Percutaneous Treatment of Biliary Strictures After Pediatric Liver Transplantation

Background

In spite of the ongoing progress in pediatric liver transplantation (LTx) biliary strictures (BS) remain a significant cause of morbidity with the incidence varying between 3.7% and 25.3% [1,2]. Usually these patients require repeated endoscopic, percutaneous or surgical interventions and may lead to graft loss in up to 14.8% of cases [3–5]. There are anastomotic biliary strictures (ABS), non-anastomotic biliary strictures (NABS), also called ischemia type biliary lesions (ITBL) or a combination of both [6]. ABS result mainly from anatomy and surgical issues like small size or multiple bile ducts, improper technique or type of biliary reconstruction [1], whereas NABS are linked with ischemic, immunological, or infectious agents [7,8]. Anticipatory diagnostic approach is of most importance in BS because of the diversity of symptoms and the frequent subclinical onset [9]. In children, the most frequent indication for LTx is biliary atresia, thus the majority of reconstruction is hepatico-jejunal anastomosis (HJA). In HJA, endoscopic access to biliary anastomosis is technically difficult. Thus, the gold-standard approach is percutaneous transhepatic biliary drainage (PTBD) which has gradually replaced surgery as the first-line treatment, with successful outcome reported in 76% to 89% of cases [10]. PTBD is considered safe and effective and in most centers, surgery is only reserved for severe and/or refractory strictures. The aim of this study was to analyze our experience in percutaneous management of BS after pediatric LTx.

Material and Methods

PERCUTANEOUS TRANSHEPATIC BILIARY DRAINAGE (PTBD):

In all patients, PTBD sessions were performed under general anesthesia with intravenous antibiotic prophylaxis (a second or third generation of cephalosporin). Punctures into the liver were made through the lateral approach into the right lobe in procedures performed for whole-liver graft patients or punctures were made subxiphoid in patients with left lateral segment graft. All procedures were performed under either fluoroscopic control or ultrasound guidance. The strictures were crossed with the guidewire, and then dilated with a standard angioplasty balloon. After successful dilatation, a pigtail catheter ranging in size between a 6- and 10-French catheter (Flexima^®, Boston Scientific, Ultrathane^®, Cook Medical) was inserted and left for external gravity drainage. In cases of poor drainage, the catheter was flushed with saline once or twice a day. If cannulation of BS failed, external 5-French catheter was placed in the biliary tract and the patient was qualified to surgical treatment. In 2-month (±4 weeks) intervals, cholangiogram, re-dilatation, and catheter replacement were performed. The treatment was successful when the control cholangiogram showed no significant residual stricture and there was free passage of the contrast media through the anastomosis.

According to cholangiography, ABS was defined as a sudden decrease in diameter of the anastomotic site with subsequent dilatation of the peripheral bile ducts and the lack of effective passage of contrast. NABS was defined as a multi-focal narrowing of bile ducts proximal to the biliary anastomosis. Multilevel biliary strictures (MBS) were comprised of NABS or combination of ABS and NABS.

After completion of treatment, a successful outcome was defined as full patency of the anastomotic site with spontaneous emptying of contrast on cholangiography, continuous improvement in liver function tests (LFTs) and lack of the features of biliary obstruction in radiological studies in the 6-month follow-up. An unsuccessful procedure was defined as failed cannulation of the BS, need for surgical revision of anastomosis, ineffective drainage with persistence of cholestasis after procedure, or the need for re-transplantation due to biliary complications.

In regard to the outcome of treatment, patients were divided into a good outcome group and a bad outcome group. Demographics and clinical parameters were compared between the groups accordingly.

STATISTICAL ANALYSIS:

Results are presented as number, percentage, mean or median as appropriate. The differences between prognostic groups were calculated with U Mann-Whitney test and Fisher exact test for small groups. Survival rates were calculated according to the Kaplan-Meier method, with the end-point defined as re-transplantation or death, P value <0.05 was considered statistically significant. Statistical analysis was performed using Statistica 6.0 (College Station, Texas, USA).

Results

DIAGNOSIS:

In most cases, the onset was asymptomatic and the suspicion of a stricture was raised due to elevation of liver enzymes activity, bilirubin levels, and/or dilatation of bile ducts in routinely performed ultrasound scan. Clinical symptoms were present in 11 patients (31%). The most common symptoms were fever (n=3), jaundice (n=6), itching (n=5), and acholic stools (n=2). Laboratory values at the time of diagnosis were as follows: median bilirubin 2.6 mg/dL (range: 0.5–14.8 mg/dL), GGTP 383 IU (range: 53–2996 IU) and ALT 114 IU (range: 30–282 IU). Bilirubin level was <1 mg/dL in 8 patients (23%), and GGT level below 100 IU was observed in 2 patients (6%). Ultrasound scan indicated dilatation of bile ducts in 32 patients (91%). MRCP was performed in 15 patients (43%) and all presented with dilated peripheral bile ducts. Hepatobiliary scintigraphy revealed impaired uptake in 12 patients (34%), impaired excretion in 27 patients (77%), and dilatation in 23 patients (66%). Liver biopsy was performed in 32 patients (91%). In 21 patients (66%) histopathology was consistent with biliary obstruction and presented with cholestasis and ductular proliferation.

TREATMENT AND OUTCOME:

PTBD was successful in 20 (57%) patients and median duration of treatment was 0.4 years (0.1–3.3 years). Overall, 92 PTBD procedures were performed (mean 2.5 per patient) and most patients required more then 2 sessions of treatment (Table 2).

The most common complications after PTBD were cholangitis which occurred in 5.4% (n=5), perforation of duct (n=1), bleeding (n=1), and catheter displacement (n=2). None of these complications required surgical intervention.

Unsuccessful PTBD was mostly attributed to critical narrowing not allowing to traverse the stricture or to insufficient drainage in case of MBS. These patients were referred for surgery. Revision of HJA was performed in 14 patients with good outcome in 10 cases (71%). During median overall follow-up of 9.2 years (range: 1.4–18.5 years), 4 patients required re-transplantation due to progressive deterioration of graft function (Figure 1). In 3 of them, other co-morbidities of HCV infection, autoimmune hepatitis or chronic rejection, significantly contributed to graft loss. Overall, good outcome of treatment, including PTBD and surgery, was achieved in 31 patients (88.5%) and the probability of 5-year graft survival was 94%. One patient was deceased after re-transplantation due non-graft related complications.

We compared several variables between groups in regard to the outcome, but only the era of treatment was significant; 80% of patients treated after 2007 had good outcome of PTBD compared to only 40% of those treated before 2007 (Table 3).

Discussion

In patients with HJA, the management of post-transplant BS is based on percutaneous and/or surgical interventions. In our experience, PTBD was effective in almost 60% of cases and another 25% of patients underwent successful surgery. Our results are similar to studies presented previously, where PTBD was effective in between 70% and 95% of cases [7,11–18]. BS are often asymptomatic, and may present with inconsistent radiological findings. Especially the dilatation of peripheral bile ducts, which is often not visualized; thus, anticipatory approach is mandatory for early diagnosis [9,14,17].

In most centers, PTBD is the treatment of choice in BS, nevertheless total duration of initial approach, intervals between balloon dilatations, and timing of drain removal differ between centers, and no control trials have been performed on this topic. Usually, duration of treatment varies between 3 and 6 months with re-evaluation of the stricture every 3–4 weeks [7,11,12,14]. The mean number of PTBD courses per patient is between 2 and 4, however, a single intervention may be effective in up to 75% of cases [14,17,18].

Percutaneous treatment of BS is considered safe and effective [19], however, some proportion of patients still progress to liver cirrhosis. Feier et al. analyzed 489 pediatric after living donor LTx and 71 (14.5%) developed biliary complications. The overall mortality rate of patients with BC was 14% and the re-transplant rate was 9.8%, however, only 4.2% were directly related to BC [18]. Lorenz et al. reported an overall complication rate around 12.5%, but severe complications (sepsis and hemoperitoneum) were observed only in 2 cases (1.7%) [11]. Contraindications are rare and include uncorrectable coagulopathy, allergy to iodinated contrast, and large volume ascites [20].

Biliary strictures not responding to dilatation and stenting require surgical re-anastomosis of HJA. A combined surgical and percutaneous approach may prevent re-transplantation in the majority of patients [6,14–16,21–23]. Moreover, Darius et al., presented a surgical approach as a first-line treatment of BS with compelling results [24]. The primary patency rate of surgically treated ABS was 80% (n=47 out of 59) with a mean follow-up of 92 months (range: 1–210 months). The relapse necessitating a second surgical biliary intervention developed in 20%, however, the overall patient survival exceeded 90% regardless the type of the graft.

Data on what factors may affect the outcome of interventional treatment remains scarce and inconsistent. In previous reports, patients with hepatic artery thrombosis and NABS or combination of NABS and ABS had a higher likelihood of recurrence after percutaneous catheter removal [7,25]. Other factors, like type of the graft, history of chronic rejection, or initial diagnosis did not appear to impact the outcome [7]. Moreira et al. analyzed recipient’s weight <10 kg, previous cytomegalovirus infection, donor-recipient sex and weight, autoimmune disease or biliary atresia after Kasai operation as indication for LTx, use of reduced liver grafts, and chronic or acute rejection, however, none of these variables influenced the outcome of percutaneous treatment [17].

The major goal of PTBD is to avoid unnecessary surgery, however, external long-term drainage may be very demanding for the patient and family. It might be the source of chronic discomfort and affect daily activities of the child, thus psychological support plays an important role in the adherence to treatment and overall outcomes.

The main limitation of our study was the retrospective design, the evolution of clinical approach over time, and the single-center experience. Also, the small number of patients included in the study.

Conclusions

Percutaneous methods are effective, safe, and currently recommended as the first-line treatment in post-transplant BS in patients with HJA. A close monitoring and an anticipatory approach are essential for early recognition and effective treatment. In selected patients, combination of PTBD and surgery may be required, especially in severe or refractory cases.