Update on the optimisation of endoscopic retrograde cholangiography (ERC) in patients with primary sclerosing cholangitis

Introduction

Primary sclerosing cholangitis (PSC) is a rare cholestatic disorder with a prevalence of 16.2 per 100 000 population. It is characterised by progressive inflammation and destruction of the intrahepatic and extraheptic bile ducts culminating in progressive fibrosis and cirrhosis.^1–3 The course of PSC is complicated by biliary strictures, recurrent cholangitis and a 400-1500 times higher risk of cholangiocarcinoma (CC) and other hepatopancreatobiliary malignancy than the general population.^{1 4–9} Treatment of PSC revolves around managing symptoms and complications as they arise. Endoscopic retrograde cholangiography (ERC) is a valuable tool that allows therapeutic interventions to optimise biliary drainage and facilitate biliary sampling.¹⁰ Despite the utility, controversies remain as to when ERC should be performed.^{11 12} This article aims to clarify some of the issues surrounding this and to provide practical guidance on the ERC-based assessment and management of biliary strictures in PSC.bile ducts culminating in progressive fibrosis and cirrhosis.^1–3 The course of PSC is complicated by biliary strictures, recurrent cholangitis and a 400-1500 times higher risk of cholangiocarcinoma (CC) and other hepatopancreatobiliary malignancy than the general population.^{1 4–9} Treatment of PSC revolves around managing symptoms and complications as they arise. Endoscopic retrograde cholangiography (ERC) is a valuable tool that allows therapeutic interventions to optimise biliary drainage and facilitate biliary sampling.¹⁰ Despite the utility, controversies remain as to when ERC should be performed.^{11 12} This article aims to clarify some of the issues surrounding this and to provide practical guidance on the ERC-based assessment and management of biliary strictures in PSC.

Natural history of PSC

The aetiology of PSC is unclear but may involve cholangiocyte injury resulting from an abnormal immune response to environmental exposure in genetically susceptible individuals.^{3 13} PSC most commonly affects men between the ages of 30 and 40 and usually occurs in the presence of inflammatory bowel disease (IBD). It may be detected as part of routine patient evaluation in IBD. Most patients are asymptomatic at the time of diagnosis.¹⁴ Those who present with symptoms may report abdominal pain (20%), pruritus (10%), fatigue (6%) and jaundice (6%).^{13 14} Bacterial cholangitis can be the presenting feature in 6% of patients with PSC.¹⁴

Patients with PSC are at risk of both benign and malignant biliary obstruction. Therefore, worsening biochemical cholestasis with or without fever, abdominal pain, pruritus, and jaundice should prompt further investigation. Up to half of patients with PSC are diagnosed with CC within their first year of diagnosis.^{1 15}

While most patients with PSC have large duct disease, 9% can present with small duct disease with normal appearances of the bile ducts on cholangiography but with cholestatic liver enzymes and histological findings typical of PSC.^{1 11 16} While small duct PSC may have a less aggressive clinical course, 5%–15% may progress to large duct disease.^17–19

Asymptomatic patients may have a better prognosis; however, this may be due to diagnosis at an earlier stage prior to developing extensive biliary strictures with the sequelae of recurrent cholangitis and synthetic liver dysfunction.^{11 13} Currently, there are no effective medical therapies to alter the natural history of the disease, but trials are currently focused on cholestatic and fibrotic targets including nor-ursodeoxycholic acid and drugs that target the farnesoid X receptor fibroblast growth factor 19 axis.¹³ PSC is a progressive disease, and 40% may require liver transplantation, with 24% experiencing disease recurrence in the graft after a median of 5 years.^{20 21}

Biliary strictures and the role of ERC

Biliary strictures are the hallmark of PSC, with high-grade strictures (HGS) occurring in 45%–65% of patients.^{13 22} Originally, dominant strictures were defined as stenosis with a diameter of up to 1 mm in the intrahepatic ducts (within 2 cm of the bifurcation) or up to 1.5 mm in the common bile duct (CBD) on ERC.^{13 22} However, this ERC-based definition is not universally accepted as, in current clinical practice, diagnostic ERC is not recommended in PSC. Detection of strictures, therefore, is more likely to be with magnetic resonance cholangiopancreatography (MRCP), usually prompted by changes in the patient’s clinical symptoms and/or liver biochemistry. As such, the proposed nomenclature has been updated to reflect this, with HGS being defined as biliary strictures on MRI/MRCP with >75% reduction of duct diameter in the CBD or hepatic ducts and a relevant stricture with signs or symptoms of obstructive cholestasis and/or bacterial cholangitis.^{7 23} HGS may present with symptoms of cholangitis, progressive jaundice or pruritus, with evidence of progressive proximal bile duct dilatation on imaging. The median survival of patients with HGS is worse than those without (14 years vs 23 years), with a 26% risk of developing CC.²⁴ Therefore, consideration should be given to interrogation of HGS via ERC to investigate for the presence of malignancy with tissue obtained via biliary brushings for cytology and consideration of single-operator cholangioscopy (SOC) with targeted biopsy. SOC with targeted biopsy has higher sensitivity for a diagnosis of CC in comparison with biliary brushings (65% CI 35% to 87% vs 43% CI 35% to 52%) with higher specificity (97% CI 87% to 99% vs 97% CI 95% to 98%) and/or endoscopic ultrasound (EUS) sampling.^{10 25}

ERC in PSC: the practicalities

When is ERC indicated?

The role of ERC in PSC is primarily in the workup and management of HGS and should be reserved for patients who need tissue acquisition or therapeutic interventions.¹¹ Once HGS is diagnosed on imaging, ERC may be considered to facilitate biliary sampling and optimisation of biliary drainage. The latter includes dilatation of biliary strictures to manage episodes of cholangitis, pruritus and jaundice. Biliary intervention should be considered on a case-by-case basis with appropriate discussions in a multidisciplinary team meeting (MDM) (table 1).

Table 1.

Summary of society guidance: indications for ERC in PSC

BSG11	Biliary strictures Biliary strictures requiring tissue acquisition where CC is suspected on cross-sectional imaging. Mandatory sampling of HGS suspicious for CC. If therapeutic intervention is indicated, biliary dilatation is preferred to stenting.
AASLD41	Biliary strictures Biliary strictures requiring tissue acquisition where CC is suspected on cross-sectional imaging with brushings for cytology and fluorescent in situ hybridisation. If cytology is negative, imaging should be repeated in 6 months. If cytology is suspicious, ERC should be repeated in 3 months. Cholangitis Cholangitis with inadequate response to antibiotics.
EASL23	Biliary strictures Development of a new or rapidly progressive HGS on cross-sectional imaging with suspicion of CC with tissue sampling. If cytology shows LGD or benign, repeat ERC or MRI in 3 months. Cholangitis Bacterial cholangitis after imaging.

AASLD, American Association for the Study of Liver Diseases; BSG, British Society of Gastroenterology; CC, cholangiocarcinoma; EASL, European Association for the Study of the Liver; ERC, endoscopic retrograde cholangiography; HGS, high-grade strictures; LGD, low grade dysplasia; PSC, primary sclerosing cholangitis.

Such MDMs should include biliary endoscopists, radiologists (with a specialist interest in hepatobiliary disease), hepatobiliary surgeons and hepatologists to discuss the merits of biliary intervention. Liver transplantation may be considered for liver failure, recurrent bacterial cholangitis or pruritus, and these patients should be discussed with the regional liver transplant MDM.¹¹

Surveillance in PSC is primarily via cross-sectional imaging and serology (ie, Cancer Angigen [Ca] 19-9), with considerable variation in surveillance strategies and intervals among different centres.²⁶ Ca 19-9 may increase with the development of HGS or CC; therefore, these patients should undergo cross-sectional imaging.^{27 28} Including scheduled ERC in surveillance strategies may positively impact mortality, as shown in a retrospective study of 2975 patients with PSC that showed an overall HR for death of 0.64 (0.48–0.86) for ultrasound/MRI and 0.53 (0.37–0.75) for follow-up strategies that included scheduled ERC, although reactive and diagnostic imaging was not differentiated from imaging performed purely for surveillance.²⁶ However, yearly surveillance with Ca 19-9 and MR followed by ERC may not effectively detect early cancers and thus improve long-term survival.²⁹ Figure 1 outlines a proposed algorithm for the assessment and management of biliary strictures in PSC.

Figure 1.

Proposed algorithm for the assessment and management of biliary strictures in PSC. *ERC to be carried out in a high-volume centre with an operator experienced in the management of complex hilar strictures. CC, cholangiocarcinoma; ERC, endoscopic retrograde cholangiography; EUS, endoscopic ultrasound; MDM, multidisciplinary team meeting; MRCP, magnetic resonance cholangiopancreatography; PSC, primary sclerosing cholangitis; SOC, single-operator cholangioscopy.

ERC to improve biliary drainage

The main aim of endoscopic therapy of strictures is to improve cholestasis by relieving biliary obstruction. This can be achieved by balloon dilatation or stents. There is a general consensus that biliary balloon dilatation should be the primary initial treatment for patients with HGS, with dilatation performed to the maximum duct diameter.^{11 30} The calibre of intraductal balloon dilatation (4 mm, 6 mm or 8 mm) should be carefully matched to the non-stenotic duct calibre on the cholangiogram. Serial dilatations are often needed to achieve technical and clinical success.³¹ Scheduled yearly ERC in patients with PSC with serial planned dilatations of HGS may also improve transplant-free survival.^{22 30 32}

In patients undergoing stenting, 10 Fr plastic stents are the primary intervention.^{30 33} However, these small-diameter stents are prone to develop biofilms and occlude over time, possibly leading to an increased risk of cholangitis.³⁴ Plastic stents may also lead to an increased risk of pancreatitis; therefore, guidelines recommend that plastic stents should only be considered for strictures refractory to dilatation.^{12 33 35} Short-term stents with a maximum duration of 2 weeks have been shown to have similar recurrence-free rates compared with dilatation in a randomised control trial; however, this was terminated after an interim analysis showed higher rates of serious adverse events in the stent group with an increased rate of pancreatitis and cholangitis.^{22 33}

More recently, the use of fully covered metal stents (FCSEMS) has been described in patients with PSC (see case scenario 2) with refractory biliary strictures (ie, resistant to conventional therapy, including balloon dilatation with or without plastic stents), with the resolution of HGS in 65% of patients after 3 months but with a recurrence rate of 30% at 6 months.³⁶ In this study, the risk of post-ERC cholangitis with FCSEMS was ~5%.³⁶ Currently, FCSEMS are not routinely recommended for use in PSC, and further studies are needed to assess their role.

More recently, biodegradable stents made of polydioxanone (a synthetic biodegradable polymer) are increasingly being used in various indications.³⁷ They hydrolyse with variable degradation times and may be novel alternatives to reduce treatment-related adverse events by removing the necessity of repeat procedures for stent removal. These stents have been shown to be clinically effective and safe in patients without PSC with symptomatic biliary obstruction.³⁸ However, currently, there is no evidence for their routine use in PSC.

Nasobiliary drains have been described in the management of pruritus associated with cholestatic diseases as well as in the management of cholangitis.^{39 40} Their use in PSC may facilitate the management of cholangitis, but in isolation they would not be sufficient to remodel biliary strictures without concurrent biliary dilatation.

ERC for tissue acquisition

A radiological diagnosis of HGS in a patient with PSC often raises concerns about CC, prompting the need for tissue acquisition to confirm or refute the diagnosis. The standard modality is biliary brushings (for cytology), which has a high specificity of 97% (95% CI 95% to 98%) but is hampered by a lower sensitivity of 43% (95% CI 35% to 52%) for CC.²⁵ Fluorescence in situ hybridisation, in addition to standard cytology, may increase the sensitivity of biliary brushings.^41–43

More recently, SOC (eg, SpyGlass DS, Boston Scientific) has become an important adjunct that allows direct visualisation of biliary mucosa and facilitates targeted biopsies of areas (figure 2). In addition, SOC allows the endoscopist to identify features of malignancy and provide a visual diagnosis of biliary strictures. This leads to a higher sensitivity in all patients with ‘indeterminate’ strictures, including those with malignancy and those with or without PSC.^{44 45} Features more suggestive of malignancy are erythema, nodularity, ulceration and neovascular proliferation (figure 3). The Edmonton Classification is a novel proposed system classifying extrahepatic PSC strictures into inflammatory, mass-forming, nodular and fibrostenotic.⁴⁶ However, there is wide interobserver variation in describing these findings.⁴⁷ Once dysplasia or high-risk features are identified at index SOC, surveillance SOC with biopsies may be required.^{46 48} There is a general consensus that SOC is effective in the evaluation of HGS in PSC.^{11 12 23} ERC and SOC may have an additional role in the diagnostic pathway of patients with ‘indeterminate’ strictures to differentiate PSC from IgG₄ sclerosing cholangitis and CC.⁴⁹

Figure 2.

Biliary cholangioscopy in the presence of a guidewire demonstrating fibrostenotic disease.

Figure 3.

Biliary cholangioscopy demonstrating erythema, nodularity and neovascular proliferation.

Artificial intelligence is an area of development that may facilitate better imaging and stratification. Differentiating benign from malignant biliary strictures using convolutional neural networks via SOC is gaining traction and may offer greater accuracy than traditional methods in the future, and this is an area that requires further study.^50–52

In addition to biliary brushings and targeted biopsy, biliary fluid can be sampled at the time of ERC. This liquid biopsy allows mutational analysis of cell-free DNA which can detect relevant mutations associated with malignant cells in the biliary system with high sensitivity.⁵³

ERC for biliary stone disease

Stone disease is common in patients with PSC, and biliary stones should be considered in those presenting with worsening liver enzymes in the context of pain and fever. Intraductal stones are also common in patients with PSC and are frequently intrahepatic.^{54 55} Small intraductal stones may be difficult to identify on MRCP in the setting of cholangiopathy but may cause acute obstruction. Choledocholithiasis in PSC is managed with ERC with sphincterotomy and balloon trawl. SOC may be used to target intrahepatic stones for electrohydraulic lithotripsy. If there is concurrent HGS, passing the 10.5 Fr (3.3 mm) cholangioscope or extracting calculi following fragmentation may be challenging.

Patient preparation for ERC

Patient consent

Patients should be carefully counselled on the risk of complications. A recent meta-analysis comparing ERC-related adverse events in patients with PSC (n=715) and without PSC (n=9979) demonstrated a significant threefold increase in the 30-day odds of cholangitis in PSC, despite the majority receiving antibiotics (OR 3.26, p=0.037).⁵⁶ Conversely, there were no significant differences in post-ERCP pancreatitis (PEP), bleeding or perforation. All patients should receive rectal Non steroidal anti-inflammatory drugs (NSAIDs) for prophylaxis of PEP, even in the presence of colitis. The overall risk of pancreatitis was 4.2%, bleeding 0.3% and perforation 0.7%.⁵⁶ It is unclear if increased cholangitis risk relates to overall procedure time, bacterial colonisation of inadequately drained ducts or use of contrast agents.⁵⁷ In PSC patients with cirrhosis, the risk of ERC-related complications does not appear to be increased as compared with those with PSC without cirrhosis; however, it is unclear if this is affected by referral bias.^{58 59} Preassessment of patients prior to ERC is advisable to optimise them for the procedure and perform up-to-date liver biochemistry.

Risk of cholangitis

Antibiotics should be used in all patients with PSC undergoing ERC due to the increased risk of cholangitis.¹¹ This may be exacerbated by longer procedure times and SOC.^{57 60} The risk of cholangitis may be increased with the lack of adequate drainage of contrast from the obstructed intrahepatic ducts.⁶¹ Newer techniques that are being described for hilar strictures, such as carbon dioxide cholangiography, have not been described in PSC.⁶¹ ‘Down firing’ balloons for contrast injection may avoid overfilling intrahepatic ducts. The addition of antibiotics to contrast media does not seem to decrease cholangitis rates, which is an area that has not been investigated in PSC.⁶²

Single-use duodenoscopes may confer a reduced risk of duodenoscope-associated infection and possibly a reduced risk of cholangitis, but further studies are needed.⁶³

Sedation

ERC in patients with PSC is often technically challenging, requiring longer procedural duration for stricture assessment, brushings and dilatation. Therefore, performing ERC under general anaesthesia (GA) or propofol deep sedation is recommended. Although evidence suggests that propofol-assisted lists may be associated with increased endoscopic success, the provision of GA-ERC or propofol-assisted lists is limited in the UK.^64–67

Procedural details

The operator

ERC in patients with PSC should be performed in high-volume centres by operators experienced in managing complex hilar strictures. Less experienced ERC practitioners may have higher rates of post-ERC pancreatitis and bleeding, lower success rates, and increased hospitalisation postprocedure.^68–70 Biliary strictures in PSC are challenging; subsequently, intervention should only be performed in centres where appropriate MDM discussion can occur. This also facilitates the review of all available imaging with specialised hepatobiliary radiologists prior to undertaking ERC.

Biliary cannulation adjuncts

Anecdotal evidence suggests that the major papilla is often smaller and retracted.⁷¹ The inflamed and thickened bile duct wall may make cannulation challenging. Care should be taken to avoid overinjection of segments with contrast that may not drain. Multiple cannulation attempts have been shown to increase the risk of pancreatitis.⁷² Consideration should be made to use tools that may facilitate cannulation and deep biliary cannulation, including hydrophilic guidewires.⁷³ Although 0.025″ guidewires may be used, they have not been shown to increase the success of primary cannulation.⁷⁴ Tapered-tip cannulas can be considered to increase ease of access. Patients with PSC undergoing ERC should preferably have a sphincterotomy performed (unless there is a specific contraindication) in view of the likely need for further future biliary access.⁷² Additionally, sphincterotomy may potentially reduce the risk of pancreatitis if further intervention is needed in the future.⁷²

Endoscopic ultrasound

Perihilar lymph nodes are common in patients with PSC and occur in the absence of CC.⁷⁵ EUS has high sensitivity and specificity in the diagnosis of CC.⁷⁶ In cases of HGS, EUS, in addition to ERC, may be used to sample perihilar lymph nodes, thickened bile duct walls and associated masses. However, concerns remain for seeding of malignant cells and iatrogenic upstaging in sampling of the primary lesion.^77–79 In a recent study, EUS detected regional lymph nodes in a higher percentage of patients than cross-sectional imaging (86% vs 47%), with EUS fine needle aspiration (FNA) identifying malignant regional lymph nodes (MRLN) in 87% of patients ultimately found to have MRLN.⁸⁰

Further potential applications of EUS include estimation of liver fibrosis with real-time shear wave measurements, EUS portal pressure gradient estimation or EUS-guided liver biopsy where indicated.⁸¹

Follow-up after ERC

Clear documentation of endoscopic findings, including the location, length and maximum diameter of the stricture, therapy performed (including the size of the balloon used for dilatation) and the sectoral ducts targeted is vital. In addition to ensuring clear communication between the teams caring for patients with PSC, it also guides further endoscopic intervention. Patients should have a planned date of stent removal if inserted and follow up with clinical consultation. They should be advised on which hospital to attend if the procedure was conducted in a tertiary centre.

Conclusion

ERC is a valuable tool in investigating and managing HGS in PSC, with a primary role in tissue acquisition and endotherapy. All patients with HGS should be discussed in a specialist MDM prior to proceeding with ERC, ideally performed in high-volume centres, following appropriate patient counselling. All patients with PSC undergoing ERC should receive prophylactic antibiotics, and sphincterotomy should be considered at index ERC. The priority in cases of HGS is to actively exclude CC using all available adjuncts, including cholangioscopy-guided biopsies and EUS. Endotherapy of HGS predominantly relies on serial dilatations to achieve stricture remodelling. Stenting, if done, should be reserved for short-term duration only. Optimal methods to treat strictures continue to evolve, with a potential future role for biodegradable stents.

PSC clinical scenarios

Scenario 1

A man (age range 30–40 years) with liver biopsy-proven PSC presented to his local hospital with increasing bilirubin (180 μmol/L, from 46 μmol/L). CT scan showed prominent intrahepatic ducts, a mildly enlarged left liver lobe and mild splenomegaly. No HGS was demonstrated. He was treated for cholangitis, with improvement in liver blood tests. Three months later, he presented with another episode of cholangitis, and MRCP demonstrated HGS in the extrahepatic duct with progressive dilatation of the intrahepatic ducts. His UK Model for End-Stage Liver Disease (UKELD) score was 57 (bilirubin 197 μmol, international normalised ratio (INR) 1, creatinine 56 μmol/L, sodium 135 mmol/L) and his Child-Pugh score was B9 (albumin 25 g/L, no encephalopathy, no ascites). He was referred for liver transplant assessment on the basis of repeated episodes of cholangitis. He was discussed at the liver MDM and the decision was made for an ERC with brushings of the HGS in the extrahepatic biliary tree. His cholangiogram showed a strictured extrahepatic duct from the hilum to the ampulla. The stricture was dilated incrementally to 8 mm and brushings were taken. A straight plastic stent was placed in view of his significant jaundice, and a planned stent removal was carried out a week later. Repeat dilatation of the extrahepatic duct was performed in increments to 9.5 mm without repeated short-term stenting. Biliary brush cytology was negative. He was listed for transplantation, with consideration for all types of suitable grafts. While remaining active on the transplant list, 7 months after his index ERC, he experienced a further episode of cholangitis and worsening of pruritus. Following reimaging with MRCP, he underwent a further ERC with dilatation of the extrahepatic stricture. Subsequently, he remained symptom-free for many months (without prophylactic antibiotics). His UKELD score improved to 44 (bilirubin 16 μmol, INR 1, creatinine 64 μmol/L, sodium 144 mmol/L). After further MDM discussions, he was delisted from the transplant waiting list. He remains under close follow-up in the liver clinic.

Scenario 2

A man (age range 50–60 years old) diagnosed with PSC 18 months previously presented to his local hospital deeply jaundiced, with a bilirubin of 400 μmol/L. His Ca 19-9 was raised at 152 U/mL (normal range 0–37 U/mL). He underwent an MRCP, which demonstrated HGS in the proximal CBD. He was transferred to the regional liver centre. He was discussed in the MDM and a decision was made for EUS assessment of the HGS, in addition to ERC. His EUS showed a proximal CBD stricture below the hilum with a markedly thickened CBD. The lumen was reduced to 2 mm and the duct wall measured 4–6 mm, with no extension outside the duct wall. A contrast study was performed and the duct wall enhanced in a similar pattern to adjacent normal tissue. Fine needle biopsy (FNB) was performed. On ERC, his cholangiogram showed irregularity and stricturing of intrahepatic ducts, in keeping with cholangiopathy with a stricture at the hilum. Cholangioscopy showed featureless bile duct mucosa with no nodularity, luminal masses or projections. Brushings were taken in addition to cholangioscopy-guided biopsies. Temporary stenting was carried out. Overall, his EUS and ERC findings were interpreted as more in keeping with an inflammatory process.

His FNA and biliary brushings were suspicious for malignancy with scanty tissue from the cholangioscopy-guided biopsies. A positron emission tomography-CT did not show increased uptake. He was rediscussed in the MDM and a decision was made for repeat ERC and diagnostic laparoscopy. The repeated biliary brushings were benign, as were the laparoscopic biopsies. He was therefore listed for a liver transplant. Repeat CT while on the transplant list showed disease progression, and repeated laparoscopy showed peritoneal deposits.

Learning points from the two cases are highlighted in box 1.

Box 1. Learning points from case presentations.

• An increase in liver function tests or cholangitis symptoms should prompt cross-sectional imaging.

• Discussion at the MDM should happen before biliary intervention, with consideration of patient transfer to the regional centre.

• Incremental dilatation matched to the non-stenotic duct calibre is the mainstay of treatment.

• If stenting occurs, it should be short term, with a planned date for stent removal given.

• Consider EUS assessment for HGS to assess for ductal thickening and solid masses.

• Biliary brushings should be taken at each ERC, and consideration should be made for multimodal sampling of HGS.

Ethics statements

Patient consent for publication

Not required.