Biliary complications are among the most significant issues following liver transplantation, affecting approximately 20-30% of patients. Pediatric liver transplant recipients are no exception, and pediatric transplantation itself may pose a risk for the development of biliary complications. This is particularly true in cases where reduced grafts are used, such as left-sided splits or livers from living donors, which often involve extremely delicate bile ducts and require complex reconstructions, including bilio-digestive anastomoses sometimes double-duct—or biliary plasty with enlargement (1, 2).

Early biliary complications (occurring within the first 6 months to 1 year post-transplant) are most commonly represented by fistulas or anastomotic strictures. Additionally, bile leaks from reduced graft segments are frequent and typically have significant clinical impact, often requiring interventional approaches. These range from endoscopic therapies (ERCP) to interventional radiology procedures with placement of percutaneous biliary drains or possible bilioplasties (3, 4). In more complex or refractory cases, relaparotomy and redo anastomoses may be necessary (5).

The management of late-onset biliary complications, however, presents more complex decision-making challenges. These complications include delayed anastomotic strictures, particularly in cases involving bilio digestive anastomoses, or ischemic bile duct lesions (ITBL). The incidence of ITBL is reportedly increasing due to the systematic use of extended criteria donors, such as DCD (donation after circulatory death) or elderly donors (6). Nonetheless, it is believed that the use of perfusion machines, which have proven to be safe and effective even for pediatric liver transplants, may partially mitigate their impact (7–9).

Late biliary complications can severely affect the quality of life in pediatric transplant recipients, manifesting with symptoms such as jaundice or pruritus, which are often refractory to treatment, or severe and recurrent cholangitis. As a result, repeated invasive treatments are typically the first-line approach in transplant centers (8). Clinicians are also aware that repeated acute episodes of biliary damage can worsen the overall clinical picture, affecting both the biliary tree and liver function, ultimately leading to re- transplantation in 2-5% of patients or, in rare and complex cases, mortality rates of 1-2% (5).

An increasingly prominent group of patients in the international transplant landscape comprises those who underwent transplantation during childhood and have now reached 20–30 years of follow-up. These individuals still have a long life expectancy ahead, but there is little to no data available on long-term graft survival and quality of life beyond 20 years (with only a few reports in the literature extending beyond this period) (9). In these patients, managing late biliary complications becomes particularly challenging, as the long history of the graft and the need to ensure good quality of life for several more years must be taken into account (9, 10).

In this context, the available literature is extremely scarce, and the management of biliary complications requires a tailored approach, with strategies defined on a case-by-case basis. Our experience as a center with 34 years of activity and more than 4,000 liver transplants performed, including approximately 200 pediatric transplants, is situated within this highly specific patient setting (5).

Since 1995, the year the pediatric transplant program was launched at our center, 192 children have undergone liver transplantation. The follow-up of these patients has essentially been “lifelong,” although the frequency and types of examinations have gradually decreased over time.

Initially, a very close follow-up was conducted, with blood tests every 15 days after discharge from the inpatient unit, accompanied by an ultrasound examination. Over time, the frequency of follow-up decreased to approximately every six months, involving ultrasound, clinical examination, and blood tests, and became annual after 10 years post-transplant.

At our center, we still perform protocol biopsies at 1, 3, and 5 years post-transplant, and then every five years for subsequent follow-up. Additional second-level tests, such as CT scans or MR cholangiography, are ordered only if clinically indicated, as is the case for endoscopic examinations.

In this cohort of patients, we identified those with a minimum of 20 years of follow-up to investigate the presence of long-term biliary complications, excluding patients who had experienced early biliary complications within the first year post-transplant.

For all patients with more than 20 years of follow-up, we reviewed their medical records, reports from outpatient follow-up visits, trends in blood test results, and immunosuppressive therapies.

For patients in whom we found documented biliary complications, either clinically or through second-level tests such as MR cholangiography, we collected data on hospital admissions, endoscopic or radiological interventional procedures, and the need for surgical re-intervention or re-transplantation.

Additionally, we identified four “model” clinical cases, in which we chose to describe our approach to foster discussion on what could have been done differently and to share the lessons learned from managing these complex cases in such a specific patient population.

In our series, we additionally excluded four patients who underwent retransplantation for biliary complications (2% of cases), as they were retransplanted before reaching 20 years of follow-up and therefore did not meet the study’s inclusion criteria.

We included 40 patients in this study with a minimum follow-up of 20 years post liver transplantation.

The management of biliary complications is one of the most frequent challenges faced by transplant surgeons. Biliary complications, which affect 20-30% of transplanted patients according to the major studies in the literature, may be increasing, likely due to the use of extended-criteria donors such as elderly or steatotic donors, as well as the growing use of donors after circulatory death (DCD) across Europe (10, 11).

While the management of early complications, such as anastomotic leaks or strictures of both end-to-end and biliodigestive anastomoses, is part of the standard skillset of clinicians working in transplantation, and is relatively straightforward in most cases, the treatment of late-onset complications, such as anastomotic or intrahepatic biliary strictures, proves to be more complex and nuanced (12). These complications often suggest an underlying ischemic issue that complicates treatment and, in severe cases, may lead to the need for retransplantation (13). As specified in the Materials and Methods section, four patients in our historical cohort also underwent retransplantation for biliary complications before reaching twenty years of follow-up.

A distinct yet emerging subgroup within the wide and diverse population of liver transplant patients comprises those who underwent transplantation in childhood. Today, these patients have a long follow-up history and a substantial future life expectancy (14). In this context, every clinical decision must consider these factors (10).

In our experience, after analyzing a classic case of biliodigestive anastomotic stricture in a pediatric transplant patient who received a left split graft, treated with common but still complex interventional radiology techniques, such as percutaneous bilioplasty, we recognized what became a strategic and management error in the long run. In the second case presented in our results, we describe an extremely challenging experience for our center and, more importantly, for the patient we treated. By inadvertently targeting an excluded bile duct with no possibility of restoring proper bile outflow, we condemned the young patient to three months of external biliary drainage, with no chance of removal or closure. This significantly worsened her quality of life, essentially preventing her from attending school regularly. Minor management complications, such as bile leakage at the drainage insertion site, only compounded this already precarious situation. The sole positive outcome of this drainage placement was obtaining a bile culture, which allowed us to initiate targeted antibiotic therapy that has, so far, produced good results. The patient has remained free of drainage and cholangitic episodes for approximately six months. This case led us to adopt a more cautious and less interventional approach, as demonstrated in the third case, and prompted us to conduct a more thorough review of imaging. We focused not only on biliary anatomy and the local complication but also on the volume of parenchyma involved in the excluded segment, which, in some cases, may atrophy spontaneously, as we observed upon reviewing the MR cholangiograms of both girls in cases 2 and 3. It is clear that the conservative treatment we implemented in both cases, involving prophylactic antibiotic therapy and close surveillance, does not preclude the possibility of future interventions with more aggressive approaches, such as hepatic resections or listing for retransplantation, if the less drastic options are deemed to have failed or become futile. A stepwise approach is, in fact, the one we employed in the patient described in case number four. In cases where a side-to-side anastomosis has been performed between the biliary tract of the graft and that of the recipient, percutaneous or endoscopic interventional options remain the treatment of choice in most centers. Surgical options are generally reserved for cases refractory to these treatments. In case number four, the impossibility of performing percutaneous bilioplasties led us to schedule a surgical intervention to reconstruct a biliodigestive anastomosis. When such an indication arises, it is mandatory to carry out a thorough study of the vascularization of the transplanted liver to confirm adequate arterial supply to the graft and the primary biliary convergence where the new anastomosis will be performed. At our center, in addition to routine Doppler ultrasound surveillance, we systematically perform contrast-enhanced CT imaging prior to any surgical or interventional radiology procedure on the biliary tract, in order to assess the patency of the hepatic artery. In planning the interventional management of biliary complications, some promising options have recently been proposed, which may become part of the management protocols for these patients in the coming years. The Barcelona group (15) recently presented positive results on the use of biodegradable stents in managing anastomotic strictures. Although our experience with this technique is currently limited and with less satisfactory results, the potential contribution these options may offer to the non-surgical management of these patients is undoubtedly worth considering. The aspects we consider most interesting in this study relate to the conservative management of patients under our care with biliary complications (intrahepatic strictures involving the anastomosis in a clinically insignificant manner), identified through MRCP and characterized by elevated GGT levels. In such cases, we deemed it prudent to follow a close monitoring protocol, including biannual ultrasound and blood tests, and annual MRCP in the absence of significant clinical or laboratory changes. This approach partially contrasts with other reports in the literature, which suggest more aggressive interventional approaches (16–18) often driven by concerns that potential clinical deterioration or repeated episodes of cholangitis could worsen biliary damage and progressively affect graft function. However, this must be weighed against the relatively high risk of inducing cholangitic events through percutaneous procedures, which carry the associated risk of septic complications. The group from Bergamo (18) recently described their experience with these patients, confirming that while the risk of post- procedural cholangitic events is relatively high, the clinical impact is often moderate. The colleagues from the Bergamo group also emphasize the importance of obtaining bile cultures via drainage, in order to initiate targeted antibiotic therapy. In our experience, a program of close clinical monitoring can support a more conservative, wait-and-see approach. In more doubtful and complex cases, significant decision- making support may come from pathological data obtained through liver biopsy. Many centers, including ours, continue to follow protocol biopsy programs every five years in pediatric transplant patients. The pathological data are essential in evaluating fibrosis and detecting signs of acute and chronic rejection and can also be directed toward assessing the condition of the bile ducts and detecting signs of cholangitis in the graft (19). In addition to protocol biopsies, in patients with elevated GGT levels and an unclear radiological picture, histological assessment of biliary damage could assist in guiding management towards a more or less interventional approach. In our case described as number 3, for example, a biopsy negative for chronic cholangitic changes in the left lobe parenchyma supported our decision to implement a “watch and wait” protocol, although we are fully aware that this approach requires caution and careful monitoring—particularly with the need to escalate to more invasive treatments in cases of recurrent infections, which may complicate the clinical course and make potential retransplantation more challenging. The role of antibiotic prophylaxis in these patients remains controversial. A recent review and meta-analysis (20) conducted in a different patient setting, specifically children who underwent Kasai procedure for biliary atresia, showed no differences in terms of patient outcomes or in prolonging the life of the native liver without the need for transplantation. Although there is no clear evidence (21) in the long-term transplanted population that prolonged antibiotic prophylaxis improves outcomes, and indeed, infectious disease specialists are rightly concerned about the emergence of antibiotic resistance due to inappropriate antibiotic prescriptions, in selected cases, targeted therapy based on culture results could be considered. In any case, a significant study by the Barcelona group recommends the systematic use of antibiotic prophylaxis in all pediatric patients undergoing biliary interventional procedures. The pathogens most frequently responsible for post-procedural cholangitic conditions identified by the Spanish colleagues were Gram-negative (64%), Gram-positive cocci (28%), and Candida spp. (8%). This information should be carefully considered when contemplating specific antibiotic prophylaxis for this patient population (22, 23).

The number of pediatric liver transplant recipients with long-term follow-up, often exceeding 20 to 30 years, is increasing. These patients are unique due to their extensive medical histories and their long life expectancy. Therefore, transplant-related complications, especially biliary ones, which are the most common, require careful and tailored management. Traditional interventional approaches have proven effective in addressing most of these complications, reserving more invasive surgical and re-transplantation options for highly selective cases. In our experience, a subset of these patients may benefit from a more conservative approach, provided that strict and attentive follow-up is maintained, even if this option should not delay or replace radical intervention when the latter is feasible and potentially curative.