Endoscopic Treatment of Biliary Stenosis in Patients with Alveolar Echinococcosis – Report of 7 Consecutive Patients with Serial ERC Approach

Background and Aims Biliary vessel pathology due to alveolar echicococcosis (AE) results in variable combinations of stenosis, necrosis and inflammation. Modern management strategies for patients with cholestasis are desperately needed. The aim is proof of principle of serial ERC (endoscopic retrograde cholangiography) balloon dilation for AE biliary pathology. Methods Retrospective case series of seven consecutive patients with AE-associated biliary pathology and ERC treatment in an interdisciplinary endoscopy unit at a University Hospital which hosts a national echinococcosis treatment center. The AE patient cohort consists of 106 patients with AE of the liver of which 13 presented with cholestasis. 6/13 received bilio-digestive anastomosis and 7/13 patients were treated by ERC and are reported here. Biliary stricture balloon dilation was performed with 18-Fr balloons at the initial and with 24-Fr balloons at subsequent interventions. If indicated 10 Fr plastic stents were placed. Results Six patients were treated by repeated balloon dilation and stenting, one by stenting only. After an acute phase of 6 months with repeated balloon dilation, three patients showed “sustained clinical success” and four patients “assisted therapeutic success,” of which one has not yet reached the six month endpoint. In one patient, sustained success could not be achieved despite repeated insertion of plastic stents and balloon dilation, but with temporary insertion of a fully covered self-expanding metal stent (FCSEMS). There was no loss to follow up. No major complications were observed. Conclusions Serial endoscopic dilation is a standard tool in the treatment of benign biliary strictures. Serial endoscopic intervention with balloon dilation combined with benzimidazole treatment can re-establish and maintain biliary duct patency in AE associated pathology and probably contributes to avoid or postpone bilio-digestive anastomosis. This approach is in accordance with current ERC guidelines and is minimally disruptive for patients.


Introduction
Alveolar echinococcosis (AE) is a parasitic disease characterised by liver lesions with infiltrative growth comparable to malignancies. On radiological imaging microcystic honeycomb like lesions are considered characteristic but solid tumors and necrotic cavities ('pseudocysts') are also frequently seen which brings solid and cystic differential diagnoses into play [1]. With continuous benzimindazole treatment the 10 year survival rate is excellent for patients with noncuratively resectable AE lesions.
A subgroup of AE patients presents with lesions of the liver hilum. They eventually lead to infiltration and stenosis of major biliary vessels, encasement of vascular structures, lobar atrophy and dilatation of peripheral bile ducts [2][3][4].
Surgery is the mainstay of AE treatment if the entire parasitic process is resectable with safe distance and has been used as a palliative procedure (bilio-digestive anastomosis) to restore biliary flow [5][6][7][8][9][10]. More recently endoscopic approaches receive attention. Serial endoscopic dilation with or without placement of plastic stents is a standard tool in the treatment of benign biliary strictures. Furthermore, FCSEMS are increasingly being used in benign biliary conditions such as i.e. strictures and complex bile leaks with the advantage of large calibre and longer duration of patency as well as relative ease of removal [11]. Various approaches in conditions such as post-transplant strictures and primary biliary sclerosis have been described [12][13][14][15][16][17][18].
The AE-driven biliary vessel pathology results in variable combinations of stenosis, necrosis and inflammation. Consequently, occlusion of biliary plastic stents due to debris needs to be considered. The objective of this series is to communicate that serial ERC treatment with balloon dilation offers a valuable solution for AE-related biliary pathology.

Clinical Setting and Patients
The Section of Clinical Tropical Medicine at Heidelberg University Hospital runs an interdisciplinary clinic for echinococcosis in cooperation with the Department of Diagnostic and Interventional Radiology with weekly radiological conferences, the Department of Surgery and the Department of Gastroenterology since 1999. Our unit is a national clinical reference center for echinococcosis. The AE patient cohort comprises 106 patients. 80 patients had peripheral and 26 central liver lesions on radiological imaging. Cholestasis was present in in 13/26. Of those 7 patients with cholestasis were treated with ERC, and 6 patients had bilio-digestive anastomosis.
Of this cohort all patients with biliary AE-associated pathology and ERC-D (endoscopic retrograde cholangiography-dilation)/ stenting are reported. The diagnosis of AE was confirmed in accordance with the IWGE-WHO expert consensus criteria [2]. Once AE was diagnosed all patients were started on long-term albendazole treatment and are still under treatment at the time of writing this report.
The following data were extracted from patient notes: age at diagnosis, sex, treatment previous to referral, time from diagnosis to referral, biliary pathology, date of interventions and follow-ups, pre-treatment and latest results of total bilirubin, alkaline phosphatase (AP), CRP, first and maximum balloon size for dilatation, types of stents, post ERC complications cholangitis, bleeding, perforation and pancreatitis.

Ethics Statement
The Ethical Board of the University of Heidelberg approved (S039/2013) the retrospective analysis of patient data without additional patient consent.

Intervention
Endoscopic treatment: ERC was carried out using a therapeutic duodenoscope (TJF160R, TJF160VR, TJFQ180V, Olympus Corp., Tokyo, Japan). Selective cannulation of the common bile duct was performed with a guide wire (Jagwire, 0.035 inch, Boston Scientific, Natick, MA, USA, Visiglide, 0.035 inch, Olympus Corp., Tokyo, Japan) or a standard catheter for cases with pre-existing sphincterotomy. All procedures were performed under conscious sedation with propofol and short-acting opiates. All patients received peri-interventional antibiotic prophylaxis.
After visualization of the biliary stricture balloon dilation was performed with 18-Fr balloons at the initial intervention and 24-Fr balloons at subsequent interventions if the stricture was distal to the hilum. If indicated 10 Fr plastic stents (Endoplus Drainage, Pflugbeil, Germany) in appropriate length and number were inserted to bridge strictures.
Outcome ERC outcomes were classified as (1) 'sustained clinical success': period without ERC-D or stenting for 6 months after the last endoscopic intervention; 'assisted clinical success': period without ERC-D or stenting for < 6 months after the last endoscopic intervention; 'failure of endoscopic treatment': persistent stricture and/or cholangitis.

Results
Between 2006 and 2015 seven consecutive patients with hepatic AE and biliary infiltration with cholangitis were referred for endoscopic treatment. All patients presented with jaundice. Patient characteristics, pre-referral treatment and biliary duct pathology is summarized in Table 1. Table 2    At the beginning there is monthly follow-up spacing for 24 months and changes to yearly intervals thereafter. Clinically stable patients are usually followed-up in yearly intervals. Patient 3 shows "sustained clinical success" after FCSEMS removal although biliary duct stenosis is still demonstrable on MRCP (Fig 3). Patient 5 was initially treated in our clinic. In the interval of nearly 2 years without follow-up the patient had non curative liver resection in another hospital. doi:10.1371/journal.pntd.0004278.g001

Discussion
Alveolar echinococcosis (AE) of the biliary tree is characterised by destruction of biliary vessels due to infiltrative, malignancy like growth of AE liver lesions. In general, growth of AE can be halted with albendazole, a benzimidazole with parasitostatic effect. ERC is the treatment of choice for benign biliary strictures and general ERC treatment recommendations are being applied in AE patients [11]. Our series shows that serial endoscopic balloon dilation and  stenting combined with benzimidazole treatment can re-establish and maintain biliary duct patency for many years. Thus, interventions with a more profound impact on the quality of life such as percutaneous bile drainage can be avoided or postponed. Well established ERC management for AE patients could possibly even postpone liver transplantation which is highly problematic in this entity as immunosuppression favors re-growth of non-resected or nonresectable AE components and spread with distant metastases. We have observed stent occlusion of plastic stents in two patients. Of which in one repeated stent occlusion is reflected by the high frequency of stent changes at the beginning of ERC treatment. The problem of stent occlusion is also mentioned in the current expert consensus guidelines [2] and may be increasingly so in AE patients due to inflammation and necrotic debris production. This favours the concept of balloon dilation alone with restrictive policy of stent placement. Although biologically and technically plausible the limited number of patients does not yet allow drawing final conclusions on the preferable endoscopic technique. In one patient sustained success could not be achieved despite repeated insertion of plastic stents and balloon dilation but with temporary insertion of a FCSEMS, an evolving technique in benign biliary disease [11].
Our report aims at proof of concept as a first step in further research of endoscopic treatment of AE patients [19,20].
Innovative management strategies for AE patients with cholestasis not eligible for curative surgery are desperately needed. There is no published evidence to support the current recommendation of percutaneous drainage as an equivalent treatment alternative to ERC management [2]. Repeated balloon dilation is in accordance with current ERC guidelines and appears a promising first line management of biliary obstruction. This approach is in accordance with current ERC guidelines [11] and in general minimally disruptive for patients.