere University of Technology, Tampere, Finland) and in CSEMS group, five with a fully covered self-­‐
expandable metal stent (diameter 10 mm, length 80 mm; Wallstent, Olympus PBD-­‐3Z; Tokyo, Japan). During the follow-­‐up stent patency and location were confirmed by repeated serum liver function tests, x-­‐ray. At six months, tissue samples were harvested from the CSEMS and BDBS treated BBSs and the animals were sacrificed. The control samples were harvested from intact bile duct (Intact BD). For all the animal experiments and operations, anaesthesia was induced after 24 hour fasting by propofol (Propofol Alpharma 10 mg/ml, Alpharma AS, Oslo, Norway) 5 mg/kg i.v. bolus after atropin (Atropin 1mg/ml, OY Leiras Finland AB, Turku, Finland) 0.05 mg/kg i.m. plus azaperone (Stresnil 40mg/ml, Janssen Animal Health BVBA, Beerse, Belgium) 4 mg/kg i.m. premedication. The anaesthesia was maintained with propofol 15 mg/kg/h and analgesia with fentanyl citrate (Fentanyl; 50 μg/ml; Janssen Pharmaceutica, Beerse, Belgium) 5 μg/kg/h after intubation with a cuffed endotracheal tube. Prior to extubation, buprenorfine (Temgesic; 0.3 mg/ml; Reckitt&Colman Products Ltd, Hull, UK) 0.009 mg/kg i.m. was given for postoperative pain medication; the dose was repeated in 8 hours and continued twice daily for the three following days or longer if needed. The animals received cefuroxim (Zinacef; GlaxoSmithKline, London, U.K.) 30 mg /kg i.v. for infection profylaxis before operations and cefalexin (Kefexin, Orion, Espoo, Finland) 750 mg p.o. daily for three days after endoscopy to prevent cholangitis. Omepratzole (Losec mups, AstraZeneca, Södertälje, Sweden) 20 mg p.o. was given daily for the entire follow-­‐up period to prevent duodenal ulcers. The animals were fed with standard pig chow and were allowed free access to water and free movement in their cages. A histopathologic analysis was performed to ascertain the histologic similarity of samples. The statistical significance was assessed by Student´s two-­‐tailed T-­‐test, where p value of < 0.05 was considered significant. 2D Gel Electrophoresis (DIGE) Proteins were subjected to a fractionated extraction protocol as described previously [19] Protein labeling for DIGE was conducted as described in the Ettan DIGE user manual. 50 µg of each protein sample were labelled with 400 pmol CyDye DIGE fluor minimal dyes Cy2, Cy3, and Cy5 (Amersham Biosciences, Freiburg, Germany). Isoelectric focusing was performed for a total of 125 kVh after loading 50 µg of total protein/strip onto linear immobilised pH gradient (IPG) strips (Immobiline DryStrips pH 3–11; Amersham Biosciences). After that, proteins were reduced by dithiothreitol, alkylated by iodoacetamide, and second dimension separation was performed on 12.5% polyacrylamide gels. Each sample was run at least three times. 3
The separated proteins in DIGE gels were visualised by Typhoon 9400 variable mode imager (Amersham Biosciences) using the wavelengths of the respective CyDyes. DeCyder image anyalysis software (Amersham Biosciences) was used to analyze the DIGE images as described in the Ettan DIGE user manual. Experimental Mw and pI values were calculated internally. Protein identification by MALDI-TOF-MS Conventional SDS-­‐Page gels were stained by modified silver staining compatible with MALDI-­‐TOF-­‐MS [20]. Proteins of interest were manually excised from the corresponding preparative gel and subjected to in-­‐gel tyrptic digestion (Promega, Mannheim, Germany) as described [21]. Digested protein samples were analysed using MALDI-­‐MS in the positive ion mode (Autoflex II time-­‐of-­‐flight instrument, Bruker Daltonics, Massachusetts, US). The resulting tryptic, monoisotopic peptide masses were searched against the NCBInr or SwissProt nonredundant protein sequence database (Mascot; Matrix Science Ltd., London, UK) using the Peptide Mass Fingerprint (PMF) method. Identification was based on a significant Mascot score (p < 0.05) and on matching peptides with a protein sequence coverage of > 20%. The experimental Mw and pI values determined from the protein pattern had to be in agreement with the theoretical value of the identified proteins. Ethical aspects The animal study protocol was reviewed and approved by the Provincial Government of Eastern Finland and the Animal Ethics Committee of the University of Kuopio, Finland. Results Tissue samples were analyzed from swine with intact bile duct (intact BD, n=5), untreated BBS (n=5) and after six months of therapy with BDBS (n=4) or CSEMS (n=5). Proteins indentified in the screening were Apolipoprotein-­‐A1, Annexin-­‐A4, Galectin-­‐2, Transgelin, Myosin light polypeptide-­‐6, Albumin, Superoxide dismutase,-­‐1, Heat-­‐shock protein beta-­‐6, Peroxiredoxin-­‐5 and Muscle creatine kinase, all potentially associated to tissue injury and healing. Protein expression pattern from an intact BD, untreated BBS and after treatment with either BDBS or CSEMS is shown in Figure 2. Housekeeping protein Apolipoprotein-­‐1 expression was stable in all samples. In BBS, the, expression of Annexin-­‐A4 was reduced to 37% and expression of Galectin-­‐2 was reduced to 14% (p=0.03) compared to the intact BD. Fragmented Transgelin expression was increased to 290% compared to the intact BD. No difference in Myosin light polypeptide-­‐6 (MLP-­‐6) expression was observed. (Fig 2A-­‐D). 4
After BDBS and CSEMS treatment, the expression of Annexin A4 remained at the level seen in BBS. After BDBS treatment the expression of Galectin-­‐2 returned to the level of intact BD, whereas after CSEMS treatment the expression remained at the low level seen in the BBS (p=0.02). Transgelin expression, being undetectable in intact BD, was increased to 450% in CSEMS treated animals compared to BDBS. Expression of fragmented Transgelin remained at the increased level of untreated BBS after both BDBS (p=0.04) and CSEMS treatment. MLP-­‐6 expression was increased to 300% after BDBS treatment, but remained unchanged after CSEMS treatment (Fig. 2A-­‐D). Single gels of each sample showed similar results to pooled samples. For other screened proteins no major differences were found. Discussion To the best of our knowledge, this is the first study to evaluate patterns of protein expression in BBS and after treatment period of six months with either with BDBS or CSEMS. Protein analysis of BBS treated with stents not only provides additional knowledge in attempting to understand the pathogenesis of BBS but also contributes to our understanding of tissue response to different types of stents. The current treatment of BBS is based mainly on the dilation of a stricture followed by an insertion of either plastic or CSEMS. The treatment of BBS with multiple plastic stents is associated in nearly 90% clinical success [22], but up to 38% rate of stricture recurrences in long-­‐term follow-­‐up have been reported [3]. The results have been much worse in strictures secondary to calcifying chronic pancreatitis and when only one stent has been used instead of multiple plastic stents [4, 23]. The best results are achieved in post-­‐operative strictures by trimonthly stent exchange and aggressive increase in the number of stents [2], with repeated demanding endoscopic procedures. CSEMS are increasingly used in BBS, the most important benefit being the requirement of fewer endoscopic sessions and possibly fewer adverse events and lower overall costs [1, 6]. The weaknesses of CSEMS include difficult removal due to tissue embedding and overgrowth [24, 25] and risk of development of de-­‐
novo strictures after stent removal [26, 27]. The tissue response of biliary epithelium to CSEMS is not widely studied [28, 29], and no data on the changes on protein expression has been published. Literature of braided, self-­‐expanding, biodegradable stents in BBS is promising but scarce. Endoscopic insertion has been shown feasible and poly-­‐lactide stent therapy has been shown not to cause scar formation, granulation or hyper-­‐epithelisation in animal models [7, 8]. Besides, BDBS have been safe and effective in the conventional type of hepatico-­‐jejunostomy performed in swine, where it improves 5
biliary drainage during an 18-­‐month follow-­‐up [30]. They also appear better in management of a cystic duct leakage than a plastic stent in an animal model [8]. In humans, they have been successfully used for securing a hepatico-­‐jejunal [9] and pancreato-­‐jejunal anastomosis [31]. Commercially available BDBS are made of polydioxanone, a co-­‐polymer of poly-­‐lactide, the degradation pattern of which is similar to PDS surgical sutures [32]. The endoscopic implantation device is not yet in clinical use. Published results with percutaneously inserted BDBS have been excellent in 16 months follow-­‐up [10]. Similarly to poly-­‐lactide stents, a predictable degradation in three months as well as good histologic biocompatibility has been reported in an animal model [33]. We discovered remarkable changes in a few proteins that have been previously associated to tissue injury and healing on other tissues. Galectin-­‐2 expression has reportedly been related to acute and chronic inflammatory responses as well as in production of cytokines and inflammatory mediators, cell adhesion, migration, and apoptosis [17]. Galectin expression may also be related to intestinal wound healing [16] and apparently play a role in mucosal inflammation and stricture and fistula formation in inflammatory bowel disease related strictures [15]. Annexins are related to cellular functions such as endo-­‐ and exocytosis, actin configuration, signaling, and plasma membrane repair [11]. Transgelin levels have been linked to smooth muscle differentation [14] and in mesangial cell migratory and proliferative response to injury [12]. Myosin light polypeptide expression is connected to intestinal tight-­‐junctions essential for epithelial function [13]. The ischemic model of BBS induced a statistically significantly decrease in galectin-­‐2 expression and an increase in transgelin expression. Additionally, a decrease was observed in Annexin -­‐A4 and Myosin light polypeptide-­‐6. In the light of these findings it could be hypothetized, that Annexin-­‐A4, Transgelin and Galectin-­‐2 play a role also in the reaction to ischemia in the biliary duct. We also compared the effects of BDBS and CSEMS on the protein expression in the stricture. We found that the protein expression appears to differ considerably depending on the type of biliary stent Interestingly, BDBS treatment seemed to normalize Galectin-­‐2 level, but with CSEMS therapy it resembled untreated BBS. Moreover, Transgelin expression, which was low in intact BD and in the BBS, was elevated as a reaction to CSEMS but not to BDBS. In contrast, Myosin light polypeptide-­‐6 being normal in BBS was increasingly elevated in strictures treated with BDBS compared to intact bile duct or CSEMS. Besides, reduced Annexin-­‐A4 levels of BBS were not normalized after therapy with either BDBS or CSEMS stents. However, it´s expression was less decreased in BDBS than in CSEMS treatment group. 6
Conclusions This study reports protein expression in an untreated BBS and after six months of treatment with BDBS or CSEMS in an experimental ischemic stricture model. Significant differences in the expression of proteins related to inflammatory response, apoptosis and smooth muscle differentiation between intact BD and ischemic BBS were found. Furthermore, the response appears different depending whether the stricture is treated with CSEMS or BDBS, possibly attributed to different healing response. In the light of previous findings on BDBS and on the role of Annexins, Galectins and Transgelin, it may be hypothesized that BDBS compared to CSEMS better reverses the changes in protein expression induced by BBS. The result may pave the road for future therapeutic implications such as selecting the optimal stent therapy in BBS or developing drug-­‐eluding stents. However, this study does not answer the question whether the observed changes were of benefit. Further research is thus warranted to confirm the results from the relatively small sample since it is currently not known what would be the optimal protein expression for stricture healing. Figure 1: 2-­‐Dimensional Electrophoresis image of biliary stricture from swine ischemic stricture after 6 months of stenting. albumin [fragm.]
muscle creatine kinase
annexin A4
trypsin precursor
transgelin
apolipoprotein A-I
myosin light polypeptide 6
mol.
weight
heat-shock protein beta-6
transgelin [fragm.]
peroxiredoxin 5 [fragm.]
superoxide dismutase 1
galectin-2
pH 3
pH 11
7
Figure 2A-­‐D Expression of Annexin-­‐A4 (A), Galectin-­‐2 (B), Transgelin (C) and MLP-­‐6 (D) in swein: intact bile duct (Intact BD), BBS at two months (BBS 2 mo) and after six months of therapy with BDBS or CSEMS. In all groups, samples from five animals were analyzed, except in the BDBS group, where samples from four animals were analyzed. In figure p<0.05 in BBS 2 mo compared to intact duct, CSEMS compared to intact duct and CSEMS compared to BBS 2 mo. In figure C, p<0.05 in BDBS compared to intact duct. 3500"
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Competing interests The authors report no competing interest nor disclosures. Acknowledgements The authors wish to thank the staff of the National Laboratory Animal Center, Kuopio University, Finland, for their competent technical assistance and for the use of laboratory facilities. We are grateful to Dr Martina Schnölzer (German Cancer Research Center, Heidelberg, Germany) for assistance and access to DIGE Typhoon Imager and DeCyder image analysis software and Prof. Neumaier (Institute for Clinical Chemistry, Mannheim, Germany) for access to MALDI-­‐TOF mass spectrometer. This study was financially supported by the National Technology Agency of Finland (TEKES) and the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital, Finland. References 1. Baron TH S, Davee T: Endoscopic management of benign bile duct strictures. Gastrointest Endosc Clin N
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JOURNAL OF LAPAROENDOSCOPIC & ADVANCED SURGICAL TECHNIQUES
Volume 25, Number 5, 2015
ª Mary Ann Liebert, Inc.
DOI: 10.1089/lap.2015.0068
Case Report
Biodegradable Biliary Stent in the Endoscopic
Treatment of Cystic Duct Leak After Cholecystectomy:
The First Case Report and Review of Literature
Antti Siiki, MD,1 Irina Rinta-Kiikka, MD, PhD,2 Juhani Sand, MD, PhD,1 and Johanna Laukkarinen, MD, PhD1
Abstract
Background: The preferred therapy for simple postcholecystectomy biliary leak consists of percutaneous
drainage and biliary stent insertion under endoscopic retrograde cholangiopancreatography (ERCP). With a
novel endoscopic insertion device, a biodegradable biliary stent (BDBS) may be used in the treatment of a
cystic duct leak without repeated endoscopy for stent removal. The objective of this article was to report the first
case of endoscopic insertion of BDBS for postoperative bile leak and assess its feasibility and safety.
Patient and Methods: A 64-year-old man with a postoperative leak from the cystic duct stump was treated with
ERCP, biliary sphincterotomy, and insertion of a self-expandable 40- · 8-mm polydixanone BDBS (Ella CS,
Hradec Králové, Czech Republic) after insertion of a percutaneous drain.
Results: Endoscopic insertion of BDBS was successful and uncomplicated. On Day 7 after ERCP, the patient
was in good condition, no signs of bile leak or inflammation were observed, and the percutaneous drain was
removed. At 3 months, magnetic resonance imaging showed that the BDBS was patent and in the right location.
At 6 months, the stent had expectedly degraded.
Conclusions: A novel endoscopic insertion device with a polydixanone BDBS appears feasible in treating
disorders of the human biliary duct. BDBS now offers an encouraging option for endoscopic therapy of bile leaks.
Introduction
Patient and Methods
B
A previously healthy 64-year-old man was admitted 2 days
after an elective open cholecystectomy with elevated temperature and upper abdominal pain to the tertiary referral
center of Tampere University Hospital, Tampere, Finland.
The serum C-reactive protein concentration was elevated
(93 mg/L), and the bilirubin level was within normal limits
(17 lmol/L). Transabdominal ultrasound, magnetic resonance imaging (MRI), and computed tomography scan revealed a 5- · 6-cm fluid accumulation in the gallbladder bed
without common bile duct stones or signs of biliary obstruction or concomitant vascular injury. A radiologist inserted a percutaneous 8-French pigtail drain under ultrasonic
guidance to drain the fluid accumulation, which proved to be
bile juice (fluid bilirubin level = 231 lmol/L).
As bile flow into the drain continued for 8 days after surgery, ERCP was performed with the patient under conscious
sedation (7 mg of oxycodone [Oxynorm; Takeda GmbH, Linz,
Austria] and 7 mg of midazolam [Hameln Pharmaceuticals
eing one of the most common complications of cholecystectomy,1 a bile leak either from the stump of the
cystic duct or from an aberrant biliary duct (Strasberg grade
A–C) may be treated endoscopically.2–4 The well-established
therapy consists of percutaneous drainage followed by endoscopic retrograde cholangiopancreatography (ERCP), endoscopic sphincterotomy, and insertion of an inexpensive 7–
10 French plastic stent to ensure the bile flow downstream
through the papilla. In the biliary duct, a biodegradable biliary
stent (BDBS) has been successfully used in animal models in
endoscopic treatment of iatrogenic bile leak.5 The obvious
advantages of a self-expandable BDBS, with a postdeployment diameter of 8 mm, include no need for removal in repeated endoscopy and improved bile flow due to larger stent
diameter. Although the feasibility and long-term degradation
pattern of polydixanone BDBS have been proven in percutaneous use in humans,6 so far no endoscopic implantation
device has been available for use in clinical studies.
Departments of 1Gastroenterology and Alimentary Tract Surgery and 2Clinical Radiology, Tampere University Hospital, Tampere,
Finland.
This study is registered with Clinicaltrials.gov with clinical trial registration number NCT02353286.
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FIG. 1. A cholangiography image at the beginning of the
biodegradable stent implantation. *A faint contrast leak
close to the stump of the cystic duct is seen just below the
surgical clips. **Percutanous 8-French pigtail drain. ***The
tip of the stent implantation device is inserted over a stiff
guidewire into the distal common bile duct.
GmbH, Hameln, Germany]) administered intravenously and
monitored by the endoscopy team. An anti-inflammatory
suppository (100 mg of diclofenac [Novartis, Espoo, Finland])
was given approximately 60 minutes before ERCP. Duodenal
peristalsis was reduced with 40 mg of hyoscine butylbromide
(Buscopan; Delpharm Reims, Reims, France) intravenously.
A standard duodenoscope (model TJF-Q180V; Olympus,
Hamburg, Germany) with air insufflation was used. After
uneventful cannulation with a standard short guidewire, a full
biliary sphincterotomy was performed (Dreamtome RX44;
Boston Scientific Corp., Natick, MA) with pure-cut electrocautery (Erbe ViO 200D electrosurgical system; Erbe
Elektromedizin GmbH, Tübingen, Germany). Cholangiography (Philips BV Endura; Philips Medical Systems, Best,
The Netherlands) using 240 mg/mL of iohexol (Omnipaque;
GE Healthcare, Little Chalfont, United Kingdom) with a
biliary balloon (9/12 mm; Extractor Pro RX; Boston Scientific Corp.) revealed a slight leakage of contrast outside the
biliary duct in the vicinity of the cystic duct stump (Fig. 1).
This study received approval (protocol number R12021)
from the Ethical Committee of Pirkanmaa Hospital District,
FIG. 2. A custom-made braided self-expandable
biodegradable polydixanone noncovered biliary
stent with golden radiopaque markers at both ends
with a postdeployment diameter of 8 mm (Ella CS)
and an endoscopic insertion device.
SIIKI ET AL.
FIG. 3. An endoscopy view of the biodegradable stent in
final position with a guidewire still in place.
Tampere. The research use of BDBS was previously approved by the Regional Ethics Committee of Pirkanmaa
Hospital District. Informed consent to the use of BDBS was
obtained from the patient.
Results
Before stent implantation, a stiff long guidewire (0.035
inch; 450 cm; Dreamwire; Boston Scientific Corp.) was
positioned. A custom-made braided self-expandable biodegradable polydixanone noncovered biliary stent with
golden radiopaque markers at both ends and 40 mm in
length with a postdeployment diameter of 8 mm (Ella CS,
Hradec Králové, Czech Republic) was then successfully
inserted (Fig. 2). The stent was adjusted to the proper location with its distal end clearly visible inside the duodenum
(Fig. 3). After discharge, the output of the percutaneous
drain diminished to less than 10 mL/day, indicating that the
BDBS had successfully treated the postcholecystectomy
biliary leak. The drain was removed on Day 7 after ERCP at
an outpatient visit when the inflammatory markers were
normalized, with no signs of icterus, and the patient was
feeling well. No ERCP- or stent-related complications occurred during the first 30 days. At the follow-up MRI at 3
months, the stent was patent and in the right location inside
ENDOSCOPIC BIODEGRADABLE BILIARY STENT IN BILE LEAK
FIG. 4. (A) T2-weighted, fat-suppressed magnetic resonance axial image shows the fluid-filled distal part of the
common bile duct and the biodegradable stent inside it
(white arrow). (B) T1-weighted magnetic resonance axial
image shows the distal part of the common bile duct and the
biodegradable stent inside it (white arrow).
the common bile duct (Fig. 4). At 6 months the stent was no
longer visible in MRI.
Discussion
Endoscopic stent treatment is the preferred treatment in
simple bile duct injury and leakage from the cystic duct after
cholecystectomy.2–4 Although minor bile duct injury after
cholecystectomy (Strasberg grade A–C) is relatively uncommon with an incidence of less than 1%,1,4 the large
numbers of cholecystectomies performed make this complication an important clinical issue in tertiary-care centers for
both surgeons and endoscopists. Efficient therapy with a
plastic stent necessitates repeated endoscopy for stent removal, usually 1–2 months after insertion. To overcome the
burden of multiple endoscopies to patients and the healthcare
system, a BDBS appears to offer a perfect solution. However,
until recently, only transhepatic and no endoscopic insertion
devices have been available from stent manufacturers for
biliary use in biodegradable biliary stenting. We report the
first case of successful endoscopic insertion of a BDBS with a
commercial insertion device for postcholecystectomy cystic
duct leak with 6 months of follow-up.
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Earlier studies have shown that the biodegradable stents
may be safely used in the hepatobiliary duct.7–9 An endoscopically inserted BDBS also offered a safely and faster
treatment of bile leakage than a plastic stent in an animal
model of iatrogenic cystic duct leak.5 Polylactide stents appear to remain patent for at least 3 months and disintegrate at
6 months with no residual changes in the histology of the
biliary epithelium.5 The polydixanone BDBS used in this
case has been proven to be safe and fully degradable in 6
months in percutanous biliary use in humans and in the
animal model.6,8 Its molecular structure and degradation
profile are comparable to those of polylactide.6 Furthermore, there is accumulating clinical experience of the use of
polydixanone biodegradable stents in, for example, esophageal strictures.10
In this case, a prototype model of an endoscopic insertion device was successfully used with a custom-made selfexpandable radiopaque braided polydixanone biliary stent
40 mm long and 8 mm in diameter. Although the stent was
introduced over a stiff guidewire, we found it challenging to
push the stent insertion device into the common bile duct as
the prototype instrument appeared inflexible; during implantation, only careful manipulation of the tip of the duodenoscope and limited use of an elevator were possible as the
insertion device was easily bent by axial force.
In our experience the most important issue for the successful use of the BDBS was good endoscopy technique with
a stable position in the duodenum to be able to proceed
straight down the duodenoscope and to avoid excessive use
of the elevator as the insertion device passes the tip of the
scope. The gold radiography markers at both ends of the stent
provided adequate visibility in radiography. However, the
stent itself is x-ray negative, and endoscopic visualization of
the stent as it moves inside the insertion device may be
challenging.
The endoscopic implantation of a polydixanone BDBS
was successful with excellent clinical outcome in this case.
At 3 months MRI showed that BDBS was still patent and had
not migrated. Although the degradation profile has already
been proven in clinical studies and now most issues associated with the implantation device seem to have been solved,
BDBS offers a fascinating option for endoscopists treating
postoperative bile leaks. The main advantages—no need
for removal and large diameter—are obvious. However, results from larger prospective studies are needed to confirm
the feasibility of the insertion device, as well as its costeffectiveness and safety compared with plastic stents.
Acknowledgments
This study was financially supported by the Competitive
State Research Financing of the Expert Responsibility area of
Tampere University Hospital, Tampere, Finland.
Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Johanna Laukkarinen, MD, PhD
Department of Gastroenterology
and Alimentary Tract Surgery
Tampere University Hospital
Teiskontie 35
FIN-33521 Tampere
Finland
E-mail: [email protected]