Endoscopic retrograde cholangiopancreatography (ERCP) is a common procedure performed for the nonoperative management of a variety of biliopancreatic disorders. Despite vast advances in techniques, relative safety, and clinical efficacy, post-ERCP pancreatitis (PEP) remains one of the most serious and frequent complications of this procedure, with an incidence ranging from 2%–10% depending on the patient population and outcome definitions.1-3 Although majority of PEP cases are mild, a significant number of patients may develop severe pancreatitis that necessitates management in the intensive care unit and prolonged hospital stay.1,4

Since PEP continues to be a serious problem, there is an ongoing interest in identifying reliable prophylactic measures for PEP or in reducing its severity. Multiple prospective trials employing multivariate analysis have identified an array of patient- and procedure-related risk factors that are associated with an increased risk of PEP.5-12 The exact mechanisms by which these factors cause PEP is not well understood and may include mechanical factors from instrumentation, chemical, or hydrostatic injury related to contrast instillation, and thermal injury from electrocoagulation/electrocautery incision during therapeutic interventions.8,13

Commonly employed preventive measures include pharmacological measures, such as intravenous somatostatin,14 gabexate,15 octreotide,16 and rectal nonsteroidal anti-inflammatory drugs (NSAIDs),17-21 or interventional strategies, such as wire-guided cannulation22 and prophylactic pancreatic duct (PD) stent placement.23,24 The cascade of events leading to the development of PEP involves three major successive steps: (1) inciting events, (2) zymogen activation, and (3) inflammation due to a variety of cytokine pathways.13 Current prevention strategies aim to either reduce the impact of inciting events by employing interventional modifications or by inhibiting the inflammatory end-products of zymogen activation through pharmacological agents, such as NSAIDs.

Zymogen activation in acinar cells is a critical step in initiating the inflammatory cascade that results in pancreatitis. Therefore, an effective means of inhibiting zymogen activation via an external stimuli can potentially arrest the inflammatory cascade, thereby preventing the development of PEP. In a novel animal study conducted by Orabi et al.,25 the authors found that early events in zymogen activation leading to PEP are induced through the calcium-activated phosphatase calcineurin. In addition, PEP is dependent on acinar cell calcineurin in vivo. The same investigators also showed that PEP does not occur in calcineurin-knockout mice globally. These elegant animal studies suggest that calcineurin is critical in zymogen activation, and its inhibition can potentially arrest the progression of events that lead to PEP. In support of these preliminary findings, a large multi-center study involving patients who had undergone ERCP after liver transplantation showed that the consumption of tacrolimus, a calcineurin inhibitor, reduced the risk of PEP by 79%.26 Tacrolimus is primarily used as an immunosuppressant in transplant recipients. It is a macrolide produced by Streptomyces tsukubaensis. It binds to an intracellular protein, FKBP-12. A complex consisting of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is subsequently formed, which inhibits the phosphatase activity of calcineurin.27

Building on this emerging body of evidence, an interventional pilot study was conducted to explore the feasibility, safety, and preliminary efficacy of oral tacrolimus (cumulative dose of 4 mg) in the prevention of PEP by comparing two prospective cohorts.

Pancreatitis is a known complication of ERCP.2,3,11 The evolution of PEP from the initial pancreatic insult to the eventual local and systemic complications of pancreatitis is a multi-step process dependent on zymogen activation, enzymatic activation, and the release of a variety of mediators that ultimately sets in motion an inflammatory cascade that is self-propagating. Prophylactic measures that have been found useful thus far, are restricted to the interventional measures that soften the initial blow to the pancreas and those that reduce pancreatic injury below the threshold required for zymogen activation. Prophylactic measures also include pharmacological agents that target inflammatory mediators that aid in propagating the inflammatory cascade. However, these measures cannot be collectively exhaustive to eliminate the incidence of PEP. This may be due to two reasons. First, we are currently unable to accurately identify a threshold for zymogen activation that can reliably predict subsequent events in these patients. Second, our knowledge of the gamut of downstream inflammatory mediators is far from complete. Zymogen activation seems to be a point of convergence that can theoretically be permissive to the propagation of inflammation. Therefore, it would be an ideal therapeutic target that can reliably and effectively arrest the inflammatory cascade despite inciting pancreatic injury. Initial promising animal experiments conducted by Orabi et al.25 demonstrated that calcium signaling pathways had a central role, more specifically via the calcineurin receptor, which might activate zymogen and induce the subsequent enzymatic activity that led to inflammation. Moreover, the same investigators showed the absence of PEP in calcineurin-knockout mice. Intraductal infusion of calcineurin inhibitors into PD prevented contrast-induced pancreatitis in mice, as demonstrated by histological findings, along with a decrease in amylase and interleukin 6 levels. In an interesting study by Law et al.,29 the incidence of PEP in liver transplant recipients was found to be substantially lower. Although they found a weak correlation between steroids and the incidence of PEP, subsequent studies failed to demonstrate this benefit.30 More recently, a large retrospective study showed a significant reduction in the risk of PEP with tacrolimus and rectal indomethacin consumption.26 In light of these findings and in conjunction with the study by Orabi et al.,25 it is possible that tacrolimus has a significant impact on the prevention of PEP.

In our study, the rate of PEP among the Tac group was lower than that in the control group (8.3% vs. 15.7%). Age and sex distributions, along with comorbidities, were comparable between the two groups. The factors known to increase the risk of PEP, such as difficult biliary cannulation with multiple attempts, instrumentation, inadvertent PD cannulation, contrast injection, and sphincterotomy, were equally distributed, with no statistically significant differences between the two groups. More importantly, the number of patients with difficult cannulation who received PD stents and rectal NSAIDs was comparable between the two groups.

We also examined the serum trough Tac levels in patients who developed PEP, which were found to be significantly lower in patients with PEP than in those without (3.3 ng/mL vs. 6.98 ng/mL, p=0.001). The optimal cutoff for trough tacrolimus levels to prevent PEP is unknown. In a retrospective study of liver transplant recipients, a trough tacrolimus level of 2.5 ng/mL was found to lower the odds of PEP by 79%.26 Notably, only two patients (4.6%) had tacrolimus levels lower than 2.5 ng/mL; among these two, one patient developed PEP. The remaining three patients who developed PEP in the Tac group had levels exceeding 2.5 ng/mL. In this study, using the receiver operating characteristic analysis, an optimal cutoff of 3.38 ng/mL was determined which could prevent PEP, with a sensitivity of 86.2% and specificity of 83.3%. However, it should be mentioned that there was considerable variability in the trough tacrolimus levels in this study (range, 1.8–13.5; variance, 10.2). This can be further explained by the fact that oral tacrolimus has been shown to exhibit erratic absorption with varying bioavailability in healthy volunteers.27,31 These observations suggest that the pharmacokinetic properties of oral tacrolimus, such as optimal dosage, ideal trough tacrolimus level, and safety, are important aspects that merit further study.

This study is the first clinical trial to assess the feasibility and safety of oral tacrolimus for the prevention of PEP. The relatively higher rate of PEP, albeit mild in severity and without mortality within 30 days after ERCP, in our patient cohort is an important finding. A relatively higher incidence of PEP was noted by some investigators in large university hospitals and tertiary referral centers. This may be related to the higher proportion of patients with prior unsuccessful attempts at cannulation, difficult cannulation, and complicated disease with multiple comorbidities being referred to these centers.32 The more liberal use of PD stenting and rectal NSAIDs can be a potential intervention for future practice. Although oral tacrolimus at a cumulative dose of 4 mg was found to be feasible and safe, its efficacy in preventing PEP has to be assessed further in a larger sample size. In addition, isolated case reports of acute pancreatitis among renal transplant recipients, which could possibly be attributed to tacrolimus, was described in the literature.33,34 Although rare, this is an important aspect that merits consideration in future studies on the use of tacrolimus in the prevention of PEP.

In conclusion, this pilot study clearly demonstrates that oral tacrolimus at a dose of 4 mg can safely prevent PEP in patients undergoing ERCP. Further randomized studies with larger sample sizes can help establish an ideal trough tacrolimus level that can reliably prevent PEP following ERCP procedures.