The biliary tract is the most common site of postoperative complications after orthotopic liver transplantation (OLT), with biliary tract complications occurring in 11% to 25% of patients. Biliary strictures constitute an important subset of biliary complications and can be categorized as either anastomotic strictures (ASs) or nonanastomotic strictures (NASs). Unlike ASs, which are primarily related to surgical techniques and/or focal ischemia, many NASs are thought to be secondary to immune-mediated injury, as evidenced by an increased incidence of NASs in ABO-incompatible transplants and in recipients with primary sclerosing cholangitis. As a result of persistent allograft dysfunction, the development of NASs significantly affects patient outcomes, and retransplantation may ultimately be required.
Cytomegalovirus (CMV) infection in the posttransplant period has been associated with multiple complications and an increased risk of allograft loss and death. The clinical presentation may vary from a syndrome of fever and pancytopenia to localized disease affecting the gastrointestinal tract or even the allograft itself as a result of direct tissue invasion. At the cellular level, it produces an inflammatory response within the vascular endothelium and bile ducts that has been linked to chronic rejection and biliary complications after OLT, including stricture formation.[5-7]
Although current evidence suggests an association between CMV infection and the development of post-OLT biliary strictures, results remain conflicted, and definitive causation has yet to be demonstrated.[1, 3, 4] However, studies of other disease states have lent support to the possibility of such an association. For example, the autoimmune destruction of bile ducts in biliary atresia is thought to be initiated by a viral infection, and CMV has been implicated as a potential cause. Moreover, posttransplant CMV infection has been linked to an increased risk of primary sclerosing cholangitis recurrence.
Prior studies evaluating the association between CMV and post-OLT biliary complications detected CMV only in the blood and/or resected liver specimens.[4, 6, 10, 11] None directly identified CMV in the biliary tract of living humans, and this would be a necessary step in making the leap from association to cause and effect. Therefore, the study reported by Gotthardt et al. is exciting because it is the first to isolate CMV DNA in the biliary tract of living humans, and it offers a more direct link between CMV infection and posttransplant biliary complications.
To examine this relationship, the authors prospectively performed CMV polymerase chain reaction for biliary fluid from all posttransplant patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for suspected biliary complications over a 4.5-year period at a single center. They enrolled 124 patients: 53 with ASs and 71 with nonanastomotic biliary lesions (NABLs). The NABL group was subdivided into (1) those with macroscopic lesions on ERCP (n = 59) and (2) those with microscopic lesions in the absence of macroscopic abnormalities (n = 12). A significantly greater proportion of patients with an NABL had detectable biliary CMV [16.9% (12/71) versus 3.8% (2/53), P = 0.02]. However, when they were stratified by macroscopic lesions versus microscopic lesions, the proportion with biliary CMV was higher only for those with microscopic biliary lesions [33.3% (4/12) versus 13.6% (8/59)]. The presence of biliary CMV, however, was not associated with an increased risk of graft failure [28.6% (4/14) versus 29.1% (32/110), P = 0.97].
This study by Gotthardt et al. advances our understanding of the role of CMV in the development of biliary strictures after liver transplantation by demonstrating (1) the presence of CMV in the biliary fluid of posttransplant patients with biliary complications and (2) a higher frequency of biliary CMV in patients with an NABL. As a result, our approach to the treatment and diagnosis of posttransplant nonanastomotic biliary complications may need to shift if these findings are confirmed in larger studies.
The standard evaluation of posttransplant biliary lesions includes (1) noninvasive imaging (magnetic resonance imaging/magnetic resonance cholangiopancreatography) and invasive imaging (ERCP and/or percutaneous cholangiography) to evaluate for bile leaks or strictures, (2) hepatic artery interrogation to assess for hepatic artery stenosis or thrombosis, and (3) liver biopsy to evaluate for rejection or another cause of biliary complications (ie, recurrent or de novo primary sclerosing cholangitis). In the absence of reversible causes of NABLs (ie, rejection), management options are limited to medical control of symptoms (ie, pruritus), decompression via ERCP and/or percutaneous cholangiography, and retransplantation. These data by Gotthardt et al. suggest that testing for CMV in the biliary tract and/or empirical treatment of CMV may be another potential option. Importantly, similarly to what has been noted for CMV disease in other organs (ie, the colon), a negative blood CMV polymerase chain reaction and/or antigen test did not rule out CMV in the biliary system: 7 of 14 patients with biliary CMV had undergone liver biopsy within 2 weeks of ERCP, and none had detectable CMV, whereas all 14 were negative for pp65 antigen and CMV DNA in the blood within the 21 days before or after ERCP.
However, these findings must be taken in the context of the limitations of these data. First, as the authors note, although the identification of CMV in the biliary fluid is novel, it does not definitively prove a cause and effect mechanism. CMV may directly cause the biliary injury or, alternatively, be a secondary phenomenon due to biliary abnormalities resulting from another mechanism (ie, microvascular injury to branches of the hepatic artery not detected on angiography). To prove cause and effect, there must be a demonstration of resolution of NABLs (or at least an improvement) with CMV treatment; these data were not presented in this analysis. Second, although the authors reached their primary endpoint of a difference in the proportion of patients with biliary CMV among those with NABLs versus those with ASs, this difference was limited to those with microscopic NABLs. The clinical significance of microscopic biliary abnormalities in the absence of macroscopic findings is unknown. These histological findings may represent a variant of CMV hepatitis and not what is classically considered a posttransplant biliary complication. Third, there were a limited number of cases in which biliary CMV was detected, and this is important for 2 reasons. First, the small sample size may have prevented clinical and/or demographic differences between the 2 groups from reaching statistical significance, despite important clinical differences. For example, the median donor age for patients with biliary CMV was 4.6 years greater than the median donor age for patients without biliary CMV. Thus, the higher prevalence of NABLs in the group with biliary CMV may have been in part related to increasing donor age and not to CMV. Second, biliary CMV was detected in fewer than 20% of patients with an NABL, and this highlights the fact that although CMV may be associated with post-OLT biliary complications, it would be a potential causative mechanism in only a minority of these patients.
Although further investigation is needed to determine whether CMV is the causative entity for NABLs, this research advances our understanding of the role of CMV in the development of biliary complications after transplantation. Furthermore, because it has demonstrated the feasibility of detecting CMV in biliary fluid in living humans, future multicenter studies involving large cohorts of patients can be conducted to further elucidate the role of CMV in causing NABLs and the potential for therapeutics to reverse these lesions.