FUNDAMENTALS OF ERCP, SERIES #2

Getting Down, Lining Up, and Getting In

October 2022 • Volume XLVI, Issue 10
Daryl Ramai,Douglas G. Adler

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Endoscopic  Retrograde  Cholangiopancreatography (ERCP) can be performed for diagnostic and therapeutic purposes. With the development and widespread dissemination of advanced imaging modalities (i.e. Magnetic resonance cholangiopancreatography (MRCP) and Endoscopic Ultrasound (EUS)), ERCP in the modern era is rarely performed without therapeutic intent. As most ERCP procedures involve the selective cannulation of the common bile duct (CBD) and/or pancreatic duct (PD), failure to effectively cannulate results in global procedural failure, highlighting the importance of successful deep cannulation of the desired duct. As a result, a strong command of techniques aimed at cannulation is important for any advanced or therapeutic endoscopist. In this article, we explore endoscope insertion, orientation, and the fundamentals of selective cannulation of the biliary and pancreatic ducts using various endoscopic techniques.

Intubation

Following adequate sedation of the patient, a selfretaining mouth guard is placed, and the patient is re-positioned into a prone position, although a small number of centers routinely perform ERCP with the patient supine.1,2 A meta-analysis of 6 studies reporting on 309 supine and 1415 prone ERCPs reported that the pooled technical success rates for completion of ERCP in the supine and prone positions were 89.1 % (95 %CI = 80.9 – 94.0) and 95.6 % (95 %CI = 91.5 – 97.7), respectively. The pooled rates for complications (cardiopulmonary and post-ERCP pancreatitis (PEP)) in the supine position were 37.5 % (95 %CI = 19.1 – 60.3) and 3.5 % (95 %CI = 1.6 – 7.3), respectively.3 The pooled rates for complications (cardiopulmonary and PEP) in the prone position were 41.0 % (95 %CI = 20.9 – 64.8) and 3.9 % (95 %CI = 2.4 – 6.4), respectively. Overall, prone ERCPs appear to have a higher technical success rate with a slightly lower mean duration but a higher number of adverse events.

To perform ERCP, the duodenoscope should be inserted safely into the second portion of the duodenum – the location of the major papilla, also known as the Ampulla of Vater. To this end, it is vital that endoscopists understand normal foregut anatomy as seen with a side viewing instrument and how to insert the duodenoscope into the esophagus, stomach, and duodenum.4 (Figure 1) Patients with altered anatomy may also pose another layer of difficulty but ERCP should only be attempted in these patients after obtaining significant experience in patients with normal anatomy.

As the patient lies in the prone position, esophageal intubation is achieved with the duodenoscope held horizontally and parallel to the examination table with the patient’s neck slightly flexed. Upward tip deflection (backward tension on the large wheel) together with gentle advancement is required to pass through the hypopharynx, although some right or left tip deflection (via backward rotation of the lateral wheel) can often be helpful. The vocal cords are located obliquely upward of the visual field. The duodenoscope should then be gently advanced, passing the vocal cords. The endotracheal tube is often seen clearly in the pharynx if the patient is under general anesthesia. Further, despite the notion that intubation is done blindly, endoscopists can evaluate the oral cavity, epiglottis, vocal cords and the pharynx with the use of side viewing instruments.

As the duodenoscope is advanced to the upper esophageal sphincter (UES), esophageal intubation can proceed with subtle tip deflection combined with gentle pressure. Light downward tip deflection (forward on the large wheel) and gentle torque will enable the endoscopist to perform esophagoscopy if required. Using a neutral position, the duodenoscope can be advanced while examining the walls of the esophagus for landmarks including the Z-line and the transition to the gastric mucosa. Immediately upon entering the stomach, leftward endoscope torque and brief tip extension (large wheel forward) combined with endoscope advancement and air insufflation will allow visualization of the fundus and a portion of the gastric body, giving the endoscopist a clear sense of which direction to proceed in. With the tip of the scope angled downwards, the duodenoscope is then slowly advanced along the greater curvature of the stomach towards the distal stomach.

With further advancement, the duodenoscope will pass the incisura angularis. Should the endoscopist need to examine the cardia, this can be done by upward tip angulation and slow withdrawal and rotation of the duodenoscope to evaluate the lesser curvature. On the other hand, as the tip of the instrument is further angled downwards and advanced, the scope passes the incisura, and the pylorus comes into view. The scope is positioned so that the pylorus is in the center field of vision. However, as the tip of the scope is returned to the neutral position, the pylorus fades from endoscopic view along the bottom of the viewing screen to the point of disappearing: this is referred to as “setting the sun” and alerts the endoscopist that they are in the proper orientation for forthcoming pyloric transit.

It should be noted that, despite its advantages, passage through the stomach can sometimes be difficult, particularly in the prone position.5 To help overcome this, the patient’s right knee can be flexed while the patient’s shoulders are rotated to approximate a left lateral decubitus position and usually facilitates gastric passage and entry into the duodenum. Trainees or inexperienced operators will often over-flex the duodenoscope tip upon entering the stomach, leading to undesired retroflexion in the fundus. Unless the operator in this situation can realize that the source of their difficulties is over-flexion, they will not be able to find the pathway to the distal stomach. This process is referred to as becoming “lost in the fundus.” However, the duodenoscope was designed to easily pass through the stomach, and in most cases the transit from the mouth to the second portion of the duodenum is rapidly accomplished with ease. If repeated attempts to pass the duodenoscope to the small bowel end in failure, it is rarely the fault of the instrument and usually due to operator error. In these cases, the endoscopists should carefully withdraw the instrument, remove excessive air, and attempt to re-intubate again while carefully looking for, and responding to, the various landmarks as outlined above.

Once past the pylorus, advancement to the duodenum requires tip extension (large wheel forward) which provides a global view of the duodenal bulb. This view also enables proper alignment for further movement towards the second portion of the duodenum. With subsequent tip flexion, gentle advancement of the duodenoscope allows the shaft of the instrument to align with the greater curvature of the stomach. This maneuver, which if performed properly will place the duodenoscope into long endoscope the shaft of the duodenoscope to sit on the greater curvature and leaves the tip of the duodenoscope at the second or beginning of the third portion of the duodenum. For most patients, the long endoscope position will enable proper orientation to the major papilla. However, for patients under conscious sedation, the long endoscope position is less tolerated due to gastric distention. In addition, while the long position often gives excellent views of the major papilla, it limits the ability of the duodenoscope to maneuver. As such, most endoscopists routinely transfer to the so-called “short position” via reducing the endoscope to a position wherein the shaft lies flush with the lesser curvature of the stomach. The standard shortening maneuver consists of full rightward deflection, with subsequent locking, of the lateral wheel and upward movement of the large wheel followed by withdrawal and simultaneous clockwise torque applied to the endoscope shaft by the right hand. This shortening maneuver allows the operator to hook the tip of the duodenoscope in the descending duodenum which results in a straighter duodenoscope and brings the papilla The standard shortening maneuver consists of full rightward deflection, with subsequent locking, of the lateral wheel and upward movement of the large wheel followed by withdrawal and simultaneous clockwise torque applied to the endoscope shaft by the right hand. This shortening maneuver allows the operator to hook the tip of the duodenoscope in the descending duodenum which results in a straighter duodenoscope and brings the papilla into full view.

Orientation and Initial Positioning

Once in the second portion of the duodenum, and using the standard shortening maneuver, the endoscopists will usually be able to directly visualize the major papilla without difficulty.5 In the literature, endoscopists have classified the major papilla according to four major types using Haraldsson’s classification: Type 1: “regular papilla” or “classic appearance” most common type with no distinctive features; Type 2: “small papilla,” small, often flat with a diameter not bigger than 3 mm (2 sphincterotome diameter); Type 3: papilla with a large protruding and/or pendulous infundibulum and visible orifice; Type 4: large papilla with multiple overlying folds over the orifice (commonly referred to as a hooded papilla or a Shar-Pei dog papilla).6 Haraldsson’s classification schema is largely used in research studies, and in practice there are many additional varieties of papillary anatomy that can be encountered. Patients can have a single ampullary orifice or clearly separate biliary and pancreatic orifices, and many variants exist.

In rare instances, the papilla may be difficult to identity as it may be concealed behind a fold, distorted, or ablated in patients with malignancy, or indistinct in patients with significant bowel wall edema (such as encountered in patients with acute pancreatitis or severe hypoalbuminemia). In other rare instances, patients may have aberrant anatomy where the papilla is located more proximally, just beyond the apex of the duodenal bulb, or distally, between the second and third portion of the duodenum, the aberrant distal papilla is more common than the proximal one.

The appearance of the major papilla can also be significantly altered if it has undergone prior biliary sphincterotomy, pancreatic sphincterotomy, or dual sphincterotomies. Once identified, a brief evaluation of the ampulla allows for assessment of its type and size, as well as any unusual features which may impede (or facilitate) cannulation or the procedure as a whole (i.e. periampullary diverticula, visibly impacted stones, patulous orifice, prior sphincterotomy, etc.). Most patients with a native ampulla will have a single orifice that provides access to the common channel which bifurcates into the common bile duct and main pancreatic duct (the main pancreatic duct is also known as the duct of Wirsung). A minority of patients will have two separate orifices, however, due to their very close proximity, this may be difficult to discern without close examination.

While the size and shape of the papilla provides useful information, particularly with regards to the angle of the intraduodenal portion of the common bile duct and pancreatic duct, as well as the length of the common channel, defining intra-ampullary anatomy can be challenging even once attempts at cannulation have begun. However, spending adequate time on proper inspection and positioning is beneficial and worthwhile. Furthermore, the endoscopist can thoroughly examine the ampulla from various positions prior to attempting cannulation to get a more complete picture of the local ampullary anatomy, which is often helpful. 

Cannulation of the Common Bile Duct

The common bile duct can be cannulated via a variety of endoscopic methods. Some of these methods include:

  • Standard catheters
  • Sphincterotomes preloaded with guidewires
  • Placement of a pancreatic guidewire or stent followed by biliary cannulation
  • Access sphincterotomy also known as “precut” sphincterotomy
  • Rendezvous techniques that can be performed in combination with EUS-guided biliary access or percutaneous biliary access

The preference for using any one method for cannulation over another (i.e. cannula vs. sphincterotome) is usually a matter of personal choice. However, this decision is partly based on the indication for the procedure, and whether a sphincterotomy is required. Regardless of which device or method is applied in cannulating the biliary tree, several core principles universally apply.

Prior to cannulation, obtaining optimal positioning of the major papilla is vital for success. To this end, when facing the major papilla en face, the biliary orifice will almost always be in the left upper quadrant, corresponding to the 9 o’clock to the 12 o’clock position. It is important to emphasize that the clock face is not with respect to the endoscopic image one sees on a video monitor, but rather with respect to the intraduodenal portion of the common bile duct (i.e., the intraduodenal portion of common bile duct delineates the 12 o’clock position).

When properly oriented and with the ability to interpret the image of the papilla correctly, in this position, the angle of the common bile duct can be extrapolated, at least partly, by evaluating the angle and direction of the intraduodenal portion of the distal common bile duct. By combining this angle with the presumed location of the biliary orifice in the major papilla, attempts at cannulation can proceed in a more orderly and coordinated manner. Using this technical information, one can project an imaginary line into the lumen showing the direction the common bile duct would take if it extended beyond the papilla. The endoscopists should manipulate the duodenoscope and cannulating device to move along this imaginary line when attempting to obtain deep biliary access.

Novice endoscopists will frequently approach the biliary orifice with a catheter or sphincterotome in a manner such that the selected device impacts the duodenal wall at a right angle; this almost universally will result in cannulation failure. Under fluoroscopy, the catheter position can be appreciated, and trainees should be taught to use the information obtained via fluoroscopy to achieve a proper cannulation angle, which is parallel to the intended biliary angle, not perpendicular. By using an upward sweeping motion of the catheter, the device tip mirrors the true direction of the distal common bile duct which very often facilitates successful cannulation.

As the tip of the selected device engages with the biliary orifice at its most superior point, and hopefully, above the septum which separates the pancreatic duct from the common bile duct, direct access can be obtained by applying gentle pressure to the cannulating device and/ or advancing the guidewire. Depending on the device used for cannulation, other maneuvers can be applied such as gentle relaxation of the elevator, a subtle withdrawal of the device and/ or the duodenoscope, and reduced bowing (if a sphincterotome is being used) will facilitate deep access to the common bile duct. Additionally, once the tip of the sphincterotome has been inserted into the papillary orifice, simultaneous unbowing of the sphincterotome along with slowly pulling the scope shaft more tightly along the lesser curvature of the stomach is often a useful technique to achieve selective cannulation of the common bile duct. While these basic techniques are simple in conception, cannulation of the common bile duct is often very challenging, even for well-seasoned endoscopists. There is a very concrete reason that most advanced endoscopy fellowships are a minimum of one year in length: skills such as cannulation are only obtained slowly over a long period of time. Patients may have aberrant papillary or duodenal anatomy which affect the rate of cannulation. Other times, patients may have seemingly normal anatomy, yet achieving successful cannulation may be difficult despite properly performing standard maneuvers. At this time, more advanced techniques may be relied upon to assist in a variety of difficult situations.

Cannulation Techniques
Using a Sphincterotome

In modern practice, initial attempts at cannulation are most often performed using a sphincterotome rather than standard biliary catheters. (Figure 2) The primary advantage of using a sphincterotome lies in its ability to be bowed once it passes beyond the tip of the duodenoscope. Sphincterotomes can be bowed at their tips via tension on the same cutting wire that delivers thermal energy via electrocautery to perform sphincterotomy. Tension on this wire achieves the actual mechanical bowing of the device.

Sphincterotomes have a variety of different properties: catheter shaft thickness, degree of bowing, length of cutting wire (ranging in length from 15 to 35 mm), catheter tip diameter (most commonly 0.025″ or 0.035″), length, degree of tapering, number of ports, location of wire exit from the tip of the catheter, etc. Sphincterotome cutting wires typically consist of a single-metal monofilament. The monofilament configuration is commonly used compared to braided filaments

which has a higher risk of inducing more thermal injury to surrounding tissue.7

For example, a sphincterotome with a 30 mm length of cutting wire will often flex to a greater extent than a sphincterotome with a 20 mm length of cutting wire but will need to be more fully advanced into the lumen to allow complete bowing. A sphincterotome with a 20mm cutting wire can bow even when partially still inside the duodenoscope working channel. Likewise, a sphincterotome designed to accommodate a 0.035″ wire is likely to be stiffer than a device for a 0.025″ wire. However, no specific sphincterotome design has universally been shown to be superior. Therefore, selection of a particular sphincterotome is generally based on operator experience and individual preference. Some sphincterotomes have additional features, such as the ability to rotate or to reverse-bow (as might be helpful in a patient with Billroth II anatomy). It should be stressed that for the sphincterotome to fully bow, the cutting wire should be advanced out of the duodenoscope and into the lumen. If the cutting wire remains partially within the duodenoscope channel, this may impede its ability to fully flex, although performing this maneuver can often provide significant advantages during cannulation itself. Bowing with the cutting wire partially in the duodenoscope channel may allow the sphincterotome to flex in a more dynamic fashion when advanced out of the channel and simultaneously applying tension.

Several reports have evaluated outcomes comparing the use of standard biliary catheters and sphincterotomes. Schwacha et al. randomized 100 consecutive patients undergoing ERCP into a standard catheter group and a guidewire sphincterotome group.8 Success rate with regards to biliary cannulation was significantly higher in the guidewire sphincterotome group (84%) than with the standard catheter group (62%) (P = 0.023). Sixteen patients who had cannulation failure with a standard catheter achieved cannulation success using a guidewire sphincterotome, bringing the total success rate in that group to 94%. Rates of post ERCP pancreatitis were similar in both groups. Similar outcomes have been reported in other studies comparing the use of a sphincterotome versus a standard catheter.9,10,11

Importantly, trainees should avoid overly using the sphincterotome in order to line up and cannulate the biliary orifice from afar. Instead, the endoscopists should rely on using upper body movements and the dials of the duodenoscope to achieve optimal positioning and orientation. It should be stressed that it is fully within the standard of care to cannulate with a simple catheter even in the modern era, although few choose to do so in practice. Achieving deep cannulation with a straight catheter takes skill and many endoscopists who trained in earlier eras still practice in this manner.

Guidewire Cannulation

The term “guidewire cannulation” refers to a set of techniques that allow deep biliary and/or pancreatic access without the use of contrast injection during ERCP. If contrast is used during the cannulation process, and before deep access to the desired duct has been obtained, the term “guidewire cannulation” cannot truly be applied. (Figure 3)

In the event cannulation with a sphincterotome or standard catheter is unsuccessful, a guidewire can be inserted through a sphincterotome or a catheter to aid in achieving biliary cannulation. The guidewire can be inserted using two primary techniques. First, after lining up with what it felt to be an optimal angle for biliary access the accessory is placed into physical contact with the papilla and then the guidewire is advanced. The operator can then see and feel if deep biliary access is obtained. This technique can be referred to as Single Wire Technique #1. (Figure 4)

Alternatively, the sphincterotome can be advanced near the ampulla without making actual physical contact, and the guidewire is advanced across the small “air gap” into contact with the ampulla. The endoscopist can monitor guidewire movement and progress endoscopically and fluoroscopically. If the guidewire is seen to enter the biliary tree, the catheter or sphincterotome can then advance over the wire into the duct itself. This technique can be referred to as Single Wire Technique #2. (Figure 5) Attempts at biliary cannulation can sometimes lead to repeatedly cannulating the pancreatic duct (PD) with the guidewire itself. In these instances, the initial guidewire can be left in the pancreatic duct while the sphincterotome is removed to allow insertion of a second guidewire to be used to reattempt biliary cannulation. The guidewire that remains in the pancreatic duct should preferably be advanced to at least the level of the pancreatic genu to ensure a stable wire position. Deep pancreatic duct access is preferable, but this is not always possible. This technique can be referred to as the Double Wire Technique or the Two Wire Technique. (Figures 6 and 7) The wire in the PD can help to identify the pancreatic orifice, reveal the PD angle, and straighten the papilla as a whole. Additionally, with the initial guidewire in the PD, it is easy to identify fluoroscopically if the second wire is also entering the PD or if biliary cannulation is successful. Several studies have demonstrated that leaving a guidewire in the PD does not generate sufficient hydrostatic pressure to increase the risk of post-ERCP pancreatitis.12-14

Although the 2-wire technique is generally considered safe and effective, one group evaluated the prophylactic effect of placing a PD stent in patients who had undergone PD wire placement as an aid to achieving biliary cannulation, with regards to the incidence of post-ERCP pancreatitis.15 The authors randomized 70 patients who underwent PD wire placement to receive a prophylactic PD stent (a 5 F by 4 cm stent with a single pigtail) or no stent (35 patients in each group). Post-ERCP pancreatitis was less frequently encountered in the stent group (2.9%) versus the no-stent group (23%) (RR: 0.13,

confidence interval: 0.016, 0.95). However, biliary cannulation was achieved in only 80% of patients in the stent group (compared to 94% of patients in the no-stent group). It is somewhat difficult to reconcile the extremely high rate of post-ERCP pancreatitis seen in the group that was not stented, as it is discordant with similar studies.

The inverse of the double guidewire technique is the Reverse Double Wire Technique a.k.a. the Reverse Two Wire Technique. This technique is performed when attempts at pancreatic duct access result in biliary access. This is typically indicated in patients with a variety of disorders which require selective pancreatic duct cannulation such as idiopathic recurrent acute pancreatitis, chronic pancreatitis, pancreatic ductal injuries, pancreatic fistulas, and other indications.16

Similar to the aforementioned techniques, the Reverse Double Wire Technique loads a guidewire through a sphincterotome while cannulation of the common bile duct is attempted and confirmed using selective contrast injection. The sphincterotome is then withdrawn, leaving the guidewire in the common bile duct. This helps to pull and realign the septum more superiorly. It also straightens the pancreatic duct. The sphincterotome is then reloaded with a second guidewire where cannulation of the pancreatic duct is performed, usually with minimal injury to the pancreatic duct or ampulla.17 Despite its reported success, this technique is hardly ever performed due to the risk of pancreatitis. As a result, most published data is limited to case reports.18 Overall, guidewire cannulation is considered effective and safe with a low rate of adverse events. A meta-analysis involving 12 randomized related adverse events.18 The guidewire, in theory, does not generate significant hydrostatic pressure to induce postERCP pancreatitis, although it can occasionally cause injury to the pancreas, particularly if the guidewire accesses and injures a pancreatic duct side branch. However, under fluoroscopy, the

guidewire can easily be identified and repositioned to minimize this risk. It is important to note that the risk of post-ERCP pancreatitis is higher when the guidewire is forcibly advanced into a side branch of the pancreatic duct and causes trauma. Furthermore, the risk of guidewire perforation is very small.19

Recently, repeated single guidewire cannulation was compared to the double wire technique. Laquiere et al. randomized 142 patients; selective bile duct cannulation was achieved in 57/68 patients (84%) in the early double guidewire group and in 37/74 patients (50%) in the repeated single guidewire group within 10 minutes (relative risk 1.34; 95% confidence interval 1.08-6.18; P < 0.001). The overall final selective bile duct cannulation rate was 99.3%. The time to access the CBD was shorter using the double guidewire technique (6.0 vs. 10.4 minutes; P = 0.002). Mild PEP was not observed more frequently in the double guidewire group than in the repeated single guidewire group, further demonstrating the safety of wire entrance into the pancreatic duct. While the current data show a higher cannulation rate, within a shorter period, ultimately, selecting between both techniques is a matter of endoscopist preference. However, when challenged by difficult cannulations, the endoscopists should be versatile with an extended armamentarium of advanced endoscopic techniques.

Pancreatic Duct Stent Placement

If attempts at biliary cannulation are unsuccessful, endoscopists can consider placement of a pancreatic stent. (Figure 8) This approach has several benefits. First, pancreatic stents reduce the risk of the patient developing post-ERCP pancreatitis by decompressing main and side duct branches of the pancreas. Second, placement of a pancreatic stent reduces the risk of the pancreatic duct being repeatedly cannulated by the guidewire during ongoing cannulation attempts. Third, by having a pancreatic stent in place, the endoscopists can key-in on the angle of the pancreatic duct and, by extrapolation, the common bile duct. This later point is most beneficial in cases of distorted or altered anatomy.

Precut biliary sphincterotomy and associated techniques

The term “precut” refers to the action of performing a sphincterotomy (or “cut”) prior to obtaining deep biliary access (the “pre-”) with a guidewire. The term is often used, both in print and in speech, interchangeably with the term “needleknife sphincterotomy.” In fact, the term “precut” refers rather to a group of high-risk techniques to obtain biliary access if standard maneuvers are unsuccessful. These techniques are collectively termed access sphincterotomy techniques and carry a greater risk of complications. A meta-analysis of seven clinical trials with a total of 1039 patients compared early pre-cut biliary orifice and moving in a cephalad direction. Needle knife sphincterotomy is typically performed when biliary cannulation attempts using less invasive techniques have been tried without success and should be regarded as a relatively highrisk procedure. Because the endoscopist is cutting into the papilla and the duodenal wall without the benefit of a guidewire sphincterotomy vs. persistent attempts at cannulation by standard approach.22 The overall cannulation rate was 90% in the pre-cut sphincterotomy vs. 86.3% in the persistent attempts group (OR = 1.98; 95%CI: 0.70-5.65). The risk of post-ERCP pancreatitis (PEP) was not different between the two groups (3.9% in the pre-cut sphincterotomy vs. 6.1% in the persistent attempts group, OR = 0.58, 95%CI: 0.32-1.05). Similarly, there was no statistically significant difference between the groups for overall complication rate including PEP, cholangitis, bleeding, and perforation (6.2% vs. 6.9%, OR = 0.85, 95%CI: 0.51-1.41).

Needle-knife sphincterotomy

Needle-knife sphincterotomy refers to the use of a catheter capable of delivering electrosurgical current through a wire to directly dissect the major papilla and the intraduodenal portion of the common bile duct to obtain biliary ductal access. (Figure 9) Needle knife sphincterotomy is rarely used to obtain pancreatic access, although it is possible. The standard needle knife design incorporates a bare wire that can be extended through a modified straight biliary cannula. These devices do not have the capability to bow as do most sphincterotomes. The most common way this device is used involves beginning the sphincterotomy at the level of the in the CBD, the true orientation of the duct is, at least in part, unknown during the needle knife sphincterotomy. It should be noted that complication rates from needle-knife sphincterotomy may not necessarily decrease based on the experience of endoscopists. Following 253 consecutive patients undergoing needle knife sphincterotomy by a single endoscopist over a 7.5-year interval, success rate remained high (with the success rate the highest at the end of the study), and overall complication rates (and complication severity) remained similar throughout the study.23 Overall complication rates ranged between 12% and 20% throughout the time blocks of the study and included pancreatitis, bleeding, perforation, among others.

Still, other studies have shown that needle-knife sphincterotomy is not necessarily associated with higher rates of post ERCP pancreatitis. A study of two prospective trials of native papilla cannulation evaluated 732 total patients and included 94 patients undergoing needle-knife sphincterotomy.24 The authors found that an increased number of attempts at cannulation of the papilla were independently associated with post-ERCP pancreatitis. Needleknife sphincterotomy was not an independent predictor of post-ERCP pancreatitis.

Another prospective study also concluded that higher rates of post-ERCP pancreatitis are likely associated with increased number of attempts to cannulate the papilla and were not associated with the precut sphincterotomy itself. This study evaluated patients undergoing ERCP where the endoscopist was unsuccessful at achieving biliary cannulation after 10 minutes.25 Patients were then randomized to an immediate needle-knife sphincterotomy versus a late-access group in which cannulation was then attempted for another 10 minutes (after that point the endoscopist could either perform a precut sphincterotomy or continue attempts at cannulation). The overall incidence of complications between the 2 groups was similar; however, the rate of pancreatitis was higher in the late-access group (14.9% vs. 2.6%, P = 0.008). These studies suggest that higher rates of postERCP pancreatitis are associated with repeated attempts to cannulate the papilla and may not be associated with needle-knife sphincterotomy in and of itself. Some endoscopists may elect to perform prophylactic pancreatic stent placement prior to performing needle knife sphincterotomy in order to use the stent as a guide for the incision and in an attempt to reduce the rate and severity of post ERCP pancreatitis (PEP). A meta-analysis demonstrated that prophylactic pancreatic stent placement significantly reduced the rate of post ERCP pancreatitis. However, if stent placement fails then pancreatitis rates increased by 35-66% in select high risk patients.26

Precut fistulotomy a.k.a. needle knife fistulotomy

Another variation of the needle-knife sphincterotomy technique involves beginning the incision above the level of the ampullary orifice and attempting to cut directly into the CBD via the creation of a biliary fistula; this approach is referred to as precut fistulotomy a.k.a. needle knife fistulotomy. Once the CBD is accessed, a standard sphincterotome can be used to extend the sphincterotomy, if needed, recognizing that a fistulotomy approach may result in a smaller sphincterotomy size overall. A meta-analysis of four prospective studies and three randomized trials showed that using this technique the pooled cannulation success rate was 95.7% (95% CI, 83.1–99.0, P < 0.001), and the rate of post-ERCP pancreatitis was 1.5 % (95% CI, 0.6–3.9, P < 0.001). When compared with conventional wireguided technique, the odds of developing postERCP pancreatitis with pre-cut fistulotomy were 0.22 (95% CI, 0.04–1.04, P = 0.06).

Endoscopic transpancreatic papillary septotomy

The aim of transpancreatic papillary septotomy is to incise the septum between the pancreatic duct and bile duct to expose the bile duct orifice. A standard pull- or traction-type sphincterotome is used with its tip located in the pancreatic duct, but with the endoscope and the sphincterotome oriented for a biliary sphincterotomy. This allows the cut to begin in the pancreatic duct but to traverse the septum between this structure and the CBD, ultimately resulting in biliary access. The technique is typically employed when only pancreatic duct access is obtained during attempts at securing deep biliary access.

In technical terms, transpancreatic sphincterotomy may offer better control of the incision’s depth facilitated by the progressive withdrawal and lateral tension applied to the sphincterotome, thus targeting the common bile duct toward the 11 o’clock position. The intention is to cut across the septum and into the CBD and expose the lumen.27 Endoscopic transpancreatic papillary septotomy is not widely performed at the present time as it is unclear if it offers any significant benefit over standard needle-knife sphincterotomy. Some have concerns about causing pancreatitis or pancreatic ductal injury as well. To this end, results with this technique have been mixed with varying rates of success. A randomized trial comparing transpancreatic biliary septotomy versus the double-guidewire than the two guidewire technique (69.7 % [69/99]; P = 0.01), though similar rates of post procedure pancreatitis (13.5 % vs. 16.2%, P=0.69, respectively).28 The success rates seen with the two wire technique in this study are exceptionally low, making this study somewhat of an outlier and the results difficult to interpret.

Recently, a network meta analysis comparing the efficacy of different strategies for difficult biliary cannulation supported the use of transpancreatic sphincterotomy over persistence with standard cannulation techniques (risk ratio [RR], 1.29; 95% confidence interval [CI], 1.05-1.59) and over any other adjunctive intervention (RR, 1.21 [95% CI, 1.01-1.44] vs. pancreatic guidewire-assisted technique, RR, 1.19 [95% CI, 1.01-1.43] vs. early needle-knife techniques, RR, 1.47 [95% CI, 1.032.10] vs. pancreatic stent-assisted technique) for increasing the success rate of biliary cannulation.29 In addition, both early needle-knife techniques and transpancreatic sphincterotomy led to lower PEP rates as compared with pancreatic guidewireassisted technique (RR, .49 [95% CI, .23-.99] and .53 [95% CI, .30-.92], respectively).

Despite the current data, transpancreatic sphincterotomy is currently used on a limited basis. However, this technique should be considered when attempting difficult biliary cannulation.

Pancreatic duct cannulation

To achieve pancreatic duct cannulation similar techniques and concepts can be applied. In most cases, guidewire cannulation of the pancreatic duct can easily be performed using many of the techniques previously described in this article.

The ideal distance of the duodenoscope from the major papilla is the “middle distance” (2-3 cm). The endoscope should be at or slightly above or at the level of major papilla (as opposed to the bile duct where a “below” the papilla position is favorable). Typically, pancreatic cannulation is obtained with the endoscope oriented more toward the anterior aspect of the duodenum, using less bow on the sphincterotome, and with the lateral ratchet more leftward (anterior) than when performing biliary cannulation. A flatter angle between the sphincterotome and the duodenal wall is often desirable as well, and this can be identified on endoscopic and fluoroscopic views. Guidewire cannulation is the technique least likely to produce hydrostatic overpressure in the pancreatic duct. This may minimize the risk of postERCP pancreatitis and should be considered for pancreatic cannulation, if possible. Dye injection, it should be stated, is not contraindicated and is often helpful in some cases, especially with unusual pancreatic ductal anatomy (pancreas divisum, an ansa loop in the pancreatic head, etc.).

In cases where the anatomy of the pancreatic duct has been altered or the duct is difficult to cannulate, the Reverse Double Wire Technique or the Reverse Two Wire Technique (described above) may be helpful. Other advanced techniques, such as needle knife sphincterotomy, are rarely required for pancreatic duct access but can be considered on a case-by-case basis.

In patients with prior biliary sphincterotomy, the pancreatic duct orifice can sometimes be identified as a separate orifice. In these patients, the pancreatic orifice is seen as a separate opening located below and to the right (as the endoscopist faces the papilla) of the biliary sphincterotomy. However, in some cases it may be more difficult to identify. The orifice may be located within the prior biliary sphincterotomy in a patient with a longcombined sphincter (>10 mm). The endoscopist may find it beneficial to closely examine residual ampullary structures such as mucosal folds before attempting pancreatic cannulation, as the pancreatic orifice may be hidden.

CONCLUSION

The success of an ERCP is dependent on achieving successful cannulation of the desired duct. Anatomical assessment and selection of the proper cannulation technique is critical not only for procedure success but also to reduce the risk of serious adverse events, most notably post-ERCP pancreatitis. Cannulation is a skill that can take a significant amount of time to master; this often requires years of training and practice. Knowledge of available techniques is critical, as one can never know in advance which maneuvers and devices will be required to complete any given ERCP.

References

  1. Kim J. Training in Endoscopy: Endoscopic Retrograde Cholangiopancreatography. Clin Endosc. 2017;50(4):334-339.
  2. Cotton PB. ERCP overview. A 30-year perspective. In: Advanced digestive endoscopy: ERCP., editor. Cotton P, Leung J, editors. Massachusetts: Blackwell Publishing Ltd; 2005. pp. 1–8.
  3. Mashiana HS, Jayaraj M, Mohan BP, et al. Comparison of outcomes for supine vs. prone position ERCP: a systematic review and meta-analysis. Endosc Int Open. 2018;6(11):E1296-301.
  4. Pohl J. Normal Endoscopic Retrograde Cholangiopancreatography. Video Journal and Encyclopedia of GI Endoscopy. 2013;1(2):507-509.
  5. Canard JM, Lennon AM, Létard JC, Etienne J, Okolo P. Endoscopic Retrograde Cholangiopancreatography. Elsevier Churchill liv ingstone; Edinburgh, UK: 2011. pp. 370–465.
  6. Haraldsson E, Kylänpää L, Grönroos J, et al. Macroscopic appearance of the major duodenal papilla influences bile duct cannulation: a prospective multicenter study by the Scandinavian Association for Digestive Endoscopy Study Group for ERCP. Gastrointest Endosc. 2019;90(6):957963.
  7. Kethu SR, Adler DG, Conway JD, et al. ERCP cannulation and sphincterotomy devices. Gastrointest Endosc. 2010;71(3):435-445.
  8. Schwacha H, Allgaier HP, Deibert P, et al. A sphincterotome-based techn ique for selective transpapillary common bile duct cannulation. Gastrointest Endosc. 2000;52(3):387-391.
  9. Cortas GA, Mehta SN, Abraham NS, et al. Selective cannulation of the common bile duct: a prospective randomized trial comparing standard catheters with sphincterotomes. Gastrointest Endosc. 1999;50(6):775-779.
  10. Karamanolis G, Katsikani A, Viazis N, et al. A prospective cross-over study using a sphincterotome and a guidewire to increase the success rate of common bile duct cannulation. World J Gastroenterol. 2005;11(11):1649–1652.
  11. Laasch HU, Tringali A, Wilbraham L, et al. Comparison of standard and steera ble catheters for bile duct cannulation in ERCP. Endoscopy. 2003;35(08):669-674.
  12. Maeda S, Hayashi H, Hosokawa O, et al. Prospective randomized pilot trial of selective biliary cannulation using pancreatic guide-wire placement. Endoscopy. 2003;35(9):721– 724.
  13. Draganov P, Devonshire DA, Cunningham JT. A new technique to assist in difficult bile duct cannulation at the time of endoscopic retrograde cholangiopancreat ography. JSLS. 2005;9(2):218 –221.
  14. Saad M. Biliary cannulation and pancreatic guide– wire placement. Endoscopy 2004;36:743; author reply 743– 4
  15. Ito K, Fujita N, Noda Y, et al. Can pancreatic duct stenting prevent post-ERCP pancreatitis in patients who undergo pancreatic duct guidewire placement for achieving selective biliary cannulation? A pros pective randomized controlled trial. J Gastroenterol 2010;45(11):1183–1191.
  16. Bor R, Madácsy L, Fábián A, et al. Endoscopic retrograde pancreatography: When should we do it? World J Gastrointest Endosc. 2015;7(11):1023– 1031.
  17. Shamah S, Okolo P. Reverse double-wire cannulation of the pancreatic duct. Clin Gastroenterol Hepatol. 2017;15(5):782-783.
  18. Sakai Y, Ishihara T, Tsuyuguchi T, et al. New cannulation method for pancreatic duct cannulationbile duct guidewire-indwelling method. World J Gastrointest Endosc. 2011; 3(11): 231–234.
  19. Tse F, Yuan Y, Moayyedi P, Leontiadis GI. Guidewireassisted cannulation of the common bile duct for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Cochrane Database Syst Rev. 2012;12(12):CD009662.
  20. Enns R, Eloubeidi MA, Mergener K, et al. ERCPrelated perf orations: risk factors and management. Endoscopy. 2002;34(04):293-298.
  21. Laquiere A, Privat J, Jacques J, et al. Early double-guidewire versus repeated single-guidewire tech nique to facilitate selective bile duct cannulation: a randomized controlled trial. Endoscopy. 2022;54(02):120-127.
  22. Navaneethan U, Konjeti R, Venkatesh PG, et al. Early precut sphincterotomy and the risk of endoscopic retrograde cholangiopancreatograp hy related complications: An updated meta-analysis. World J Gastrointest Endosc. 2014;6(5):200-208.
  23. Harewood GC, Baron TH. An assessment of the learning curve for precut biliary sphincterotomy. Am J Gastroenterol. 2002;97(7):1708 –1712.
  24. Bailey AA, Bourke MJ, Kaffes AJ, et al. Needleknife sphincterotomy: factors predicting its use and the relationship with post-ERCP pancreatitis (with video). Gastrointest Endosc. 2010;71(2):266 –271.
  25. Manes G, Di Giorgio P, Repici A, et al. An analysis of the factors associated with the developm ent of complications in patients undergoing precut sphincterotomy: A prospective, controlled, randomized, multicenter study. Am J Gastroenterol 2009; 104(10):2412–2417.
  26. Fan JH, Qian JB, Wang YM, et al. Updated meta-analysis of pancreatic stent placement in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis. World J Gastroenterol. 2015;21(24):7577-7583.
  27. Halttunen J, Keranen I, Udd M. et al. Pancreatic sphincterotomy versus needle knife precut in difficult biliary cannulation. Surg Endosc. 2009; 23(4):745-749.
  28. Kylänpää L, Koskensalo V, Saarela A, et al. Transpancreatic biliary sphincterotomy versus double guidewire in difficult biliary cannulation: a randomized controlled trial. Endoscopy. 2021;53(10):1011-1019.
  29. Facciorusso A, Ramai D, Gkolfakis P, et al. Comparative efficacy of different methods for difficult biliary cann ulation in ERCP: systematic review and network meta-analysis. Gastrointest Endosc. 2022;95(1):60-71.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES # 225

Micronutrients and Gastric Bypass – What We Have Learned

September 2022 • Volume XLVI, Issue 9
Abby Bellows,Kelly O’Donnell

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Bariatric surgery is a leading treatment for severe obesity, yet brings with it the risk for micronutrient deficiencies due to resection of primary absorption sites, reduced intake, and a number of other factors. Micronutrient deficiencies can have serious, sometimes irreversible consequences if left untreated. Clinician education about signs and symptoms of deficiencies, supplementation guidelines, and recommendations for repletion and monitoring is paramount in preventing micronutrient deficiencies and the resulting complications.

CASE STUDY

A 60-year-old male was admitted to our hospital for gastrostomy tube placement into his remnant stomach 14 months after Roux-en-Y gastric bypass (RYGB) due to persistent poor intake, weakness, and a nearly 200-pound weight loss. On average, he consumed less than 500 calories and 20 grams of protein per day and was non-adherent with his vitamin and mineral regimen. Since his surgery, he had become wheelchair-bound because of lower extremity weakness, ataxia, neuropathy, and regular falls. Prior to gastric bypass surgery, he walked independently except on uneven surfaces which required a cane. Given these symptoms and his altered anatomy, several micronutrient deficiencies were suspected including vitamin B12, copper, vitamin E, thiamine, vitamin B6, and niacin.

INTRODUCTION

The prevalence of obesity in adults in the United States was 42.4% in 2017-2018, a notable increase from 30.5% in 1999-2000. Obesity is associated with a number of comorbid medical conditions including heart disease, type 2 diabetes, and stroke, and places a significant burden on the healthcare system.1 Bariatric surgery is recognized as the most effective treatment for severe obesity.2 The number of bariatric surgeries performed each year rises with the increasing prevalence of obesity. In 2019, it is estimated that 256,000 bariatric surgeries were performed in the U.S., 17.8% of which were RYGB.3 It is well established that RYGB places patients at risk for micronutrient deficiencies, and many patients are noncompliant with recommended vitamin/mineral supplementation.4-6 Clinicians must be aware of recommendations for screening, assessment, and treatment of micronutrient deficiencies in RYGB patients. A summary of specific recommendations can be found in tables 1-4. Acute inflammation may affect laboratory data for some micronutrients, details of which are included in the tables for each respective nutrient. Updated Clinical Practice Guidelines were published in 2019 and will hereafter be referred to as “CPGs.”12

Vitamin B12 (Cyanocobalamin)

Vitamin B12 (B12) is necessary for neurological function, growth and development of red blood cells, and DNA synthesis.7 A significant number of patients develop B12 deficiency after RYGB as a result of impaired absorption, decreased oral intake, lack of intrinsic factor, and reduced gastric acid.8,9 Use of certain medications, including metformin, proton pump inhibitors, and H2 receptor antagonists, may increase the risk of B12 deficiency.7

B12 deficiency is associated with dementia, paralysis, and mood disturbance, and if left untreated can result in severe, irreversible neurological complications.7,8,10 Other signs and symptoms of deficiency include megaloblastic and macrocytic anemias, fatigue, numbness and paresthesia in extremities, ataxia, magenta “beefy red” tongue, glossitis, pale skin, and slightly icteric skin and eyes.11

In the first year postoperatively, screening for B12 deficiency is recommended every three months according to the CPGs, followed by yearly screening thereafter or as indicated.11,12 Recommended laboratory assessments are serum vitamin B12 and, in some cases, methylmalonic acid (MMA).10,11,13 Serum B12 may be falsely elevated in the setting of alcoholism, liver disease, and cancer.13 Deficiency may be present even when serum B12 is normal, since serum levels are maintained at the expense of tissue stores.8,11 MMA should be considered in patients with normal or low-normal vitamin B12, macrocytosis, or clinical suspicion for B12 deficiency.13 Elevated MMA can be indicative of B12 deficiency, however, MMA levels are also increased with renal disease, so should therefore be interpreted with caution.8,11

The CPGs recommend routine B12 supplementation for all RYGB patients.12 Patients with deficiency should receive additional supplementation.12 The need for B12 supplementation beyond what is contained in a standard multivitamin is addressed in a systematic review of the literature by Mahawar et al., which showed that oral doses up to 15 mcg daily were insufficient to prevent deficiency. Doses of 600 mcg daily proved superior to 350 mcg daily, and 1000 mcg daily was sufficient to prevent deficiency in most patients.9 Concerning the route of supplementation, there is evidence to suggest that vitamin B12 sufficiency can be maintained with oral supplementation in RYGB patients.8 Regardless of route, it is important to monitor B12 status as vitamin/mineral non-adherence is common.

Vitamin D

Vitamin D is a steroid hormone and nutrient which is involved in bone metabolism as well as a number of other body processes.14 Humans primarily obtain vitamin D through exposure to UVB light, in addition to dietary intake.14,15 A review of the literature by Peterson et al. demonstrates that up to 90% of RYGB patients are vitamin D deficient (<20 ng/mL) in the pre-operative period.14 Many studies indicate ongoing vitamin D deficiency after bariatric surgery, however, some have demonstrated improvement in vitamin D status in the post-operative period purported to result from release of sequestered vitamin D from adipose tissue as patients lose weight. However, this is often followed by high prevalence of deficiency or insufficiency.14-16

RYGB patients may have decreased absorption of vitamin D due to decreased surface area of the small intestine as well as altered mixing with pancreatic secretions and bile. Additionally, risk of vitamin D deficiency may be increased as a result of sequestration of vitamin D in adipose tissue and lack of sun exposure.15

Vitamin D deficiency can result in increased risk of osteopenia and osteoporosis, muscle weakness, falls, and generalized pain and discomfort.15 Symptoms of deficiency may also include hypocalcemia, tetany, tingling, or cramping.11

Literature shows that dosages below 800 IU (20 mcg) of vitamin D3 daily are not sufficient to raise 25(OH)-vitamin D beyond 30 ng/mL in RYGB patients.14,15 Higher doses have proven effective in some patients, but others may require even greater supplementation to maintain optimal serum levels.15,17 The CPGs recommend routine supplementation and continued monitoring of vitamin D status.12 Ongoing dosage should be based on serum levels. Vitamin D3 (cholecalciferol) is the preferred form of vitamin D for supplementation due to its higher potency, according to the CPGs.12 Short term, high dose supplementation is not likely to be a comprehensive solution for vitamin D deficiency in RYGB patients; they will likely need supplemental vitamin D in the long term to maintain optimal serum levels.

Vitamin B1 (Thiamine)

Thiamine is a water-soluble vitamin essential for glucose metabolism, ATP production, and plays a role in maintaining the integrity of the nervous system. When oral intake is reduced, thiamine stores may be consumed quickly (9 to 18 days).18 Thiamine deficiency is a clinical diagnosis and if undetected and untreated, may result in Wernicke-Korsakoff Syndrome.19,20

Recognizing risk factors and early signs and symptoms are the keys to detecting thiamine deficiency. RYGB patients with persistent vomiting are at risk for thiamine deficiency since vomiting precludes adequate intake. In addition, the primary sites of absorption which include the duodenum and first part of  the jejunum are bypassed. These factors, combined with limited storage, may quickly lead to thiamine deficiency after surgery. Rapid weight loss and non-compliance with vitamins are also contributing factors.18,21  

Wernicke’s Encephalopathy (WE) is a neurological disorder caused by thiamine deficiency. Hallmark symptoms include the triad of mental status changes, ataxia, and eye movement disorders. In a recent study of WE after bariatric surgery, ataxia was the most common characteristic found in patients.21 The full triad of symptoms may be seen in an estimated 20-50% of patients with WE.21 In addition, patients may experience paresthesias, peripheral neuropathy, and weakness, usually in the lower extremities.

Thiamine diphosphate, or thiamine pyrophosphate (TPP), is the biologically active form of thiamine. Because TPP is found in erythrocytes and accounts for 90% of thiamine in whole blood, the use of whole blood or erythrocytes to measure thiamine stores is the most sensitive and specific method for testing.22,23 However, given the long turnaround time for lab assays and the acute urgency to treat suspected thiamine deficiency, clinical suspicion and awareness of risk factors should be used to diagnose and treat patients. In addition, there is no thiamine level that correlates with the diagnosis of WE.

The American Society for Metabolic and Bariatric Surgery (ASMBS) treatment for thiamine deficiency depends on the route and severity of symptoms. There is a paucity of scientific data to support recommendations for treatment.12

Vitamin A

Vitamin A is involved in cell growth and development, immune function, vision, and functions as an antioxidant against free radicals.24-26 The prevalence of deficiency in the first 4 years post-RYGB is up to 70%.12 Deficiency commonly presents as night blindness and can result in complete blindness if left untreated.10,12,24 In fact, vitamin A deficiency is the leading preventable cause of blindness.24 Patients deficient in vitamin A may also exhibit Bitot’s spots, hyperkeratinization of the skin, and poor wound healing.11,24 Risk factors for vitamin A deficiency associated with RYGB are decreased intestinal surface area for absorption, decreased overall food intake, and low fat diet in the post-operative period.26 Zinc deficiency, alcohol ingestion, and cholestyramine use can impair vitamin A absorption.24

The CPGs recommend routine supplementation of 5,000-10,000 IU vitamin A daily to prevent deficiency after RYGB, which can be attained with a multivitamin.12,27 It is noteworthy that toxicity can occur with high-dose or chronic supplementation of vitamin A.10

Vitamin E

Vitamin E functions as an antioxidant and plays important roles in neurological health, specifically in the central nervous system.28,29 Vitamin E deficiency is uncommon in bariatric surgery patients in the pre- and post-operative periods.11,12,28

However, RYGB patients may be at increased risk for deficiency due to resection of primary absorption sites, altered mixing with pancreatic and biliary secretions, steatorrhea, or small intestinal bacterial overgrowth.28 In a systematic review of the literature, Sherf-Dagan found deficiency rates of up to 65.7% in 1-5 years after bariatric surgery.28 Signs and symptoms of vitamin E deficiency include spinocerebellar ataxia, peripheral neuropathy, gait disturbances, decreased sensation, ophthalmologic disorders, nystagmus, impaired immune response, and hemolytic anemia.11,28,29 The CPGs recommend supplementation for all bariatric surgery patients, which can be attained with a multivitamin.12 Most supplements provide alpha-tocopherol, which is the most common form of vitamin E in human tissues and is the most biologically active form.28,29 Additional supplementation may be needed to replete deficiency, however therapeutic dosing is not clearly defined.11,12,28 Prompt supplementation of vitamin E can stop progression of, or even normalize, neuromuscular deficits resulting from deficiency.29 High dose vitamin E supplementation (>1000 mg/day) may increase risk for competition with vitamin K and has been associated with hemorrhage.10,30

Vitamin B6 (Pyridoxine)

Vitamin B6 participates in protein and carbohydrate metabolism, gluconeogenesis, and neurotransmitter synthesis.31,32 Factors that may increase the risk for deficiency are alcoholism and use of certain medications, including isonizid (antituberculosis), hydralazine, penicillamine, contraceptives, levo/ carbidopa, and antiepileptic medications.10,31,32

Signs and symptoms of B6 deficiency include seborrheic dermatitis, glossitis, lip and angular cheilitis, impaired immune function, peripheral neuropathy, seizures, and hypochromic microcytic anemia.10,31,32 Pellagra-like symptoms are possible in severe cases, since B6 is necessary for synthesis of nicotinic acid (see Niacin section).31,32

Treatment of deficiency varies within the literature depending on the severity of symptoms. IV supplementation should be considered for patients with severe symptoms, such as seizure.10 Long-term high dose supplementation is associated with sensory neuropathies and movement disorders, among other symptoms, and should be used with caution.10 “Toxic dose” is defined as 1000 mg/day, however there are case reports of neuropathy with lower doses.33,34 The Tolerable Upper Intake Level for vitamin B6 is 100 mg/day for adults.

Vitamin B2 (Riboflavin)

Vitamin B2 is involved in numerous reduction-oxidation reactions as well as the conversion of pyridoxine phosphate to vitamin B6.31,32 The primary absorption site is the proximal small intestine, putting RYGB patients at risk for deficiency.32 Alcoholism and diets low in meat and dairy can put patients at greater risk.31 Symptoms of deficiency include angular and lip cheilitis, glossitis, nasolabial dermatitis, scrotal and vulvar eczema, anemia, and peripheral neuropathy.31,32 The clinical presentation of B2 deficiency may mimic that of B3 or B6 deficiencies due to its role in their metabolism.31 Supplementation recommendations vary, and there is limited data.31,32 Caution should be used with long term supplementation at doses >100 mg/day due to potential effects on the ocular lens proteins and retina.10

Vitamin B3 (Niacin)

Vitamin B3 has essential roles in metabolism including ATP synthesis and glycolysis.31 In a study by Ledoux et al. (2020), B3 deficiency was observed in 13.1% and 19.8% of patients within 1 year and > 3 years, respectively, after RYGB.35 The clinical manifestation of deficiency is pellagra, which is characterized by dermatitis, dementia, diarrhea, and potentially death.10,31

Early symptoms of deficiency include weakness, fatigue, and depression. Physical exam findings may resemble sunburn on the face, neck, and dorsal extremities, hyperpigmented areas on the extremities known as the “glove” and “boot” of pellagra, or hyperpigmented areas on the neck known as Casal’s necklace.31 Additional risk factors for deficiency include alcoholism, use of isoniazid, azathioprine, or 6-mercaptopurine.31

Vitamin C (Ascorbic Acid)

Vitamin C functions as an antioxidant, supports osteoblast formation in bones and teeth, and is essential for the formation of collagen.31,36,37 It is absorbed in the upper third of the intestine, and deficiency has been observed in the RYGB population in both the pre- and post-operative periods.32,35,38 Patients may be at increased risk for deficiency in cases of alcoholism, ulcerative colitis, Crohn’s disease, or dialysis. Smoking also increases risk for deficiency due to decreased intestinal absorption and increased catabolism.31,32 Vitamin C deficiency in its most severe form is scurvy, which is characterized by perifollicular hemorrhages, ecchymosis, petechiae, xerosis, poor wound healing, corkscrew hairs, swan-neck hairs, bleeding gums, fatigue, malaise, and weakness.32,36 If left untreated, vitamin C deficiency can be fatal, therefore supplementation should be started if there is clinical suspicion for deficiency rather than waiting for a lab result to return.37 Upon initiation of therapeutic supplementation, symptoms are expected to resolve quickly, some within the first 24 hours and others taking weeks to months.31,37 It should be noted that high dose vitamin C supplementation can be associated with diarrhea, other GI upset, or falsely elevated blood glucose readings on point-of-care glucose monitors.10,31,39 Absorption of vitamin C decreases with doses over 1 g/day.10

Copper

Copper is an essential trace element that plays a role in neurotransmission, hematopoiesis, hemoglobin synthesis, and the formation of connective tissue. It is primarily absorbed in the stomach and proximal duodenum, placing a gastric bypass patient at risk for deficiency since these sites are reduced or bypassed after surgery.40 Kumar reported on 34 cases of symptomatic copper deficiency occurring an average of 9 years after surgery with 97% of the cases non-compliant with taking multivitamins and minerals.41 

Symptoms of copper deficiency include neurological deficits such as peripheral neuropathy, ataxia, and muscle weakness. Myelopathy and myeloneuropathy seen with copper deficiency closely resemble vitamin B12 deficiency. Symptoms may also include anemia and/or neutropenia. Optic neuropathy and blindness as a result of copper deficiency have also been reported.42-45 To diagnose a deficiency, serum copper levels are used. Another marker often used is ceruloplasmin, a protein that transports 80-95%

of copper. It is, however, an acute phase protein that increases during inflammation which in turn leads to an elevated serum copper level. To diagnose deficiency, one author recommends using serum copper, ceruloplasmin < 20 mg/dL, and elevated C-reactive protein.42 An MRI showing increased T2 signal in the posterior dorsal column of the spinal cord may enhance lab data when determining a diagnosis.40  

Other than case studies, little scientific evidence is available on the route, amount, or timing of copper supplementation. Supplementation halts the progression of neurological deficits, but may not reverse them. It usually takes 4-12 weeks for hematologic consequences of copper deficiency to resolve.40,42,46 Several strategies and guidelines for replacement of copper are available.41,42,47 Copper levels should be checked periodically after levels return to normal and supplementation stops since cases of relapse have been reported.12

Zinc

Zinc is a mineral that plays a role in DNA and protein synthesis, immune function, wound healing, and more than 300 enzyme systems. It is primarily absorbed in the duodenum and proximal jejunum which may lead to a deficiency since these areas are bypassed after RYGB. Poor intake and non-compliance with vitamins and minerals may also contribute. Symptoms of deficiency include alopecia, taste changes, white spots on the nails, dermatitis, skin plaques and diarrhea.48

In a recent summary, only 6 cases of symptomatic zinc deficiency were found in the literature.  On average, patients became symptomatic 6 years after surgery, 67% were female, and all had a skin rash.  Information on vitamin compliance was available for 2 patients; one had stopped taking

her supplement, and the other was compliant.48

Since it is a component of various proteins and nucleic acids, zinc levels are difficult to measure. Plasma or serum levels are often used, but levels do not necessarily reflect cellular zinc due to tight homeostatic control. Also, clinical signs can be present in the absence of abnormal laboratory indices. Some suggest pairing clinical correlation with lab values and risk factors to aid in the diagnosis of a deficiency.10,49 ASMBS guidelines do not issue a recommendation due to insufficient evidence, however, they advise caution when repleting zinc as it can induce a copper deficiency over time. Excess amounts of enteral zinc may cause nausea, vomiting, and gastric irritation. Skin lesions usually improve within days to weeks of supplementation.10,50-53

A Word about Iron

Iron deficiency is the leading cause of anemia after RYGB. Factors contributing to this include decreased hydrochloric acid production in the gastric pouch, decreased meat consumption, and bypassing the duodenum and jejunum which are the primary sites of absorption.54 Iron deficiency may occur despite routine supplementation and should be monitored within 3 months after surgery followed by every 3 to 6 months for the first year and then annually thereafter unless clinical signs and symptoms of deficiency are present.12 Adherence to supplementation may be affected by side effects which can include constipation, nausea, vomiting and a metallic taste.10 Many oral iron preparations are available, but none have been shown superior to ferrous sulfate. A recent article suggests absorption of oral iron improves when taken on alternate days in single doses versus daily or twice daily in healthy women with depleted iron stores.55

CASE STUDY CONCLUSION

A serum copper level was drawn and found to be low at 57 mcg/dL (normal 75-145 mcg/dL). The patient was anemic, but not neutropenic. He was treated with 2 mg/d oral copper gluconate. He also received 0.5 mg of copper in his multivitamin and 1.92 mg in his tube feeding for a total of 4.42 mg/d copper. Copper levels returned to normal 1.5 months after supplementation began. In addition, the patient did not experience any more falls after initiation of both copper supplementation and tube feeding. His ambulation improved to the point that he was able to walk using a cane, but remained wheelchair-dependent outside of the home. Copper levels continued to rise, and supplementation was discontinued after 7 months as the patient’s ability to ambulate without falls remained stable. Levels were checked regularly every 3 months thereafter.

SUMMARY

It is well documented that patients who have undergone RYGB are at risk for micronutrient deficiencies. There is a paucity of data regarding the treatment of micronutrient deficiencies in the RYGB population, and most evidence to date comes from case studies rather than RCTs. Clinicians should be aware of signs and symptoms of micronutrient deficiencies as they collect a detailed patient history and perform a physical exam. Adherence to vitamin and mineral supplementation should be assessed. It should also be noted that micronutrient deficiencies rarely exist in isolation; if a patient presents with one deficiency, there are likely others. Lastly, vitamin and mineral supplementation is not benign and should be monitored and adjusted as clinically appropriate.

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  25. Jalilvand A, Blaszczak A, Needleman B, et al. Vitamin A deficiency in patients undergoing sleeve gastrectomy and gastric bypass: a 2-year, single-center review. J Laparoendosc Adv Surg Tech A. 2020;30(1):20-30.
  26. Pereira S, Saboya C, Chaves G, et al. Class III obesity and its relationship with the nutritional status of vitamin A in pre- and postoperative gastric bypass. Obes Surg. 2009;19(6):738-44.
  27. Pereira S, Saboya C, Ramalho A. Impact of different protocols of nutritional supplements on the status of vitamin A in class III obese patients after Roux-en-Y gastric bypass. Obes Surg. 2013;23(8):1244-51.
  28. Sherf-Dagan S, Buch A, Ben-Porat T, et al. Vitamin E status among bariatric surgery patients: a systematic review. Surg Obes Relat Dis. 2021;17(4):816-830.
  29. Ulatowski LM, Manor D. Vitamin E and neurodegeneration. Neurobiol Dis. 2015;84:78-83.
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  36. Nosewicz J, Spaccarelli N, Roberts KM, et al. The epidemiology, impact, and diagnosis of micronutrient nutritional dermatoses part 1: Zinc, selenium, copper, vitamin A, and vitamin C. J Am Acad Dermatol. 2022;86(2):267-278.
  37. Byard RW, Maxwell-Stewart H. Scurvy-characteristic features and forensic issues. Am J Forensic Med Pathol. 2019;40(1):43-46.
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  44. Pineles SL, Wilson CA, Balcer LJ, et al. Combined optic neuropathy and myelopathy secondary to copper deficiency. Surv Ophthalmol. 2010;55(4):386-92.
  45. Naismith RT, Shepherd JB, Weihl CC, et al. Acute and bilateral blindness due to optic neuropathy associated with copper deficiency. Arch Neurol. 2009;66(8):1025-7.
  46. Myint ZW, Oo TH, Thein KZ, et al. Copper deficiency anemia: review article. Ann Hematol. 2018;97(9):1527-1534.
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FUNDAMENTALS OF ERCP, SERIES #1

Indications for ERCP

September 2022 • Volume XLVI, Issue 9
James K. Stone,Douglas Pleskow

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Key Points:
• Indications and contraindications for ERCP are various and appropriate patient selection requires careful consideration
• As our understanding of how ERCP is utilized continues to evolve, it is important to continue analyzing outcomes of the procedure to target those who will continue to benefit the most
• Expert endoscopists must be well-versed in special cases requiring ERCP to provide necessary required care to specific patient populations

INTRODUCTION

Endoscopic retrograde cholangiopancreatography (ERCP) was first introduced in the 1970’s as a tool for visualization of the ampulla of Vater. Using a specialized endoscope with a side viewing camera that allows for optimal visualization within the duodenum, ERCP has grown from a diagnostic to a therapeutic modality for pancreaticobiliary diseases. Modifications on the endoscope have been made to assist with therapeutic maneuvers. Modern duodenoscopes are equipped with a large instrument channel and small metal elevator at the end of the channel that allows for various tools to be directed towards the papilla and manipulated within the bile or pancreatic duct, making ERCP the gold standard modality for diagnosis and management of pancreaticobiliary diseases.

There are numerous indications for a patient to undergo ERCP, including both pancreatic and biliary pathologies. ERCP allows for both diagnostic and therapeutic management of pancreaticobiliary disease; however, there are considerable risks associated with ERCP. Therefore, patients must be carefully selected to ensure that they will benefit most from the procedure. This article will outline the most common indications and contraindications for ERCP, including; 1. Who needs and does not need ERCP, 2. When to safely and effectively perform the procedure, and 3. When not to perform the procedure. In addition, we will address special considerations surrounding ERCP, including ERCP in pregnancy, the elderly, those on systemic anticoagulation/antiplatelet therapy or with multi-drug resistant (MDR) infections, and those with allergies to contrast dye.

Indications for ERCP

The indications for performing ERCP will be outlined in this section and a summary of these can be found in Table 1. As radiologic imaging is often the first investigation in the workup of abnormal blood tests or presenting symptoms, this chapter will outline the specific diagnoses that require ERCP in greater detail, focusing on information that is important to the clinician who performs the procedure. For the following scenarios, ERCP is used to diagnose, treat, or facilitate various investigations of the pancreaticobiliary system.

1. Choledocholithiasis

Gallstone disease remains one of the most common gastrointestinal diseases worldwide, with a reported prevalence of 10% in adults, and remains the most common indication for ERCP.1,2 While most gallstones will be asymptomatic, 2-4% of those with gallstone disease will develop symptoms, of which 20% will become impacted within the bile duct and require intervention.2 The 2020 ASGE Guidelines on the role of endoscopy in the evaluation and management of choledocholithiasis states the diagnosis of choledocholithiasis should be made with either MRCP or EUS to confirm the presence of common bile duct stones, although in practice these investigations are not warranted in all patients before undergoing ERCP. These modalities have comparable sensitivity (93% in MRCP; 95% in EUS) and specificity (96% in MRCP; 97% in EUS) at low, intermediate and high pre-test probabilities.3

ERCP should be reserved for the therapeutic management of confirmed or high likelihood of choledocholithiasis, defined by the ASGE as a common bile duct stone on imaging, total bilirubin of >4mg/dl and a dilated bile duct, or physical and lab findings suggestive of ascending cholangitis.4 Biliary cannulation should be followed by sphincterotomy (unless contraindicated), stone removal through biliary balloon sweep, wire guided baskets or electrohydraulic lithotripsy (EHL), laser lithotripsy, or mechanical lithotripsy as needed.

Mirizzi’s syndrome is an uncommon clinical scenario that was first described by Pablo Luis Mirizzi, an Argentinian surgeon who first described the entity in 1948. Mirizzi syndrome occurs in approximately 1% of those undergoing cholecystectomy.5,6 Mirizzi’s syndrome occurs when a gallstone becomes impacted in the cystic duct, gallbladder neck or infundibulum and results in direct biliary compression of the common bile or hepatic duct (Type I Mirizzi’s syndrome). The formation of a cholecystocholedochal fistula (Type II Mirizzi’s syndrome) is due to the erosion of a gallstone directly into the common duct.5 While surgery is ultimately required in the management of patients with Mirizzi’s syndrome, there remains a role for ERCP with biliary stenting in the acute setting in these patients.4 ERCP with EHL for management of Mirizzi’s syndrome has also been studied, with success rates as high as 96% in one large longitudinal Japanese study, however this success was limited by a 16% recurrence rate.7 Current expert consensus recommends consideration of ERCP for biliary stenting in acute cholangitis as a bridge to cholecystectomy in Mirizzi’s syndrome, with consideration of ERCP with EHL in poor surgical candidates or those with Type II disease.5,7,8 Preoperative stenting in patients with Mirizzi syndrome can also aid surgeons during operative correction, as it allows clear identification of the common bile duct lumen.

2. Gallstone pancreatitis

Gallstone disease is the most common cause of pancreatitis with a reported prevalence ranging from 40-70%.9 Gallstone pancreatitis occurs from pancreatic ductal outflow obstruction secondary to retained stone(s) within the common channel or impacted (or temporarily impacted) stone(s) at the level of the ampulla.10 Over the years, the management of gallstone pancreatitis has evolved from early intervention to a more conservative approach.4 A 2012 Cochrane review including 7

RCT’s comparing early versus late ERCP on mortality, local and systemic complications in uncomplicated gallstone pancreatitis found no reported difference between groups. A significant reduction in all-cause mortality, local and systemic complications was seen in those with subsequent cholangitis, while a reduction in local inflammation was seen in those with subsequent biliary obstruction in the early ERCP intervention groups.11 A 2022 systematic review of 3 RCT’s and 1 non-randomized trial on early ERCP showed no reduction in mortality or complications in gallstone pancreatitis without cholangitis.12 Current gastroenterology guidelines agree on recommending against the use of routine ERCP in gallstone pancreatitis in the absence of biliary obstruction or cholangitis.9,12,13 If ERCP is undertaken during an episode of gallstone pancreatitis, the endoscopist has the option of performing biliary sphincterotomy and clearing the duct or simply placing a biliary stent to allow ductal decompression, with a plan to return at a later date once the pancreatitis has resolved to undergo duct clearance. Multidisciplinary consultation with both an advanced endoscopist and general surgeon is important in the management of these patients. While interval cholecystectomy used to be the standard of care, same-admission cholecystectomy has now been shown to reduce the risk of recurrent pancreatitis, readmission for biliary complications and all cause mortality.14,15 Still, same-admission cholecystectomy has not been universally adopted by the surgical community. Surgical consultation for inpatient cholecystectomy should be arranged in all patients presenting with gallstone pancreatitis. It is prudent for the endoscopist to be aware of this and potentially recommend this when consulted for potential ERCP, even in the absence of performing the procedure.

3. Cholangitis

The findings of a jaundiced patient presenting with fevers and right upper quadrant pain (Charcot’s triad) should raise the suspicion of cholangitis, with an even higher index of suspicion when hypotension and altered mental status (Reynold’s pentad) are concomitantly present. A diagnosis of cholangitis should be made promptly through clinical history, physical examination, laboratory results and imaging studies, which are all included in the 2018 Tokyo Guidelines diagnostic criteria for acute cholangitis (Table 416). ERCP for biliary decompression has been shown to have a significant mortality benefit in this patient population by providing relief of biliary obstruction and drainage of the infected biliary tree, however studies on the exact timing of ERCP in patients with cholangitis have shown conflicting results.16–22 More recently, studies have favored more urgent ERCP, however the exact definition of urgency is variable amongst studies and opinions on this question vary widely in clinical practice. One recent meta-analysis of 9 studies showed a 20% decrease for in-hospital mortality among those undergoing ERCP within 24 hours as compared to those undergoing ERCP ≥24 hours (OR 0.81, 95% CI 0.73-0.90). In-hospital mortality was also reduced when comparing those who underwent ERCP within 48 hours versus after 48 hours, and within 72 hours versus after 72 hours.18 Another large meta-analysis and systematic review examining mortality benefit in those undergoing ERCP within 48 hours showed significant reduction of in-hospital mortality, length of stay and 30-day mortality.17 Other large-scale studies have also reduced mortality and length of stay.19–21 One recent study examining outcomes in non-severe acute cholangitis using a 12-hour emergent cutoff showed no difference in in-hospital mortality, length of stay or recurrent cholangitis when compared to elective (≥24 hr) ERCP. The majority of these cases would fall under “emergent” in other studies, with only 4.7% performed ≥72 hours after presentation.22 While the data remains clear that ERCP within 24-48 hours provides improved outcomes, further randomized control trials are necessary to determine whether ERCP within 24 hours significantly improves outcomes as compared to those performed after 24 hours. It should be emphasized that the reasons for potentially delaying ERCP in patients with cholangitis include the need for patient stabilization, fluid resuscitation, and antibiotic administration: all of these make patients better candidates for ERCP when the time for the procedure arrives.

4. Bile leaks

ERCP is considered first line therapy in the management of bile duct leaks (BDLs).8,23 Endoscopic placement of a bile duct stent with or without sphincterotomy reduces transpapillary pressure, corrects the pressure gradient in the biliary tree, and allows adequate bile drainage down to the duodenum. ERCP plays an important diagnostic and therapeutic role in BDL by localizing the site of the bile leak and providing therapeutic decompression of the bile duct (thus markedly reducing the flow of bile out of the leak site, and promoting healing at the leak site itself). BDLs often occur at the cystic duct, the ducts of Luschka, the common bile duct, and less commonly the common hepatic duct, although they can develop anywhere in the bile duct in a variety of contexts.

BDLs are classified as low or high grade based on cholangiogram interpretation.8,23 Low grade bile leaks are only visualized once the intrahepatic bile ducts have been filled, while high grade bile leaks show active extravasation before intrahepatic bile duct filling occurs.8 In practice, these definitions are often less than helpful, and the leak is often graded somewhat subjectively. When a bile leak is suspected or confirmed on cholangiogram, endoscopic biliary stenting and/or sphincterotomy is recommended with success rates ranging from 80-100%.8 The adequate timing of ERCP in bile leaks is not guideline based and remains up for debate, however prior studies have not shown a difference in outcomes when comparing early (<1 day) versus late (>3 days) intervention.23 As long as the bile leak is identified and a functioning drain (e.g., Jackson-Pratt drain) has been placed, then ERCP can be performed non-urgently. Routine practice is to maintain a biliary stent in situ for 4-6 weeks, after which a repeat ERCP for stent removal and re-evaluation of the biliary tree with contrast cholangiogram is performed. If the leak has healed, the stent can be removed and not replaced. If the leak persists, a new stent is placed and the ERCP repeated another 4-6 weeks later.

5. Biliary strictures

ERCP is the gold standard for assessing, diagnosing, and managing biliary strictures. Biliary strictures can present a variety of ways, including asymptomatic obstructive jaundice, symptomatic abdominal pain, or incidentally on abdominal imaging. Biliary strictures can be benign, malignant, or indeterminate, and can be caused by abnormalities of both the biliary tree and pancreas. ERCP is unique as it facilitates access into the bile duct and has the ability to assess a stricture through a cholangiogram and/or cholangioscopy. Tissue sampling can be obtained with cytology brushing or biopsy forceps into the duct. The various etiologies and advanced workup of biliary strictures are outside the scope of this review.

6. Ampullary adenomas and tumors

The role of endoscopy and ERCP in the diagnosis and management of ampullary tumors has been outlined by both the ASGE in 2016 and more recently the ESGE in 2021.24,25 Ampullary tumors should be examined using a side viewing duodenoscope and are usually, but not always, biopsy proven prior to consideration of resection.24,25 EUS and MRCP are often used to further stage these lesions and determine the extent of invasion into the intrapancreatic bile duct and pancreatic head.25 While some suggest that when low-grade dysplasia is confirmed on two separate biopsies, or high-grade dysplasia on one set of biopsies, ampullectomy should be performed in tumors measuring ≤30mm in diameter without intraductal resection, others have used less firm criteria and make the decision to resect on an individualized basis. A single RCT argues against the routine use of submucosal injection for ampullectomy, although in practice the maneuver is widely performed. No difference in tumor recurrence, delayed bleeding or complete resection rate was noted when the maneuver was used or dispensed with.25,26 Both guidelines recommend prophylactic placement of a pancreatic duct stent to reduce the incidence of post-ERCP pancreatitis. The routine use of biliary stenting, and biliary or pancreatic sphincterotomy is no longer universally recommended but in practice remain widely employed.25

7. Cholangiopancreatoscopy

Direct visualization of the bile and pancreatic duct through cholangiopancreatoscopy has advanced the management of large biliary and pancreatic duct stones and increased the diagnostic yield of intraductal tissue sampling of indeterminant strictures.27 The use of cholangioscopy with electrohydraulic lithotripsy (EHL) or laser lithotripsy (LL) for the management of difficult to treat and/or large bile duct stones has been shown to have excellent results. Reported stone visualization and fragmentation rates have been reported to be as high as 92%, with complete stone clearance rates in a single session of 71%.28 Additional studies have reported complete bile duct stone clearance ranging from 71 to 100%.27 While the data on pancreatoscopy for stone management is less robust, stone clearance success rates have been reported from 50 to 100% in several case series.27 A 10-year retrospective analysis on 46 patients undergoing EHL/LL for pancreatic duct stones reported complete clearance in 70% of patients, with clinical success (as defined by reduction in pain scores and opioid use) in 74% of patients.29

Direct cholangioscopy is an important tool in the workup of indeterminate strictures.30 Across 10 studies, the pooled sensitivity for diagnosis of malignancy strictures was 60.1% with a pooled specificity of 98.0%. Results of this meta-analysis strongly support the use of cholangioscopy in strictures with negative or inconclusive brushings, with a sensitivity of 74.7% and specificity of 93.3% in 4 studies that examined this clinical scenario.30

8. Sphincter of Oddi dysfunction (Type I and II)

The role of ERCP in the management of Sphincter of Oddi dysfunction (SOD) is controversial in the literature, as is the very existence of the concept of SOD as a clinical entity itself (which many still do not believe exists, and not without good reason). Historically, ERCP with sphincterotomy was recommended for those with Type I SOD (biliary-type pain, bile duct dilation and liver enzyme elevation), with consideration for those with Type II (pain with either biliary dilation or elevation in liver enzymes) and Type III (pain alone in the absence no biliary dilation or liver enzyme elevation).31 Type I SOD is accepted in some circles as an organic papillary stenosis and ERCP with sphincterotomy is appropriate, although even the concept of papillary stenosis is debatable.8,31 There have been three RCT’s showing benefit of empiric sphincterotomy in those with Type II SOD with certain manometric findings, however routine practice often manages these patients similar to Type I SOD, and thus investigation with manometry is not often used in the clinical setting.31 The biggest deviation from our prior approach to SOD is seen in Type III SOD, for which current expert consensus recommends against the use of ERCP, as described in further detail below (See “Who does not need ERCP”). Similarly, the global acceptance of SOD as a concept, and the number of ERCPs performed for presumed SOD annually, has fallen precipitously.

9. Choledochal cysts

Choledochal cysts are rare congenital cystic dilations of the common and intrahepatic bile ducts, with a higher incidence in Asian (1 in 13000 Japanese) than Western populations (1 in 1,000,000-2,000,000 in England).32 Choledochal cysts can present with abdominal pain, jaundice and, rarely, a palpable mass. These biliary cysts have been shown to increase the risk of recurrent cholangitis, pancreatitis, cirrhosis, gall bladder and bile duct malignancy.32,33 These cysts are often associated with anomalous pancreaticobiliary duct junction (APBDJ) and are classified using the Todani classification system, which classifies cysts based on the number and location of cysts within the biliary tree.34 Type I (segmental or diffuse dilation of the common bile duct), Type II (common bile duct diverticulum), Type IV (multiple intra and/or extrahepatic cysts) and Type V (single or multiple intrahepatic cysts) cysts are managed operatively, with cyst excision and hepaticojejunostomy for Type I, diverticulotomy for Type II and hepatectomy or transplant for Type IV and V.32,33 Cystolithiasis and cholangitis may occur in these patients, and, while operative management is the gold standard, ERCP for stone removal and/or stenting may be indicated to manage these acute events.32,33 Type III choledochal cysts (also termed choledochoceles) occupy the intra-duodenal portion of the CBD and are rare, accounting for only 0.5-4% of all choledochal cysts.32 These cysts have a lower risk of malignancy and association with APBDJ, and therefore Type III cysts are the only ones that are primarily managed endoscopically with biliary sphincterotomy or needle knife papillotomy.32,33 Type III choledochal cysts ≥2cm should be referred to a surgeon for consideration of transduodenal excision or pancreaticoduodenectomy, although the risk of malignancy, even in these large cysts, remains low.32

Contraindications to ERCP

1. Consent

There are few absolute contraindications to ERCP, one of which is lack of patient consent outside of emergent situations wherein consent cannot be obtained i.e. septic cholangitis with an altered mental status. ERCP should not be performed in patients who do not consent to the procedure, as is expected standard practice in all medical fields. The risks associated with ERCP should be carefully discussed with each patient so as they may make an informed decision. Common complications including pancreatitis, infection, perforation, bleeding, the possibility of death and risks of undergoing conscious sedation/anesthesia should be discussed. 

2. Active or recent perforation

Active perforation of the oropharynx, esophagus, stomach or bowel is, in general, a contraindication to ERCP given the risk of worsening pneumomediastinum and/or pneumoperitoneum. Multidisciplinary discussion with surgical teams should be had if ERCP is indicated in a patient who has recently had a perforation and been managed either surgically or supportively in order to determine the timing and urgency of endoscopy.

3. Hemodynamic instability

ERCP should not be performed in critically ill patients who are inadequately resuscitated with ongoing hemodynamic instability. Critically ill patients requiring hemodynamic support in an intensive care setting that require biliary drainage should be discussed and managed in collaboration with an intensivist and anesthesiologist, if at all possible. Percutaneous trans-biliary drainage (PTBD) should be considered in these patients if ERCP is not feasible or there is reason to believe may not be successful, including imaging findings of gastric outlet obstruction from a pancreatic mass, prior failed ERCP that is not expected to be successful on subsequent attempts, history of gastric surgery that would preclude ERCP or upper gastrointestinal luminal strictures that would prevent ERCP from being accomplished.

4. Uncorrected coagulopathy

Uncorrected coagulopathy remains a relative contraindication to ERCP. Sphincterotomy should not be performed in patients on anticoagulation, non-ASA antiplatelet therapy, or with a significantly elevated INR or severe thrombocytopenia. ERCP may be considered in patients requiring biliary decompression with stenting and no sphincterotomy, even in the aforementioned scenarios. Of note, if sphincterotomy is not planned, ERCP can be safely performed in a variety of coagulopathic settings.

Who Does Not Need ERCP

1. Type III Sphincter of Oddi dysfunction

As outlined above, the role of ERCP in the management of SOD has been, and remains, controversial. While there is evidence to support its use in patients with Type I SOD, there is less supportive data for performing ERCP in patients with Type II SOD. The use of ERCP in patients with Type III SOD has been shown to be more harmful than beneficial. This shift resulted after the findings of the EPISOD trial were published in 2014. In this double-blind, sham controlled RCT of 141 patients with Type III SOD randomized 2:1 to empiric sphincterotomy versus sham, no improvement in pain related disability was seen after intervention was reported, and in fact pain-free outcomes favored the sham group with statistical significance.35 As a result of these findings, current expert consensus recommends against the use of ERCP with sphincterotomy in this patient subgroup.8,31 It should be stressed that the entire concept of SOD as a disease entity remains in question and many centers have abandoned the notion of SOD entirely.

2. Abdominal pain diagnosis

The ASGE Quality Indicators in ERCP recommends against ERCP for the evaluation of abdominal pain without evidence of pancreaticobiliary pathology (e.g., abnormal bloodwork or imaging studies) due to the low diagnostic yield and risk of adverse events or complications. Prior to proceeding to ERCP for abdominal pain, a thorough workup including basic liver enzyme and function tests, lipase, complete blood count, and pancreaticobiliary imaging (in the form of transabdominal or endoscopic ultrasound, CT or MRCP) should be performed. If there are no abnormalities seen on these investigations as outlined in the above indications, ERCP may not be in the patient’s best interest.

3. Pancreas divisum

Pancreas divisum (PD) is the most common congenital abnormality of the pancreas and results from failure of the ventral and dorsal pancreatic duct to fuse during early embryonic gestation.36 It should be emphasized that PD is not a disease, but rather a variant of normal anatomy. PD has a reported prevalence between 1-10% and has been associated with idiopathic recurrent acute pancreatitis. The association between PD and idiopathic recurrent acute pancreatitis (IRAP) remains controversial as the majority of patients with PD remain asymptomatic, with only 10% developing pancreatitis. A somewhat more accepted theory is that PD in combination with a predisposing genetic mutation (e.g., CFTR gene mutation) is required to increase the risk of IRAP.37 The use of ERCP with minor papillotomy has been studied in preventing IRAP in PD in a number of retrospective and prospective trials, with heterogenous results suggesting a modest benefit.36–38 One systematic review examining IRAP in PD reported a pooled median response rate of 76%, with a range of 44100%.36 A more recent retrospective cohort study reported a response rate at the lower end of the pooled analysis (44.4%), with even lower rates in those with chronic pancreatitis (33.3%) and chronic pancreatic like abdominal pain (33.3%).39 ERCP with minor papilla sphincterotomy can be considered in select patients with IRAP and PD, especially in the context of a dilated pancreatic duct. The SHARP (SpHincterotomy for Acute Recurrent Pancreatitis) trial is currently underway and will be the first large, multicenter RCT investigating minor papilla sphincterotomy for IRAP in PD.40 The results of this randomized trial will likely shape the future approach and recommendations to endoscopic therapy of IRAP in those with PD.

4. Management of pancreatic pseudocysts

Transpapillary pancreatic ductal stenting was once the recommended approach to treating complications from acute pancreatitis such as peripancreatic collections, alongside transmural pseudocyst drainage.41,42 With the development of a lumen-apposing metal stent (LAMS), EUS directed trans-gastric drainage of these cysts has become the standard of care and the role of ERCP in the drainage of pancreatic fluid collections has become limited. Two recent studies showed no reduction in the re-accumulation of pancreatic fluid collections via ERCP after transmural plastic stent placement post-LAMS drainage, bringing into question the utility of plastic stent placement after LAMS removal. The more conventional ERCP approach of transpapillary PD stenting is still performed, but less commonly so and with limited data on its use in the age of cyst-gastrostomy with LAMS. Transpapillary stenting can still be used to treat pancreatic fluid collections not amenable to transluminal drainage or in patients with a LAMS in place who desire additional drainage. It should be noted that transampullary stenting may not always provide direct decompression of pancreatic fluid collections but rather may decompress the pancreatic ductal system and reduce backfilling of the collection itself, thus promoting resolution.

Special Cases

There are certain clinical scenarios in which the role of ERCP warrants special attention. These include, but are not limited to, ERCP in pregnancy, the elderly, those on therapeutic anticoagulation or antiplatelet agents, those with history of recurrent cholangitis and multi-drug resistant (MDR) infection, and those with contrast allergy.

Pregnancy

The need for ERCP in pregnancy is a rare occurrence, most commonly for the management of symptomatic choledocholithiasis, which occurs in only 0.1% of pregnancies (despite cholelithiasis occurring at a rate of 12%).43 Management of the pregnant patient requiring ERCP requires knowledge and technical skill, as pregnancy has been shown to be an independent risk factor in postERCP complications, increasing the risk of postERCP pancreatitis 2.8-fold. While tertiary center experience has also been shown to be a protective factor in reducing post-ERCP pancreatitis, in practice ERCP is often safely performed in pregnant patients in a variety of clinical settings.43 A metaanalysis of 1307 pregnant patients undergoing ERCP reported adverse event rates of 15.9% and compared these events, as well as fetal outcomes, between radiation and non-radiation ERCP. There were no reported differences in fetal outcomes or pregnancy-related adverse events between radiation groups.44 To date, evidence supports the safety of ERCP in pregnant patients, however careful attention should be paid to the increased

risk of post-ERCP pancreatitis in this population. in pregnant patients. Some states require shielding Fortunately, this does not appear to correlate with of pregnant patients based upon the assumption adverse fetal outcomes. that shielding the fetus during ERCP would help

      Radiation safety is crucial in performing ERCP   to potentially decrease the dose of radiation to the fetus. However, many of the current fluoroscopy units that are commercially available will perceive the presence of lead shielding and increase the amount of radiation during the case to compensate. Many modern X-ray imaging systems use automatic exposure control, and the presence of shielding in the imaging field of view can drastically increase X-ray output, increasing patient radiation dose and degrading image quality.45,46 Thus, paradoxically, the shielding increases the dose. By collimating to the area of interest, there is minimal dose to the areas outside of the field. Utilizing the low frame rate on fluoroscopy units will also lower the radiation dose to the mother and the fetus.

Geriatric patients

The outcomes and success rates for elderly patients undergoing ERCP are important factors for the endoscopist to understand given the high prevalence of elderly patients with pancreaticobiliary diseases. Choledocholithiasis has been reported as the most common indication for ERCP in this population, accounting for 23-56.1% of ERCP’s.47–49 Variably commonly defined as those 65-80 years of age or older, elderly patients have been reported to have low rates of post-ERCP pancreatitis, ranging from 0.1 to 1.7%.47–49 While similar rates of overall adverse outcomes (including infection and mortality) have been reported, sedation-related complications have been shown to be higher among the elderly in one study (3.4% vs. 0.5%). Even among patients with acute cholangitis from common bile duct stones, there was no difference in the use of ERCP (68.8% versus 58%) or mortality in the elderly versus the non-elderly, respectively. While difficult cannulation has been shown to be a risk-factor for post-ERCP pancreatitis, a difference in difficult cannulation between elderly and non-elderly patients has not been shown and success rates in this population remain high.47 Overall, ERCP is safe and beneficial in this patient population, and advanced age should not preclude the adoption of ERCP.

Antithrombotics

Patients on anticoagulants and antiplatelet therapies commonly require ERCP. The ASGE Guideline on the management of antithrombotic agents for patients undergoing GI endoscopy divides GI procedures into low and high risk, with ERCP falling into both the “low risk” (stent placement or papillary balloon dilation without sphincterotomy) and “high risk” (biliary or pancreatic sphincterotomy) categories.50 Multidisciplinary discussion should be had prior to stopping anticoagulants or antiplatelet therapy and this decision should be based on the indication and potential risks of cessation (e.g. recent cardiac catheterization with percutaneous coronary intervention, recent deep vein or pulmonary thromboembolism, high CHADS2 stroke risk, etc.). Table 5 outlines the duration for which the most common anticoagulants and antiplatelet medications should be held prior to ERCP, and the timing of restarting these medications postprocedurally, recognizing that in many cases recommendations should be individualized. Special attention should be made to the indication and thrombotic risk of stopping these medications, as well as the risk of post-procedural bleeding when continuing or restarting them. A perfect decision cannot be made in all cases, and some patients will experience bleeding or thrombotic events even in the hands of the most deliberative endoscopist.

Multi-drug resistance (MDR) infection

The risk of infection following ERCP is low, with reports ranging from 0.8-1.4% in two large studies.51,52 Transmission of MDR organisms (eg. Carbamenem-resistant enterobacteriaceae) attributed to colonized duodenoscopes was first reported in the United States in 2013, and since that time there has been a significant interest in duodenoscope-related infection control.53,54 In several studies, despite satisfactory reprocessing techniques using high-level disinfection (HLD), CRE organisms were still implicated among patient infections and were thought to potentially result from colonization of the elevator mechanism and the therapeutic channel.53–55

Concerns about the risks of duodenoscoperelated infectious transmission resulted in increased awareness of, and interest in, more effective duodenoscope reprocessing techniques, as well as the development of

multiple potential solutions to this problem. As of April 10, 2020, “the FDA continues to recommend that hospitals and endoscopy facilities transition to innovative duodenoscope designs to help improve cleaning and reduce contamination between patients, including designs with disposable caps or distal ends.56” Single use (“disposable”) duodenoscopes are delivered in sterile packaging and eliminate the risk of contamination across patients. When singleuse duodenoscopes are used and the procedure is completed, the endoscope is recycled. The first of these duodenoscopes was introduced to the market in 2020 and have been shown to be equivalent to reusable duodenoscopes in operator usability and ERCP success metrics in both bench and human trials.57,58 In addition to single use duodenoscopes, reusable instruments have been created with disposable caps that allows for enhanced cleaning of the elevator mechanism. Each major endoscope manufacturer has a duodenoscope available with a disposable cap that is now commercially available. Currently, there are no guidelines regarding patient selection for the use of single use disposable duodenoscopes, for which widespread use is limited by cost, provider/hospital uptake and concerns regarding environmental waste.57,59 Biliary stenting, inpatient status and cholangiocarcinoma have been implicated as risk factors for CRE infection when using a contaminated duodenoscope, and the use of disposable duodenoscopes over reusable instruments has been suggested in patients that are likely to undergo multiple ERCP procedures, immunocompromised patients or those with a history of MDR infection.57,60 While the overall risk of infections, in particular MDR organisms, after ERCP remains low, the authors recommend considering the use of disposable duodenoscopes in those with a history of recurrent cholangitis, immunosuppression (e.g., post-transplant patients or those on chemotherapy with a history of cholangitis), as well as carriers of MDR organisms. It remains unclear at this time if disposable duodenoscopes will enter mainstream practice given the widespread availability of reusable duodenoscopes with disposable tips, which may be sufficient to reduce the risk of infectious transmission.

Contrast-dye allergy

Significant allergic reactions to contrast dye, used during ERCP, have been reported in rare case reports, although the incidence of these events is felt to be exceedingly low.61 Two large studies have examined the incidence of adverse allergic reactions to contrast dye during ERCP. One prospective study examining 601 patients (80 with intravenous contrast dye allergies) reported no adverse reactions to contrast administration during ERCP.62 This finding was supported by another large retrospective study of 2295 ERCP’s across 1766 patients, of which 121 ERCP’s were performed on patients with prior documented intravenous contrast allergy with no adverse contrast-related events.63 While no guidelines exist on the management of these patients prior to dye administration, in general ERCP with cholangiography and pancreatography is felt to be safe in patients with intravenous contrast dye allergies, even in the absence of premedication. The endoscopist should be well versed and reassuring in discussing the safety of contrast dye use during ERCP in patients with a history of intravenous contrast dye allergy, and institutional protocols should reflect this as well. Non-ionic contrast can also be used if there is a concern regarding contrast dye allergy.

CONCLUSIONS

ERCP is a vital therapy for the diagnosis and management of pancreaticobiliary diseases. While there exists a wide range of indications for ERCP, the expert endoscopist must be well versed in both the indications and contraindications of the procedure as well as its safe performance. As new literature continues to be produced, our understanding of ERCP has evolved and will continue to evolve in the future

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INTRODUCTION TO A NEW SERIES

Introduction to a New Series : Fundamentals of ERCP

September 2022 • Volume XLVI, Issue 9
Douglas G. Adler

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Gastroenterology, and specifically gastrointestinal endoscopy, is awash in acronyms. EGD, ESD, RFA, EUS, FNA, FNB, APC, and on and on. Among these, one acronym in particular stands out: ERCP.

As you all know, ERCP stands for endoscopic retrograde cholangiopancreatography. ERCP stands out to me as, in my experience, it is the cornerstone of therapeutic endoscopy. Now over 50 years old, ERCP has been, and remains, the bedrock on which therapeutic endoscopy has been built. Many other endoscopic procedures build on the core principles, concepts, and actions required to successfully perform ERCP. These include the operation of catheters and guidewires, the use and interpretation of fluoroscopy, the use of electrocautery, cutting tissue, the deployment of stents, and the acquisition of tissue samples from hard-to-reach places.

When I was doing my advanced endoscopy training, I first did an ERCP fellowship at the Mayo Clinic in Rochester, Minnesota. After this was completed, I headed to Boston to undertake an EUS fellowship at the Beth Israel Deaconess Medical Center at Harvard Medical School (in those days it was not uncommon to have to partake in separate ERCP and EUS training programs, as few combined training programs existed). It was obvious that I was able to learn EUS very quickly, having already Centura Health, PEAK Gastroenterology, Denver, CO

learned ERCP. Beyond this, other procedures, such as placement of luminal stents, relied on skills that felt second nature to me from my ERCP training. I was on very familiar ground with familiar tools: Stricture? Check. Catheter? Check. Guidewire? Check. Contrast? Check. Over the past 20 years I have added a wide range of new endoscopic procedures to my repertoire, but in many ways it all comes back to ERCP.

In 2022, a great many GI fellows and practicing gastroenterologists still want to learn how to perform high quality ERCP. I receive frequent calls from physicians asking to come and train with me or to come and watch ERCP procedures at our Center for Advanced Therapeutic Endoscopy (CATE) in Denver

Colorado, and many people struggle to master all that ERCP encompasses. As such, I am thrilled to introduce a new and special series for readers of Practical Gastroenterology: Fundamentals of ERCP. Over 14 articles, this series will cover everything a new or novice pancreaticobiliary endoscopist needs to know to perform high-quality ERCP procedures. The articles will cover what to do, what not to do, and all manner of special tips and tricks to make even the most complicated ERCPs seem simple. The individual article authors and I have worked hard to make these 14 articles an all-in-on resource when taken together and should be valuable for many years to come as the fundamentals never really change.

We hope you enjoy the series and find it valuable to your ERCP practice!

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MEDICAL BULLETIN BOARD

Takeda Launches Cdpath™, A Personalized Prognostic Tool, Advancing Innovation For Patients With Crohn’s DiseaseMedical Bulletin Board

CDPATH supports shared decision-making between patients and healthcare providers; provided at no cost to eligible adult patients who have not yet experienced serious complications*

CAMBRIDGE, Massachusetts, September 14, 2022 – Takeda (TSE:4502/NYSE:TAK) announced the national launch of the CDPATHTM  program, which includes an innovative, validated personalized prognostic tool that uses blood tests† to help predict the potential risk of developing serious Crohn’s disease-related complications within three years.1,2 CDPATH is available for use by US-based physicians and offered at no cost to eligible patients††, providing an opportunity for patients to partner with their physicians to map out a personalized disease management plan.

CDPATH is for adult patients (≥18 years old) diagnosed with Crohn’s disease (CD) within the past 10 years who have yet to experience serious complications defined as bowel strictures, internal penetrating disease, or non-perianal surgery (bowel resection or stricturoplasty).1,2 Patients can have blood drawn for the CDPATH test at one of more than 2,500 participating locations nationwide.

“At Takeda, we are driven by the challenge of making a meaningful difference in the lives of patients with inflammatory bowel disease, and working with partners to provide solutions that can help transform their care,” said Gamze Yüceland, Head, Gastroenterology Business Unit, Takeda Pharmaceuticals, U.S.A., Inc. “Offering CDPATH at no cost to eligible patients with CD will help deliver an innovative tool to the community that can help inform and personalize CD management.” CD is a chronic inflammatory disease that affects the gastrointestinal (GI) tract. CD is one of the two most common types of inflammatory bowel disease (IBD). In the U.S., IBD impacts approximately three million people.3 CD may be progressive and has the potential to lead to irreversible and destructive complications, which may require surgery.4 Complications—which may include fistulas, abscesses and strictures— can occur, yet the course of CD is variable and difficult to predict.5,6,7

CDPATH integrates patient-specific serologic markers and genetic marker status, identified via a blood sample, with a patient’s CD characteristics to predict a low, medium or high risk for potentially developing serious CD complications over a three-year period. Test results are intended to be used in combination with a physician’s clinical assessment and should not be the primary factor in diagnosing or making treatment decisions. Healthcare providers will receive a CDPATH test report with a graphical risk profile that can then be used to facilitate discussions with patients.1,2

To learn more and find a participating location for the required blood draw, visit: CDPATH.com

Takeda has partnered with MiTest Health (“MiTest”) and Prometheus Laboratories Inc. (“Prometheus”) to establish the CDPATH program. MiTest Health defined and established the clinical relevance of the CDPATH model through an independent clinical study. Prometheus, a certified Clinical Laboratory Improvement Amendments (CLIA) laboratory, validated the model, and has received approval from the New York State Department of Health (NYS DoH) for CDPATH as a Laboratory Developed Test (LDT). Prometheus is the processing laboratory for the CDPATH program.

“Prometheus Laboratories is pleased to partner with Takeda on the CDPATH program as they share our commitment to patients,” said Mike Walther, President of Prometheus Laboratories Inc. “CDPATH is a prognostic tool that we believe can be important when considering an appropriate management approach for an individual patient.” “Having a better understanding of their underlying disease can help patients take a more proactive role in their Crohn’s disease management,” said Corey Siegel, MD, MS, MiTest Co-Founder, Section Chief of Gastroenterology and Hepatology and Co-Director of the IBD Center at the Dartmouth Hitchcock Medical Center. “For physicians, shared decision-making is a

key component to a patient-centric management approach. CDPATH will allow healthcare providers to evaluate the potential variability and complexity of Crohn’s disease for each individual patient, and support a more collaborative approach to managing their patient’s CD.”

*Serious complications are defined as bowel strictures, internal penetrating disease, or non-perianal surgery (bowel resection or stricturoplasty).

†The CDPATH risk assessment tool was developed and validated by Prometheus Laboratories Inc., a partner of Takeda, and has received approval from the New York State Department of Health (NYS DoH) as an LDT. Test results are provided via Prometheus Laboratories Inc. to physicians.2

About CDPATH

††CDPATH is only validated in, and can only be performed on, adult Crohn’s disease patients (≥18 years old) diagnosed within the past ten (10) years, who have not experienced a Crohn’s disease complication, defined as bowel strictures, internal penetrating disease, or non-perianal surgery (bowel resection or stricturoplasty). Beneficiaries must be covered by a commercial insurance plan or be uninsured. Those with state or federal health insurance program (including, but not limited to, Medicare, Medicaid, Department of Veteran’s Affairs, Coast Guard, Public Health Service, or Department of Defense) are excluded from participating in this program. No insurance claims should be collected or processed, and no charges should be billed to the patient for CDPATH and shipping. Takeda has made arrangements to directly cover these charges. The cost of the blood draw, CDPATH, and shipping will be covered, provided a participating location is used for the blood draw. Participating locations include Quest Diagnostics (NYSE:DGX) Patient Service Centers, Prometheus-contracted phlebotomy locations and a mobile phlebotomy program. To find a participating location, please call CDPATH client services at 1-877-556-87662 or visit www.CDPATH.com. Only the cost of CDPATH and blood sample shipping will be covered if the blood draw is completed in a physician’s office and it is shipped to Prometheus, the processing laboratory, with the provided shipping label.

Due to the nature of clinical testing, there are limitations to consider for the CDPATH model:1

  • Testing was conducted with only patients from North America; the results for patients from other regions have not been established.1
  • Patients were recruited from large referral centers and may not be representative of all CD patients.1
  • The model was built and validated in CD patients with 15 years as the maximum duration of disease; as such, it is not understood whether the model is applicable for patients with longstanding CD beyond 15 years from diagnosis.1
  • The validity of the model after the first complication or surgery has not been tested or established; therefore, CDPATH is not intended to be used as a monitoring tool and may only be used one time for each patient.1

Healthcare Providers should not rely primarily on the risk predictions from CDPATH to make a clinical diagnosis or treatment decision regarding an individual patient. CDPATH should only be considered an additional piece of information in combination with a doctor’s evaluation of a

patient’s CD. Doctors can decide if this tool is appropriate for individual patients as part of their overall assessment.

More information is available at CDPATH.com

About Crohn’s Disease

Crohn’s disease (CD) is one of the most common forms of inflammatory bowel disease.8 It is a chronic, relapsing, remitting, inflammatory condition of the gastrointestinal (GI) tract that is often progressive in nature.4,9,10 CD can affect any part of the GI tract from mouth to anus, and can affect the entire thickness of the bowel wall.11 CD can present with symptoms of abdominal pain, diarrhea, and weight loss.10 The cause of CD is not fully understood; however, recent research suggests heredity, genetics, environmental factors, and/or an abnormal immune response to microbial antigens in genetically predisposed individuals can lead to CD.12,13

Takeda’s Commitment to Gastroenterology in the United States

Takeda sees an urgent need for improving patient care in gastroenterology (GI) and has focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for more than 25 years. We push boundaries and work across modalities, taking on the most complex GI conditions and the most neglected patient needs, boldly advancing original thinking and creatively tackling barriers to make a meaningful difference

for patients. Challenging expectations and enabling innovative thinking, Takeda is part of more than 200 collaborations connecting people with a mutual commitment to action. Takeda is leading in areas of gastroenterology associated with high unmet need, such as inflammatory bowel disease, short bowel syndrome and motility disorders. Our GI Research & Development team is also exploring solutions in immune-related diseases, motility and liver diseases. About Takeda Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modalitydiverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.

References

  1. Siegel CA, Horton H, Siegel LS, et al. Aliment Pharmacol Ther. 2016;43(2):262-271.
  2. Data on file. Takeda Pharmaceuticals.
  3. Crohn’s and Colitis Foundation. Inflammatory Bowel Disease vs Irritable Bowel Syndrome (Brochure). October 2019.
  4. Fiorino G, et al. J Crohns Colitis. 2016;10(4):495-500.
  5. Mazor Y, et al. J Crohns Colitis. 2011;5(6):592-597.
  6. Definitions and Facts for Crohn’s Disease. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved from: https://www.niddk.nih.gov/healthinformation/digestive- diseases/crohns-disease/definition-facts. Accessed March 14, 2022.
  7. Veloso FT. Eur J Gastroenterol Hepatol. 2016;28(10):1122-1125.
  8. Baumgart DC, Carding SR. Lancet. 2007;369(9573):1627-1640.
  9. Liverani, et al. World J Gastroenterl. 2016;22(3):1017-1033.
  10. Baumgart DC, Sandborn WJ. Lancet. 2012;380(9853):15901605.
  11. Feuerstein JD, Cheifetz AS. Mayo Clin Proc. 2017;92:10881103.
  12. Henckaerts L, et al. Gut. 2007;56:1536-1542.
  13. Kaser A, et al. Dig Dis. 2010;28:395-405.

METABOLON ANNOUNCES JOINT DEVELOPMENT AGREEMENT WITH MAYO CLINIC TO CREATE NEW DIAGNOSTIC TESTS

Metabolon and Mayo Clinic will jointly research disease biomarkers and develop novel diagnostic tests for use in Mayo Clinic’s nationwide reference laboratories

MORRISVILLE, N.C. – August 9, 2022 –

Metabolon, Inc., the global leader in metabolomics solutions advancing a wide variety of research, diagnostic, therapeutic development, and precision medicine applications, announced a joint development agreement with Mayo Clinic to develop novel metabolomic biomarker diagnostic tests. Metabolon will analyze Mayo Clinic patient clinical samples across multiple cohorts to look for disease biomarkers. New diagnostic tests for Mayo Clinic to use in its nationwide Mayo Clinic Laboratories will be designed using these biomarkers.

Metabolon and Mayo Clinic will initially focus their investigation on metabolite biomarkers indicating inflammatory bowel disease and nonalcoholic fatty liver disease (NAFLD). Additional potential collaboration areas include research into biomarkers revealing the presence of Alzheimer’s disease, pancreatic cancer, breast cancer, inflammatory arthritis, and others. “We are incredibly excited to be working with Mayo Clinic, as they bring significant clinical

strength and robust commercialization capabilities to this vital research. Mayo Clinic’s laboratories are the third-largest in the U.S., performing over 25 million diagnostic tests each year,” said Rohan Hastie, Ph.D., President and CEO of Metabolon. “Collaborating with Mayo Clinic has the potential to help both parties expand their cutting-edge research into the critical role of metabolomic biomarkers as valuable indicators of human health.” About Metabolon Metabolon, Inc. is the global leader in metabolomics, with a mission to deliver biochemical data and insights that expand and accelerate the impact of life sciences research. Over 20 years, 10,000+ projects, 2,800+ publications, and ISO 9001:2015 and CLIA certifications, Metabolon has developed industry-leading scientific, technology, and bioinformatics techniques. Metabolon’s Precision Metabolomics™ platform is enabled by the world’s largest proprietary metabolomics reference library. Metabolon’s industry-leading data and translational science expertise help customers and partners address some of the most challenging and pressing questions in the life

sciences, accelerating research and enhancing development success. The company offers scalable, customizable metabolomics and lipidomics solutions supporting customer needs from discovery through clinical trials and product life-cycle management.

For more information, please visit: metabolon.com

About Metabolomics

Metabolomics, the large-scale study of all small molecules in a biological system, is the only ‘omics technology that provides a complete current state functional readout of a biological system. Metabolomics helps researchers see beyond the genetic variation of individuals, capturing the combined impact of genetic as well as external factors such as the effect of drugs, diet, lifestyle, and the microbiome on human health. By measuring thousands of discrete chemical signals that form biological pathways in the body, metabolomics can reveal important biomarkers enabling a better understanding of a drug’s mechanism of action, pharmacodynamics, and safety profile, as well as individual responses to therapy.

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FROM THE PEDIATRIC LITERATURE

From The Pediatric Literature

September 2022 • Volume XLVI, Issue 9

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Familial Adenomatous Outcomes in Children

Familial adenomatous polyposis (FAP) is caused by mutations of the APC gene leading to formation of multiple adenomatous polyps in the colon with affected individuals experiencing malignant transformation of such polyps in their third decade of life. Thus, most patients with FAP undergo a total colectomy during their second decade of life. However, minimal data exists regarding pediatric patients with FAP undergoing colectomy, and the authors of this study used data from the United States Children’s Hospital Association (CHA) Pediatric Health Information System (PHIS) to identify patients between 2 – 21 years of age with FAP diagnosed between 2009-2019. These patients were identified using diagnostic codes from the International Classification of Diseases (ICD)-9 and ICD-10. Included patients had an ICD diagnostic code for FAP and had at least one colectomy diagnostic code. The authors then took 50 patients from three CHA-affiliated hospitals who had a history of FAP and subsequent colectomy which they identified as a “gold standard” patient list to find patients from the PHIS. This search yielded 428 pediatric patients with FAP and colectomy from 46 children’s hospitals. The median age at colectomy was 14 years (range 2-21 years, interquartile range 11-16 years), and 226 patients (56%) underwent colectomy by laparoscopy with the remainder undergoing colectomy by the open approach. Colectomy with ileal pouch anal anastomosis occurred in 264 patients (62%) while 13 patients (3%) underwent colectomy and ileorectal anastomosis while the rest of the study population had no clear surgical procedure documented. An associated desmoid tumor was present in 21 patients (5%), and 2 patients (0.5%) had a colon neoplasm. The median length of hospitalization was 7 days (interquartile range 5-9 days), and there was no significant difference in length of hospitalization based on type of colectomy. No patient experienced in-hospital mortality after colectomy, and 314 complications occurred in 169 patients (39%) within one year of surgery. Adhesive disease with or without intestinal obstruction was the most common post-surgical complication occurring in 61 patients (14%). When all pediatric hospitals in the study group were combined, 27 hospitals (59%) did fewer than one colectomy for FAP annually, and only 3 hospitals performed more than 3 colectomies for FAP annually. Interestingly, the annual colectomy rate for FAP declined by 48% during the study duration. It was noted that 257 patients (60%) had no documented endoscopic examination prior to colectomy although almost 98% of patients who did undergo endoscopic examination had some type of tissue removal (biopsy, polypectomy) prior to colectomy. 

The authors note that the relatively young median age at colectomy (14 years) suggests that a subgroup of pediatric patients with FAP exist that need more stringent guidelines regarding colonoscopy screening and potential colectomy. The relative lack of documentation of endoscopic evaluation in this group of pediatric patients with FAP suggests that clear FAP screening guidelines in young patients should be considered.

Flahive C, Onwuka A, Bass L, MacFarland S, Minneci P, Erdman S. Characterizing pediatric familial adenomatous polyposis in patients undergoing colectomy in the United States. Journal of Pediatrics 2022; 245: 117-122.

Does Pancreatic Insufficiency Occur in Children with Short Bowel Syndrome?

Short bowel syndrome (SBS) in children has many causes, including as a consequence of necrotizing enterocolitis, congenital atresia, abdominal wall defects, and intestinal volvulus. SBS has a significant morbidity and mortality rate associated with complications from central lines and due to problems associated with long-term parenteral nutrition (PN) use. Thus, reducing dependency on PN is a major goal for these patients. Since many patients with SBS have fat malabsorption, the authors of this study evaluated the use of pancreatic enzyme replacement therapy (PERT) in this specific population. Pediatric patients between 4 and less than 18 years of age and adult patients between 18 and 75 years of age were recruited for this study. Specifically, pediatric patients with SBS were included if they had a history of small bowel surgery with at least 3 months of associated PN use while adult patients were included if they

had a maximum of 200 cm of small bowel length and had more than 3 bowel movements per day. Patients were excluded from the study if they had causes of fat malabsorption not related to SBS (for example, cholestatic liver disease or pancreatic insufficiency). Study patients were provided Creon® (AbbVie, Inc.) at 1500 – 2000 units / kg per meal and 750 – 1250 units / kg per snack, not exceeding 10,000 units / kg / day. Standard anthropometrics, skinfold caliper measurements, and mid-upper arm circumference measurements were obtained to determine BMI z scores, upper arm muscle area, and upper arm muscle fat area. Whole body dual energy x-ray absorptiometry (DEXA) was obtained on all patients to determine fat mass, fat free mass, and percent body fat. Dietary fat and protein intake was recorded using a 3-day diet diary, and 72-hour stool collections were obtained on and off PERT. Fecal fat content (coefficient of fat absorption) was determined using nuclear magnetic resonance spectroscopy, and fecal nitrogen content (coefficient of nitrogen absorption) was determined using the high-temperature Dumas combustion method. Fecal elastase-1 levels also were obtained on all patients to determine exocrine pancreatic function. A total of 11 study subjects were included in this study in which 6 patients were in the pediatric age group (age range 4 – 17.9 years; mean 9 years), and 5 patients were in the adult age group (age range 18 – 75 years; mean 53.5 years). The mean pediatric small bowel length was 60 cm while the mean adult small bowel length was 80 cm.

Although the mean length of time that patient required PN was 3.4 years, only two patients were actively on PN at the time of the study.Only one patient had a low fecal elastase-1 level; however, the authors noted that this one patient had watery stool at the time of the testing which likely led to an artificially low level. Six patients had an improved coefficient of fat absorption, and eight patients had an improved coefficient of nitrogen absorption on PERT; however, there was no statistically significant change in the coefficient of fat or nitrogen absorption before or after PERT use. No significant side effects were noted during PERT use.

This study appears to show that PERT use in patients with SBS is not helpful in improving intestinal absorption; however, the number of included patients was small and the finding that some patients had an increase in either coefficient of fat absorption or coefficient of nitrogen absorption suggests that there may be a subset of patients with SBS that could benefit from PERT. However, there is no evidence currently to suggest PERT use in patients with SBS.

Sainath N, Bales C, Brownell J, Pickett-Blakely O, Sattar A, Stallings V. Impact of pancreatic enzymes on enteral fat and nitrogen absorption in short bowel syndrome. Journal of Pediatric Gastroenterology, Hepatology, and Nutrition 2022; 75: 36-41.

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A CASE REPORT

Therapeutic Challenges in Afferent Loop Syndrome Presenting as Recurrent Acute Pancreatitis with Ascending Cholangitis

September 2022 • Volume XLVI, Issue 9
Michael Eiswerth,Fred Closson,Dipendra Parajuli

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Afferent loop syndrome (ALS) is a post-surgical complication associated with gastric resections with Billroth II, or Roux-en-Y reconstructions, and pancreaticoduodenectomies which result in the creation of a blind loop. ALS occurs when there is distal obstruction of the afferent limb that results in its distension secondary to the accumulation of bile, pancreatic fluid, or small bowel secretions. Our case demonstrates a rare presentation of afferent loop syndrome that posed both diagnostic and therapeutic challenges. Understanding the pathophysiology of ALS, its cause and the role of endoscopic interventions is crucial in diagnosing and managing ALS.

INTRODUCTION

Afferent loop syndrome (ALS) is a post- surgical complication associated with Billroth II, or Roux-en-Y reconstructions, and pancreaticoduodenectomies (Whipple procedure). The gastro-jejunal anastomosis creates an afferent and efferent limb to the stomach; for Roux- en-Y reconstruction, the afferent limb is the biliopancreatic limb. ALS is a rare complication, occurring in 0.2%-1.0% of patients with partial gastrectomy and Billroth II or Roux-en-Y reconstruction.1 Patients who undergo Whipple have a combination of afferent intestine loop and biliary-enteric anastomosis. The incidence of ALS is significantly higher in patients with Whipple and has been estimated up to 13%, rapidly increasing three years post-surgery.2

Etiologies for obstruction include adhesions, internal hernias, prior gastrojejunostomy ulceration, and recurrent malignancy in those who underwent surgery for cancer.3 Less common causes include intraluminal obstructions and afferent loop intussusception or volvulus, and radiation enteritis.3 We demonstrate the importance of a comprehensive evaluation for abdominal pain in patients with post- surgical anatomy and review management options for patients with ALS in the setting of an afferent limb stricture.

Case Report

A 59-year-old male with a history of peptic ulcer disease (PUD) status post remote gastric antrectomy with Billroth II, alcohol abuse, and recurrent admissions for acute pancreatitis secondary to alcohol use presented to the hospital with one day of abdominal pain, nausea, and vomiting. Vitals on admission were normal with heart rate of 84 bpm and blood pressure of 103/52 mmHg. Physical examination demonstrated mild distress with tenderness to light palpation in the epigastrium without distension or jaundice. Laboratory results showed a leukocytosis of 24.3 (4.1-10.8 cells/ mm3), lipase of 382 (10-50 units/liter), aspartate aminotransferase of 1,285 (12-38 units/liter), alanine aminotransferase of 560 (>31 units/liter), alkaline phosphatase of 289 (34-106 units/liter), and blood cultures grew E. coli.

Abdominal ultrasonography from a recent admission demonstrated a dilated common bile duct of 1.3 cm and a right upper quadrant (RUQ) cystic structure which appeared as a gallbladder filled with gallstones. On current admission, abdominal computed tomography (CT) demonstrated that this cystic structure was actually the duodenal blind limb dilation with stones. Magnetic resonance cholangiopancreatography (MRCP) redemonstrated a distended duodenal stump with intraluminal stones without interval worsening biliary dilatation (Figure 1). Treatment for cholangitis was initiated with ceftriaxone, with clinical improvement.

Esophagogastroduodenoscopy (EGD) showed evidence of previous Billroth II gastroenterostomy and duodenal stricture in the blind limb (Figure 2).

Liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) down-trended as well, this elevation was believed to be secondary to an obstructing stone that caused a transient obstruction at the site of the stricture and ultimately passed on its own. Endoscopic intervention was deferred due to clinical improvement with medical management and resolving liver enzymes levels. Patient is now following with surgery for possible revision of Billroth II.

Discussion

ALS occurs with distal obstruction of the afferent limb and subsequent distension secondary to the accumulation of bile, pancreatic fluid, and enteric secretions. Clinical presentation of ALS occurs across a wide spectrum depending on the acuity of the obstruction. Acute obstruction often presents as pancreatitis or ascending cholangitis.4 This most commonly occurs early in the post-operative course; abdominal pain is common and may be associated with sepsis or peritonitis. Chronic ALS occurs months to years after surgery with postprandial abdominal pain that may result in food avoidance, malabsorption, and weight loss.5 CT of the abdomen is the diagnostic gold standard for ALS, however MRCP can be a helpful adjunctive test in chronic ALS. An EGD was also performed to evaluate patency of the afferent loop in this case. Our patient posed a diagnostic challenge due to recurrent episodes of acute pancreatitis due to alcohol use and a new cholangitis that was present this admission. This case necessitated the use of multiple imaging modalities to appropriately identify the underlying cause of distal obstruction of the afferent limb, which was in our case a benign stricture. Our patient was particularly challenging given his remote surgical history, making a presentation of chronic ALS with both acute pancreatitis and acute cholangitis atypical. Given the numerous etiologies for developing chronic ALS, diagnostic accuracy is imperative to provide appropriate treatment, which historically has been surgical. By identifying the stricture, problem-directed treatment via endoscopicguided stenting or dilation is a potential therapy that may

not initially demand immediate surgical intervention.6 Newer, lumen-apposing metal stents (LAMS) are potentially useful in synchronous biliary and duodenal malignant obstruction. The advent of LAMS in the treatment of ALS has been precipitated by streamlining their use from a multiple, to one-step technique.

In one recent case report, two techniques were successfully used in deployment of  LAMS: one was placed across a gastroenterostomy, bypassing the stricture; another utilized intraluminal placement directly across a stenosis, placing a transmural stent.7 There are prior case reports documenting successful use of LAMS in the treatment of ALS,4 however only one study evaluates the efficacy and safety profile of LAMS in ALS.8 This trial had 18 patients, 100% technical success was reported and abdominal pain as an adverse event was reported in 16.7% of patients.8 Furthermore, patients with LAMS placement were compared

indirectly in this trial to patients with enteroscopyassisted luminal stenting, and patients with LAMS placement required fewer repeat interventions in this comparison.8

CONCLUSION

There is little in the literature regarding chronic ALS resulting in both acute pancreatitis and acute cholangitis. Prompt diagnosis of the underlying etiology precipitating ALS is crucial, as the landscape of management options is under evolving and under active research. CT of the abdomen remains the gold standard for the diagnosis of ALS, which is a post-surgical complication of multiple surgeries including Billroth II, or Rouxen-Y reconstructions, and Whipple procedures. The advent of LAMS as an endoscopic intervention in the treatment of ALS is promising, but longitudinal studies are needed to better understand the benefits and risk profile.

References

  1. Aoki, M., Saka, M., Morita, S., Fukagawa, T. and Katai, H., 2010. Afferent Loop Obstruction After Distal Gastrectomy with Roux-en-Y Reconstruction. World Journal of Surgery, 34(10), pp.2389-2392.
  2. Benallal, D., Hoibian, S., Caillol, F., Bories, E., Presenti, C., Ratone, J. and Giovannini, M., 2018. EUS–guided gastroenterostomy for afferent loop syndrome treatment stent. Endoscopic Ultrasound, 7(6), p.418.
  3. Grotewiel, R. and Cindass, R., 2022. Afferent Loop Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK546609/ [Accessed 1 March 2022].
  4. Monino, L., Barthet, M. and Gonzalez, J., 2019. Endoscopic ultrasound-guided management of malignant afferent loop syndrome after gastric bypass: from diagnosis to therapy. Endoscopy, 52(03), pp.E84-E85.
  5. RK, G. and R, C., 2022. Afferent Loop Syndrome. [online] PubMed. Available at: [Accessed 1 March 2022].
  6. Blouhos, K., 2015. Management of afferent loop obstruction: Reoperation or endoscopic and percutaneous interventions. World Journal of Gastrointestinal Surgery, 7(9), p.190.
  7. DuBroff, J., McDonough, S. and Adler, D., 2020. Afferent Limb Syndrome Treated via Lumen Apposing Metal Stents: Report of Two Different Approaches in Two Patients – Practical Gastro. [online] Available at: [Accessed 1 March 2022].
  8. Brewer Gutierrez, O., Irani, S., Ngamruengphong, S., Aridi, H., Kunda, R., Siddiqui, A., Dollhopf, M., Nieto, J., Chen, Y., Sahar, N., Bukhari, M., Sanaei, O., Canto, M., Singh, V., Kozarek, R. and Khashab, M., 2018. Endoscopic ultrasound-guided entero-enterostomy for the treatment of afferent loop syndrome: a multicenter experience. Endoscopy, 50(09), pp.891895

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FRONTIERS IN ENDOSCOPY, SERIES #83

Artificial Intelligence in Pancreaticobiliary Disease

September 2022 • Volume XLVI, Issue 9
Catherine Y. Wang,Tyler M. Berzin

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The rapid rise of artificial intelligence (AI) applications in the field of gastroenterology has led to the recent rollout of sophisticated hardware and software systems used to aid detection and diagnosis in the endoscopy suite. These systems have primarily been applied to esophagoduodenoscopies and colonoscopies. The literature is comparatively scant in the realm of pancreaticobiliary endoscopy. This review aims to discuss the few studies that have been published evaluating AI-assisted endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). While the preliminary data are encouraging the area as a whole demands further robust clinical study in addition to close consideration of the logistical and ethical challenges that machine (ML) and deep learning (DL) present.

INTRODUCTION

Artificial intelligence (AI) applied to medicine has seen a recent acceleration in both interest and clinical implementation after five decades of development, dating back to at least the 1970s.1 In that time AI has been deployed to aid in solving the diagnostic and prognostic questions in every field of medicine from radiology to dermatology.2

AI was born as a branch of computer science with the hope of creating computer systems that could perform tasks classically requiring human input or intelligence. Machine learning (ML) is a subset of AI in which computer algorithms “learn” from training data sets by performing specific tasks and analyses on said data. ML algorithms designed for certain tasks, for instance visual recognition (e.g., recognizing lung nodules on a chest x-ray), are trained on large data sets, and the resulting trained algorithm is termed a “model.” These models are then validated on different data sets to ascertain their positive and negative predictive value. Deep learning (DL) is a subset of ML that relies on an artificial neural network (ANN), which allows for multiple layers of features to be extracted from raw data to create more complex predictive outputs, often with even less human guidance than traditional ML algorithms. These DL systems learn through successive training data sets to produce outputs that are increasingly similar to

the target output typically predetermined by experts in the field. Other AI modalities include natural language processing (NLP) which gives computers the ability to understand both text and spoken word while ambient clinical intelligence (ACI) monitors and reacts to inputs from its environment akin to Siri or Alexa. 

Over the past two decades AI has become an increasingly important topic of discussion in gastroenterology.3–5 The applications of AI in this realm are wide in scope and in general fall into one of two categories: visual tasks and combination tasks. A typical approach to a visual task is first to develop a model based on a labeled test set of still images or video (e.g., a database of colon polyp images). The next step is to validate the model on a separate data set to measure performance, and in some cases “tune” the algorithm for optimal performance. Some of the early critical progress in computer vision for gastroenterology has been in the areas of esophagogastroduodenoscopy (EGD)6– 9 and colonoscopy10–12 where many academic and industry teams have developed computer-assisted detection (CADe) software for colon polyp detection and other indications. There is a smaller subset of studies evaluating the use of AI in video capsule endoscopy (VCE)13,14 to similarly aid in detection and diagnosis of small bowel pathology. While a great deal of progress has been made in computer vision for colonoscopy and upper endoscopy, with numerous randomized control trials (RCTs) evaluating clinical use of CADe and CADx systems in real-time, the same cannot yet be said for the field of pancreaticobiliary endoscopy. The development and implementation of AI tools for endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) is still in a nascent stage. This gap is likely explained by two key barriers: 1) pancreaticobiliary endoscopy relies on a broader mix of complex visual data (i.e., ultrasound, fluoroscopy, and endoscopy) therefore presenting a greater challenge for model development and 2) the total volume of pancreaticobiliary procedures is much smaller compared to general endoscopic procedures, making it more difficult to collect data for model development (and perhaps also less of a compelling investment for industry). This review

aims to highlight the AI systems in active development for advanced endoscopic procedures to treat pancreaticobiliary disease, highlighting some of the key barriers and opportunities that lie ahead.

Endoscopic Ultrasound

EUS has emerged as an impactful modality to evaluate conditions of the pancreas, gallbladder, and liver in addition to a wide variety of other indications. A particularly most common use is in fluid and tissue sampling to aid in diagnosing pancreatic cysts and malignancy. EUS interpretation appears to be operator-dependent15–17 with significant operator heterogeneity across various studies, highlighting a need for tools to help standardize diagnosis in difficult clinical scenarios.18 While the development of AI for EUS has been relatively limited in the past decade, there have been several important trials utilizing ML and DL systems to aid in detection and differentiation of various benign and malignant pancreatic lesions. EUS elastography has been one area of recent AI investigational efforts. Elastography measures the relative stiffness and density of tissue and has been used to help differentiate between pancreatic cancer and inflammatory changes (e.g., chronic pancreatitis). EUS elastography has been shown to have good sensitivity and specificity for differentiating cancer and chronic pancreatitis in one large meta-analysis.19 In 2008 Saftoiu and colleagues20 generated mean hue histograms from EUS elastography videos of 68 patients to which an extended neural network algorithm was applied to differentiate between chronic pancreatitis and pancreatic cancer. The algorithm reported an average training performance of 97% and an average testing performance of 95%. Sensitivity and specificity were 91.4% and 87.9% respectively, which is comparable to the sensitivity and specificity of previously published literature on the use of EUS elastography for diagnosis, with strong positive (88.9%) and negative (90.6%) predictive values. Major limitations of this study include its small sample size and use of normal pancreas cases with no definitive mass to train the algorithm. A follow up study21 expanded on their original dataset and designed a blinded prospective cohort study utilizing 774 EUS elastography recordings from

recorded for each patient. Hue histograms were then examined by an experienced operator and given a final clinical diagnosis. A mathematical model using ANN input of the hue video vectors and the known final diagnosis was then generated and the two compared. The study reported a training accuracy of 91.14% and a testing accuracy of 84.27%. Sensitivity and specificity were 87.59% and 82.94% respectively, with PPV and NPV 96.25% and 57.22%. While the study enrolled predominantly pancreatic cancer patients (47 patients with chronic pancreatitis and 211 patients with pancreatic cancer), it illustrates the usefulness of neural networks in accurate diagnosis of solid pancreatic masses using EUS elastography. These studies show the high diagnostic accuracy reported when incorporating artificial intelligence and neural networks to EUS elastography image interpretation. Continuing to add to these image databases and incorporate them into EUS elastography software may further enhance diagnostic differentiation of pancreatic parenchymal diseases. Zhu and colleagues22 designed a diagnostic prospective study including EUS data from 388 patients (126 with chronic pancreatitis and 262 with pancreatic ductal adenocarcinoma) utilizing a support vector machine (SVM) to build an algorithm that distinguishes benign and cancerous image samples. Classification performance was robust with a testing accuracy

of 94.2%. Sensitivity and specificity were 96.25% and 93.38% respectively, with a PPV and NPV of 92.21% and 96.68%. As with much of the work in this subfield the system was designed using a single classifier and no head-to-head comparison of different classifiers (e.g., ANNs) was performed. In addition, this form of image analysis was completed post hoc thereby limiting its general ability to be utilized as a dynamic tool in real-time clinical scenarios. Alongside the rise of ML and DL in medicine there has also been a movement towards utilizing more advanced imaging modalities (e.g., chromoendoscopy, magnification endoscopy, contrast enhanced EUS, etc.) to permit more subtle clinical interrogation of GI lesions. These advanced imaging modalities provide ample opportunity for AI innovation. In 2015 Saftoiu and colleages23 continued to expand their work with ANNs in pancreaticobiliary endoscopy by applying similar training and testing protocols to data captured with contrast-enhanced harmonic EUS (CEH-EUS). This study of 167 patients with intra-abdominal masses (55 with chronic pancreatitis and 112 with pancreatic cancer) trained an ANN with 94.64% sensitivity and 94.44% specificity. PPV and NPV were 92.21% and 96.68% respectively. While the majority of these data were obtained contemporaneously, roughly 25% of those patients had no fine needle aspirate (FNA) sample collected at the time of CEH-EUS. These cases required confirmatory testing by surgery (n=15) or followup (n=23). One source of additional bias in this study is the fact that the same investigators who performed the CEH-EUS also performed the EUS-guided investigator who was blinded to FNA results.

Larger studies focused on traditional EUS gained more traction in the mid-2010s. In 2016 Ozkan and colleagues24 created a CADx system using data from 172 patients with an imaging data set comprised of 130 non-cancer and 202 pancreatic cancer samples. Patients were further sub-divided into three different age groups: < 40, 40-60, and > 60 (as we know appearance of the pancreas on EUS changes throughout a person’s lifespan). The ANN processed 20 features and classified each sample as either benign or malignant. The testing accuracy of this CADx system for the < 40, 40-60, and > 60 age groups were 92%, 94.11%, and 91.66% respectively. Sensitivity and specificity for all age groups were 83.3% and 93.33% respectively. Limitations of this study include the small sample size utilized for the age < 40 subgroup in particular. There was also no differentiation between noncancerous pancreas pathologies (e.g., chronic pancreatitis, pseudocysts, polyps, etc.). As with the work of Zhu and colleagues this CADx system was designed to conduct post hoc analysis of the EUS images rather than providing real-time information to guide clinical decision-making. In 2019 two additional retrospective studies performed by Kuwahara and colleagues25 and Kurita and colleagues26 were performed to differentiate malignant IPMN from benign fine need aspiration (EUS-FNA) of the mass. Despite this limitation all computer analysis of CEH-EUS videos were performed by

pancreatic cystic lesions. The former included 50 patients (27 with low- or intermediate-grade dysplasia and 23 with high-grade dysplasia or invasive carcinoma) and utilized 3970 still EUS images to build a CADx system with 94.0% testing accuracy and sensitivity and specificity of 95.7% and 92.6% respectively. The latter included 85 patients and utilized a DL system to transform multiple data points (e.g., CEA level, cytology obtain via FNA, cyst fluid analysis of surgical and endoscopic specimens) and output a predictive value to differentiate benign and malignant cystic lesions with a testing accuracy of 92.9% and sensitivity and specificity of 95.7% and 91.9% respectively. While these studies demonstrate a higher level of testing accuracy the generalizability of their results are limited by the relatively small sample sizes. There is a renewed focus on utilizing AI’s computing power for quality control and training in EUS. In 2020 Zhang and colleagues27 constructed a system called BP MASTER to aid endoscopist training in EUS. The standard EUS procedure was divided into 6 discrete stations based on pancreatic anatomy, utilizing 19,486 images. Test set included 396 video clips and system performance was compared to EUS expert determination. The algorithm achieved 94.2% and 82.4% testing accuracy in station classification at internal and external validation respectively. The accuracy of this system was deemed comparable to that of expert opinion. This study paves the way for AI in EUS to be utilized not only for real-time clinical decision and procedural quality improvement,

but also potentially to support trainee education. Indeed there is a growing body of literature28–32 that suggests AI-assisted or virtual reality simulators can serve as a useful supplemental to conventional training. EUS-based neural networks are also under investigation as a means of differentiating autoimmune pancreatitis (AIP) from pancreatic adenocarcinoma (PDAC). Marya and colleagues33 performed a study in 2021 to explore this question. Still images and videos from 583 patients were used to create a convolutional neural network (CNN) that was able to distinguish AIP (n=AIP) from normal pancreas (NP, n=73) with 99% sensitivity and 98% specificity. This CNN was also able to distinguish AI from chronic pancreatitis (CP, n=72) with 94% sensitivity and 71% specificity. Finally, the CNN distinguished AIP from PDAC (n=292)

with 90% sensitivity and 93% specificity. In total the neural network distinguished AIP from all other conditions with 90% sensitivity and 95% specificity. Given the suboptimal nature of sampling techniques to diagnose AIP this CNN is promising as a more expeditious method to obtain the diagnosis. The most recent and complete systematic review on the application of AI in EUS diagnosis of pancreatic malignancies was published by Goyal and colleagues in 2022.34 In this systematic review, 11 studies utilizing AI in diagnosing pancreatic cancer were included, with a total of 2292 patients. The patient population was predominantly pancreatic cancer (n=1383), with the remaining divided between pancreatic neuroendocrine tumors (PNET; n=3) and IPMN (n=27). Neural networks were the most studied AI modality (n=9 studies), with the remainder being SVM. Overall, the sensitivity of the AI systems in diagnosing pancreatic cancer was high, ranging from 83-100%, with a specificity of 50-99%, PPV of 75-99% and NPV of 57-100%. Subgroup analysis of the studies differentiating pancreatic cancer from chronic pancreatitis reported higher sensitivity (96%), specificity (93%) and accuracy (94%) when using SVM as compared to those that utilized ANN. This comprehensive systematic review summarizes what is outlined in the current review, and again supports the use of AI systems in improving diagnostic yield for pancreatic cancer identification by EUS.

Endoscopic Retrograde Cholangiopancreatography

AI model development in the world of endoscopic retrograde cholangiopancreatography (ERCP) has made somewhat less progress than in the realm of EUS. Proposed areas for development of AI in ERCP include: 1) characterization of strictures, 2) risk predictors for iatrogenic pancreatitis, and 3) prediction tools and guidance for difficulty of biliary duct cannulation.35 One key area of challenge in ERCP has been the differentiation between indeterminate and malignant biliary strictures, which has been hampered by relatively low diagnostic yield of cytology brushings and subjectivity of cholangioscopic findings.36–38 Contemporaneous development with AI applications in EUS, Jovanovic and colleagues39 designed a prospective study which aimed to identify patients with suspected choledocholithiasis most suitable for therapeutic ERCP. Data from 181 patients at a tertiary care endoscopy center were utilized. An ANN-generated predictive score based on laboratory values (e.g., alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase, C-

reactive protein) and features of the common bile duct (CBD) on transcutaneous ultrasound. This model displayed good discriminant ability with 92% testing accuracy in identifying patients with choledocholithiasis, suggesting ANN-generated predictive scores can be useful risk stratification tools in routine clinical practice.

It is well known that difficult cannulations increase the risk of post-ERCP pancreatitis and in turn contribute to significant morbidity and mortality, and thus utilizing AI to predict difficult cannulation by ampulla appearance has been attempted.40 In 2021 Kim and colleagues41 built an AI system to identify the ampulla of Vater (AOV) and assess difficulty of pancreatic duct cannulation during ERCP, using a sample of 531 patients for which images from 451 were used to annotate AOV location. Cannulation difficulty data were based on binary classification. The model created was able to detect AOV with precision of 76.2% and classify cannulation difficulty with recall of 71.9% in easy cases (requiring < 5 minutes) and 61.1% in difficult cases. These metrics are on par with expert determination and demonstrates the real-time clinical applicability of AI in advanced endoscopy. These promising findings also pave a path for AI systems to improve quality control and training in ERCP.

DISCUSSION

As applications of AI continue to expand in the field of gastroenterology it will be important to develop benchmark data sets that are large and heterogeneous to allow for consistency in training and testing new AI systems. These data sets may also circumvent the need for head-to-head randomized control trials comparing the many subtypes of AI systems. Another goal of this burgeoning subfield should be robust trial design. As delineated by Glissen and colleagues3 the call for more prospective randomized control studies evaluating the use of AI in endoscopy is met with the equally important need for more structure in trial design and reporting. Detailing the level of human involvement in input data manipulation and baseline expertise requirements of users, for example, will be crucial. Clearly stating which data are missing and how these data were treated in statistical analysis are critical. Identify the differences in the training and testing data sets including the eligibility criteria for inclusion in each study is also imperative. As the demand for more robust studies in this area accelerates as will our need to address the logistical42 and ethical43 challenges inherent in this work. One important logistical challenge is the manpower required to catalog images and videos to build these benchmark data sets. Another challenge is siloed data, a product of institutions utilizing different electronic medical records, endoscopy systems, and image processing software, which will make it difficult to share and integrate these data into useful AI applications. There also remain many ethical considerations in utilizing ML/ DL systems for routine clinical care including informed consent, privacy and transparency of data use, external regulation, and algorithmic bias. The latter is currently being explored and of utmost importance as this bias can contribute to pre-existing health inequities in gastroenterology and hepatology. It is clear that bias has the potential to affect nearly every aspect of ML/DL implementation in clinical practice as outlined by Uche-Anya, Anyane-Yeboa and colleagues including: research problem selection, data collection, outcome measure selection, algorithm development, and clinical deployment.44 As the field of gastroenterology continues to harness the power of AI in pancreaticobiliary endoscopy it will be important for future clinical trial design to prioritize transparency, standardized research methodology and terminology, and equity. The implications of this technology are far-reaching and, if broadly adopted, can lead to a profound change in clinical practice and outcomes.

References

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A SPECIAL ARTICLE

Chronic Pancreatitis: A Review

August 2022 • Volume XLVI, Issue 8
Brooke Alexander,Amaka Onyiagu,Mayuri Gupta

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Chronic pancreatitis (CP) is a progressive, irreversible disease that manifests as morphological changes of the pancreatic parenchyma, such as fibrosis and calcifications, and functional abnormalities including exocrine and endocrine insufficiency. However, the most common presentation of CP is abdominal pain, which has a severe impact on the quality of life of patients and is costly to the healthcare system. CP can be caused by toxic substances such as alcohol or tobacco, genetic mutations, and/or recurrent attacks of acute pancreatitis. The incidence of CP is rising and there is no curative treatment outside of total pancreatectomy. The condition can be difficult to diagnose and treat due to the varying presentations in a patient’s history of acute pancreatitis, pain levels, or degree of exocrine or endocrine insufficiency. This review article focuses on the clinic presentation, etiology, diagnosis, and management of CP.

INTRODUCTION

Chronic pancreatitis (CP) is a syndrome that radiation to the back, but patterns of pain can vary.3 results from acute and chronic inflammation The majority of CP cases are due to alcohol or and injury of the pancreas leading to fibrosis, tobacco use, genetic polymorphisms, or recurrent atrophy, and ultimately functional abnormalities attacks of acute pancreatitis, and the incidence of the pancreas including exocrine and endocrine insufficiency.1 Exocrine pancreatic insufficiency (EPI) results in steatorrhea, fat-soluble vitamin deficiency (Vitamins A, D, E and K) and its sequelae, such as malnutrition, weight loss, osteoporosis and osteopenia. Endocrine insufficiency of the pancreas manifests as type 3c diabetes mellitus (DM).2 The most common symptom of CP is abdominal pain that is usually constant, severe, and epigastric with the disease is on the rise.2,4

CLINICAL PRESENTATION

The course of CP can be divided into three phases. The early phase occurs in the first five years of the disease, and is dominated by acute pancreatitis, pain, hospitalizations and surgical treatments. The middle phase occurs from five to ten years, and is when morphological changes

of the pancreas manifest such as strictures of the main biliary duct, pseudocysts and calcifications. The late phase occurs onwards of ten years and is approximately when DM and EPI occur. The course and presentation vary widely among patients, and phases may overlap.5

Abdominal pain is the most common symptom of CP and can be found in up to 80% of patients.3 Pain is usually described as severe, constant, and located in the epigastric region with radiation to the back, but patterns of pain can differ.3 Pain from CP severely impacts patient quality of life, and over 90% of patients have been hospitalized at least once for pain associated with CP.4 Psychological comorbidities due to pain, such as anxiety and depression, are common in these patients.6 Pain also carries a major financial weight on the health care system, costing over $600 million dollars annually.4,7 The reasons for chronic abdominal pain in CP are multifaceted and poorly understood. The cause of pain can be due to inflammation of the pancreas, or pancreatic duct obstruction by stones, and/or strictures. However, changes in the peripheral and central nervous system such as peripheral sensitization and pancreatic neuropathy may also lead to a maladaptive state of neuropathic pain. Acute flares of pain such as in recurrent pancreatitis may increase sensitization of the nervous system, leading to a self-perpetuating cycle of pain.2,8,9

Another cause of abdominal pain in patients with CP could be pancreatic pseudocysts, which occur in 20% to 40% of patients with CP.10 Pseudocysts more commonly cause abdominal pain, early satiety, nausea/vomiting, jaundice, and weight loss, but can lead to more serious problems such as rupture, infection, bleeding, and obstruction.10,11

EPI refers to inadequate pancreatic secretion or deficient activity of pancreatic digestive enzymes most importantly pancreatic lipase, which has a major role in fat digestion.12,13 EPI can be due to insufficient production of pancreatic enzymes, anatomic abnormalities obstructing the excretion of enzymes via the pancreatic duct, or desynchronization of enzyme delivery to food in the intestine.14 This results in the reduced absorption of essential fatty acids, fat-soluble vitamins A, D, E and K, calcium, magnesium, zinc, thiamine and folic acid leading to malnutrition, weight loss, steatorrhea, bloating and cramping.15,16 The prevalence of EPI ranges from 40% to 75% and is greatest in those with CP due to alcohol and/or tobacco use.2 Levels of Vitamin D have a significant role in bone homeostasis, with lower levels being a risk factor for osteopenia and osteoporosis.17 The prevalence rate for osteoporosis and osteopenia in CP patients is 23% and 40% respectively.18 Although, patients with CP may also have other risk factors for osteopenia or osteoporosis, such as low body mass index or smoking use.18

Endocrine insufficiency of the pancreas manifests as type 3c DM, a type of DM that results from pancreatic disease.2,19 The risk of new-onset DM after CP is 30%, and the risk of insulin-dependent DM is 15%.20 Risk factors for the development of type 3c DM in CP include smoking, duration of disease, history of pancreatic surgery, and the presence of calcifications on imaging of the pancreas.19 Patients with CP are at increased risk of large swings in blood glucose due to nutrient malabsorption, impaired glucagon secretion, and chronic pain leading to poor oral intake.19,21

Another complication of CP is pancreatic cancer. Over a 20 year period, it has been found that pancreatic cancer develops in about 5% or less of patients with CP, however, the risk is increased in those with genetic polymorphisms.22-24 The risk of malignancy in CP appears to even decrease over time, however this may be due to pancreatic cancer being misclassified as CP in the first few years of symptoms due to overlapping clinical symptoms or radiological evidence.25

ETIOLOGY

Alcohol use is the most common etiology of CP being found in 42% to 77% of patients, and the odds of CP increase 3.1 times in patients who consumed at least five alcoholic beverages per day.26, 27 Idiopathic CP is the second most common cause, which affects 28% to 80% of patients.26 In some cases, genetic variants have been observed.26 However, multiple studies confirm that about 60% of CP cases evolved from an acute pancreatitis or recurrent acute pancreatitis (RAP).2 The TIGAR-O system, an acronym for Toxic/Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent acute or severe pancreatitis, and Obstructive risk factors, is used to categorize factors that confer risk or contribute to the etiology of CP.2,28 Please see Table 1.28,29

DIAGNOSIS

The diagnosis of CP remains a clinical challenge, especially in the early stages, as the classic signs and symptoms of CP such as morphological changes of the pancreas or functional insufficiencies, are more often seen in its advanced stages and can require years to manifest.26 Nonetheless, CP must be suspected when patients have a history of chronic abdominal pain, relapsing acute pancreatitis, symptoms of EPI (steatorrhea, or weight loss), or history of alcohol abuse.29

Computed tomography (CT) or Magnetic Resonance Cholangiopancreatography (MRCP) are first-line in the diagnosis.2 When using CT, three-phase protocols are used including an unenhanced phase, a pancreatic parenchymal phase and portal venous phase scan.30 The presence of pancreatic atrophy, calcifications, or marked pancreatic ductal changes on CT establishes the diagnosis of CP.26 Pancreatic calcifications on CT can be seen in Figure 1. On MRCP, reduced T1 signal intensity can be seen, and is a sign of fibrotic replacement of the parenchyma, as well as ductal changes including main pancreatic duct dilation or irregularity, dilation of the side branches, and the presence of at least one stricture.26,30

If the diagnosis is still in question after crosssectional imaging, endoscopic ultrasonography (EUS) can be used, but sparingly due to the procedure’s invasiveness and lack of specificity due to similar changes in the pancreas seen in older individuals, those with a history of alcohol abuse or smoking, and diabetics.2,26 Conventional criteria (Minimal Standard Terminology) for diagnosing CP based on EUS include: Parenchymal abnormalities such as hyperechoic foci, hyperechoic strands, lobular contour or cysts, and ductal abnormalities such as main duct dilation, duct irregularity, hyperechoic margins, visible side branches or stones.31,32 However, the presence of five or more of the above criteria is frequently used to establish the diagnosis of CP.32 Of note, non-endoscopic ultrasound, often used in the assessment of patients with abdominal pain, is insensitive and can only detect advanced disease.33

Secretin-enhanced magnetic resonance cholangiopancreatography (s-MRCP) is costly, however is used in patients with a high clinical suspicion of CP without a confirmed diagnosis after the above imaging techniques.2 Secretin stimulates pancreatic fluid secretion, improves visualization of the ductal side branches, and evaluates duodenal filling.26

If all tests are inconclusive, endoscopic retrograde cholangiopancreatography (ERCP) may be considered to diagnosis CP, but has the possibility of high risk complications such as pancreatitis, hemorrhage, or infection, and it is not recommended for diagnosis unless all other imaging has been inconclusive.34 Laboratory tests for EPI can be used complementarily to imaging, however the sensitivity is low because large derangements in lab values occur only with significant loss (usually over ninety percent) of pancreatic function.2 For the primary care physician, some laboratory tests are more beneficial than others. For example, tests including fecal elastase-1 are widely available, noninvasive, and require only a small stool sample.16 Very low levels of fecal elastase-1 are associated with CP, however the test is less suitable for excluding mild to moderate EPI and more invasive tests such as a secretin or cholecystokinin (CCK)

stimulation tests are needed. It should be mentioned that results of the fecal elastase-1 test may be obscured due to do excessive dilution in those with large volume diarrhea.16,35 Tests such as CCK or secretin stimulation tests are not widely available and require an invasive procedure to collect pancreatic fluid as it enters the duodenum.16 Of note, lipase is often measured in acute pancreatitis, however is not useful in CP.26

To assess for endocrine insufficiency and the diagnosis of Type 3c DM, biannual fasting glucose and glycated hemoglobin should be obtained.26 The major criteria for the diagnosis of Type 3c DM are EPI, absence of antibodies associated with type 1 DM, and pathological pancreatic imaging. Minor criteria include absent pancreatic polypeptide secretion, impaired incretin secretion, no excessive insulin resistance, impaired β cell function, and low serum levels of fat-soluble vitamins.36

Finally, genetic testing is recommended in younger patients or those with a family history of pancreatitis or a pancreatitis-associated disorder, and patients with an unclear etiology.2

MANAGEMENT

Management of CP involves a multi-disciplinary approach between the patient, primary care physician, gastroenterologist, radiologist, anesthesiologist, nutritionist and many other healthcare professionals.

Alcohol cessation and tobacco smoking cessation are cornerstones of treatment, and continued alcohol and smoking use is associated with further disease progression.2,26,37 Thus, effective intervention is necessary with emphasis on patient education. Pancreatic enzyme replacement therapy (PERT) for EPI includes adding 30–40,000 IU of lipase starting with every meal and 15–20,000 IU with snacks.12,13,38 30,000 IU with each meal should alleviate steatorrhea.12-14 Since steatorrhea only develops in advanced disease, this dose reflects

only about 10% of healthy pancreatic secretion of lipase. Patients should take half of the total dose with the first bite of the meal and the other half during or at the end of the meal.12 There has been some demonstrated benefit to the addition of a proton pump inhibitor or H2 antagonist to prevent degradation of supplemented lipase.16 PERT should not be used to control pain, but rather improve symptoms of EPI such as discomfort, abdominal cramping, or flatulence. It is appropriate to advise small, frequent meals without restriction of fat, however a low-fiber diet is recommended as dietary fiber can prevent the action of pancreatic enzymes.2,16,26 Periodic evaluation of fat-soluble vitamin deficiencies and osteoporosis is warranted, and supplementation of vitamins when indicated is recommended.2,16,18,35

Metformin is first line therapy for Type 3c DM and is continued if insulin treatment is added for better glycemic control. If insulin is necessary, general insulin dosing for type 2 DM should be used. It is important to know that insulin and insulin secretagogue treatment may increase the risk of pancreatic malignancy, whereas metformin therapy may reduce it.20 The management of abdominal pain obeys a stepwise approach based on severity. First line agents such as acetaminophen and nonsteroidal anti-inflammatory drugs are used primarily, escalating to nonopioid analgesics, then to weak opioids, and lastly strong opioids depending on the severity of pain.26 It is important to control chronic pain and monitor opioid use as both can decrease appetite and oral intake, furthering malnutrition and weight loss.16 The celiac plexus blockade is a combination of local anesthetic and steroid that can be executed through endoscopy, interventional radiology, or surgery. A single blockade can alleviate pain for 3–6 months and reduce the need for oral analgesia.2 Given the oxidative nature of substances such as alcohol, antioxidants have been used to alleviate pain in combination with other modes of pain treatment. These include a combination of at least selenium, ascorbic acid, β-carotene, and methionine.2 Pregabalin can diminish transmission of pain through nerves, and in combination with antioxidants, reduces the need for non-opioid analgesics and the number of hospital admissions in CP.39

There is little evidence suggesting benefit of screening examination for pancreatic malignancy in all patients with CP, except in forms of CP due to hereditary pancreatitis.26 When necessary, screening is performed using EUS or MRCP, with some studies finding EUS to be superior.40 Screening for malignancy is not often performed because of its invasive and costly nature, difficulty due to the structural changes of CP, and the inability to alter treatment significantly or improve survival even if malignancy is found at an early stage.2,22,26 When indicated, screening for pancreatic malignancy in CP can be performed starting at age 40, but there is no consensus on timing of interval screening.29 However, a triphasic CT can be considered in patients with CP who present with jaundice, weightloss and/or increase in pain frequency.2,26,29,41 The M-ANNHEIM Surgery Score measures disease activity through a grading scale of one to four points using evaluation of patient’s pain, imaging findings, complications, need for surgical intervention, and status of exocrine and endocrine insufficiency. The score defines severity as minor, increased, advanced, marked or exacerbated, and a score at or above 9 establishes the risk for pancreatic surgery.42

For patients with obstructive symptoms due to stones, strictures or pseudocysts, drainage can be achieved through ERCP with sphincterotomy, stricture dilation, and/or duct stenting.34 Studies have shown that endoscopic therapy for treatment of pseudocysts has similar efficacy to surgical drainage and was associated with improved quality of life and decreased healthcare utilization.11 The most common indications for surgery include intractable pain after multiple treatment failures including endoscopic intervention, or suspicion of neoplasm.2,43 The Frey surgical procedure involves coring out the head of the pancreas and a longitudinal pancreaticojejunostomy, and resulted in more improvement of pain and quality of life when compared to other surgeries.44,45 In those with refractory pain, total pancreatectomy with islet autotransplantation can be discussed.3

CONCLUSION

The diagnosis and treatment of CP involves an organized, multi-disciplinary approach. CP is a complex condition with varying manifestations that can be severely distressing to patients resulting in lower levels of quality of life and even disability. Current management involves alcohol and tobacco cessation, multimodal control of pain, replacement therapy for EPI, assessing the sequelae of malnutrition, and screening for endocrine dysfunction such as type 3c DM.

References

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FROM THE LITERATURE

From The Literature

August 2022 • Volume XLVI, Issue 8

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Treatment of Colonic Diverticular Bleeding

No large studies have evaluated the effectiveness of treatment strategies for colonic diverticular bleeding (CDB), based on stigmata of recent hemorrhage (SRH). To identify the best strategy among combinations of SRH identification

in endoscopic treatment strategies, 5823 CDB patients were analyzed who underwent colonoscopy at 49 hospitals throughout Japan (CODE-BLUE j-Study). Three strategies were compared: SRH (definitive CDB) found and treated endoscopically, found SRH (definitive CDB) and treated conservatively, and without the presence of finding SRH (presumptive CDB), treated conservatively. 

With pair-wise comparison of outcomes in these groups, propensity score-matching analysis to balance baseline characteristics between the groups being compared was carried out. 

Both early and late recurrent bleeding rates were significantly lower in patients with definitive CDB treated endoscopically than in those with presumptive CDB treated conservatively (less than 30 days – 19.6% vs. 26%; less than 365 days – 33.7% vs. 41.6%, respectively).

In patients with definitive CDB, the early recurrent bleeding rate was significantly lower in those treated endoscopically than in those treated conservatively (17.4% vs. 26.7%) for a single test or hypothesis; however, correction for multiple testing of data removed this significance. The recurrent bleeding rate was also lower, but not significantly in those treated endoscopically (32% vs. 36%). 

Definitive CDB treated endoscopically showed significantly lower early and late recurrent bleeding rates than when treated conservatively in cases of SRH with active bleeding, non-active bleeding, and in the right side of the colon, but not the left side of the colon.

It was concluded that treating definitive CDB endoscopically was most effective in reducing recurrent bleeding over the short- and long-term, compared with not treating definitive CDB or presumptive CDB. An attempt should be made to find and treat SRH for suspected CDB.

Gobinet-Suguro,  M., Nagata, N.,Kobayashi, K., et al. “Treatment Strategies for Reducing Early and Late Recurrence of Colonic Diverticular Bleeding Based on Stigmata of Recent Hemorrhage: A Large, Multicenter Study.” Gastrointestinal Endoscopy 2022; Vol. 95, pp. 1210-1222.

Pickle Brine in the Treatment of Cirrhotic Cramps

Since muscle cramps are common among persons with cirrhosis and have been associated with poor health-related quality of life and since treatment options are limited, an attempt was made to determine whether pickle juice can improve muscle cramp severity.

A total of 82 patients were enrolled with cirrhosis and a history of greater than 4/10 muscle cramps in the previous month from December 2020 to December 2021. They were randomized 1:1 sips of pickle juice vs. tap water at cramp onset. Primary outcome assessed at 28 days identified the change in cramp severity measured by the visual analog scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included the proportion of days with VAS-cramps <5, change in sleep quality and global health-related quality of life measured through the EQ-5D. 

A total of 74 patients completed the trial, age 56.6 +/- 11.5 years, 54% male, 41% with ascites, 38% with encephalopathy and model for end-stage liver disease-sodium score 11.2 +/- 4.9. Many patients were receiving other cramp therapies at baseline. The baseline VAS for cramps was 4.2 +/- 3.4. The EQ-5D was 0.8 and 43% related sleep as poor. At trial completion, the respected value of the pickle juice and control arms were -2.25 +/- 3.61 points on the VAS for cramps, compared with control 35% and the change in sleep quality was not different. 

The end-of-trial EQ-5D was 0.78 vs. 0.80. No differences in weight change were observed in those with and without ascites. 

In this randomized trial, sips of pickle brine consumed at cramp onset improve cramp severity without adverse events. 

Tapper, E., Salim, N., Baki, J., et al. “Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Control Trial.” American Journal of Gastroenterology, 2022; Vol. 117, pp. 895-901.

Functional Gastrointestinal Symptoms in Celiac Disease

In order to explain persisting gastrointestinal symptoms on celiac disease (CD), patients on a gluten-free diet (GFD) and considering functional gastrointestinal disorders (FGIDs), an online health questionnaire was completed by adult members of Celiac UK in October 2018 that included validated questions on Rome IV FGIDs, nongastrointestinal somatic symptoms, anxiety, depression, quality of life, health care use, GFD duration, and its adherence using the celiac dietary adherence test score (with a value ≤ 13 indicating optimal adherence). The prevalence of FGIDs and associated health impairment in the celiac cohort was compared against an age- and sex-matched, population-based controlled group. Of the 863 individuals with CD (73% female; mean age 61 years), all were taking a GFD for at least 1 year, with 96% declaring that they had been on the diet for 2 or more years. The adherence to a GFD was deemed optimal in 61% (n = 523), with the remaining 39% (n = 340) nonadherent. Those adhering to a GFD fulfilled criteria for FGID in approximately one-half of cases, although this was significantly lower than nonadherent subjects (51% vs. 75%). The prevalence of FGIDs in GFDadherent subjects was significantly higher than in matched population-based controls (35%, OR, 2.0). This was accounted for by functional bowel (46% vs. 31%; OR, 1.9), and anorectal disorders (14.5% vs. 9.3%; OR, 1.7), but not functional esophageal (7.6% vs. 6.1%) or gastroduodenal disorders (8.7% vs. 7.4%).

Finally, GFD-adherent subjects with FGIDs were significantly more likely than their counterparts without FGIDs to have abnormal levels of anxiety (5% vs. 2%; OR, 2.8), depression (7% vs. 2%; OR, 3.6), somatization (31% vs. 8%; OR, 5.1), and reduced quality of life. It was concluded that one in 2 people with CD, despite having been on GFD for a number of years and demonstrating optimal adherence, have ongoing symptoms compatible with a Rome IV FGID. This is 2-fold the odds of FGIDs seen in an age- and sex-matched controls. The presence of FGIDs is associated with significant health impairment, including psychological comorbidity. Addressing disorders of gut-brain interaction might improve outcomes in this specific group of patients.

Parker, S., Palsson, O., Sanders, D., et al. “Functional Gastrointestinal Disorders and Associated Health Impairment in Individuals with Celiac Disease.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1315-1325.

Food Avoidance and Restriction in Irritable Bowel Syndrome

To evaluate and identify those patients and characterize the symptoms, quality of life and nutrient intake of patients with irritable bowel syndrome (IBS) with severe food avoidance and restriction, those patients who completed the IBS Quality of Life Instrument (IBS-QOL) at our secondary and tertiary centers were included. The 3 questions constituting the food domain were used to identify patients with reported severe food avoidance and restriction. The patients also completed validated questionnaires to assess stool form (Bristol Stool Form), gastrointestinal (GI) symptom severity (a score of IBS Severity Scoring System and Gastrointestinal Symptom Rating Scale-IBS), psychological distress (Hospital Anxiety and Depression Scale), GIspecific anxiety (Visceral Sensitivity Index), and somatic symptom severity (score of Symptom

Checklist–90-Revised and Patient Health Questionnaire–15). A 4-day food diary was used to analyze food intake in 246 patients.

 A total of 955 IBS patients (75% women; mean age 38.3), were included. In total, 13.2% of the patients reported severe food avoidance and restriction, and in these patients, all aspects of quality of life were lower and psychological, GI, and somatic symptoms were more severe. Reported severe food avoidance and restriction was associated with lower total energy intake and lower intake of protein and carbohydrates. In a logistic regression analysis, loose stools were found to be independently associated with reported severe food avoidance and restriction.

It was concluded that IBS patients with severe food avoidance and restriction constitute a subgroup with more severe symptoms overall, reduced quality of life and reduced intake of nutrients requiring acknowledgement of same in the clinical management of these patients. 

Melchior, C., Algera, J., Colomier, E., et al. “Food Avoidance and Restriction in Irritable Bowel Syndrome:  Relevance for Symptoms, Quality of Life and Nutrient Intake.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1290-1298.

Vedolizumab Vs. Anti-Tumor Necrosis Factor Agents in Older Adults with IBD

To evaluate the safety and effectiveness of IBD treatments in older adults, a study was carried out to compare the safety and effectiveness of anti-tumor necrosis factor (TNF)-a agents and vedolizumab in older adults with IBD.

A retrospective cohort study was conducted using an active comparator, new-user design for adults age 65 years and older with IBD-initiating anti-TNF-a agents and vedolizumab in the Medicare Claims Database from 2014 to 2017.

The primary safety outcome was infectionrelated hospitalization (excluding intraabdominal and perianal abscesses). Co-primary outcomes to estimate effectiveness were IBDrelated hospitalization, IBD-related surgery, and new corticosteroid use 60 days or more after biologic initiation. Propensity scores were performed, weighting to control for confounding and estimated adjusted hazard ratios and 95% confidence intervals using standardized morbidity ratio-weighted variables.

A total of 1152 anti-TNF-a new users were identified and 480 vedolizumab new users with a median age of 71 years in both cohorts and 11% were age 80 or older. Crohn’s disease patients

comprised 54% of the anti-TNF-a cohort and 57% of the vedolizumab cohort. There were no significant differences in demographics, health care utilization or frailty in both cohorts. More than half of both cohorts had a Charlson comorbidity index of 2 or higher. Vedolizumab users had a decreased risk of infection-related hospitalization (adjusted hazard ratio 0.47). There was no significant difference in the outcomes approximating effectiveness. 

It was concluded that older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNFs. There was no difference observed in effectiveness defined by hospitalizations, surgery or new corticosteroid use.

Kochar, B., Pate, V., Kappelman, M. “Vedolizumab is Associated with a Lower Risk of Serious Infections Than AntiTumor Necrosis Factor Agents in Older Adults.” Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1299-1305.

Perianal Fistula Treatment Improves with Higher Anti-TNF-a Levels

To evaluate the association between anti-TNF drug levels and radiologic outcomes in perianal fistulizing Crohn’s disease, a cross-sectional, retrospective, multicenter study was undertaken. Patients with perianal fistulizing Crohn’s disease on maintenance infliximab or adalimumab with drug levels within 6 months of perianal MRI studies were included. Patients receiving dose changes for fistula surgery between drug level and imaging were excluded. Radiologic disease activity was scored using the Van Assche Index, with an inflammatory subscore calculated using indices: T2-weighted imaging hyperintensity, collections >3 mm diameter, rectal wall involvement. Primary endpoint was radiologic healing (inflammatory subscore ≤6). Secondary end point was radiologic remission (inflammatory subscore =0).  Of 193 patients (infliximab, n = 117; adalimumab, n = 76) patients with radiologic healing had higher median drug levels compared with those with active disease (6.0 vs. 3.9 for infliximab, 9.1 vs. 6.2 for adalimumab). Patients

with radiologic remission also had higher median drug levels compared with those with active disease (infliximab 7.4 vs. 3.9 ug/mL, adalimumab 9.8 vs. 6.2 ug/mL). There was a significant incremental reduction in median inflammatory subscores with higher anti-TNF drug level tertiles. 

It was concluded that higher anti-TNF drug levels were associated with improved radiologic outcomes on magnetic resonance imaging in perianal fistulizing Crohn’s disease, with an incremental improvement in higher drug level tertiles for both infliximab and adalimumab.

De Gregorio, M., Lee, T., Krishnaprasad, K., et al.  “Higher Anti-Tumor Necrosis Factor-a Levels Correlate With Improved Radiologic Outcomes in Crohn’s Perianal Fistulas.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1306-1314.

Avoidant Restrictive Food Intake Disorder in IBD

Patients with IBD alter their dietary behaviors to reduce disease-related symptoms, avoiding feared food triggers, and control inflammation. To estimate the prevalence of avoidant/restrictive food intake disorder (ARFID), evaluate risk factors and examine the association with risk of malnutrition in patients with IBD, a crosssectional study recruiting adult patients with IBD from an ambulatory clinic was carried out. ARFID risk was measured using the Nine-Item ARFID screen. Nutritional risk was measured with the Patient Generated-Subjective Global Assessment. Logistic regression models were used to evaluate the association between clinical characteristics and a positive ARFID risk screen. Patient demographics, disease characteristics, and medical history were abstracted from medical records. 

Of the 161 participants (Crohn’s 45.3%, UC 51.6%, IBD-unclassified, 3.1%), 28 (17%) had a positive ARFID risk score (≥2.4). Most participants (92%), reported avoiding 1 or more foods having active symptoms, and 74% continued to avoid 1 or more foods, even in the absence of symptoms. Active symptoms (OR 5.35) and inflammation (OR 3.3), were significantly associated with positive ARFID risk. Patients with a positive ARFID risk screening were significantly more likely to be at risk for malnutrition (69.7% vs 15.8%). 

It was concluded that avoidant eating behaviors are common in IBD patients, even when in clinical remission. Patients who exhibit active symptoms and/or inflammation should be screened for ARFID risk, with referrals to registered dietitians to help monitor and address disordered eating behaviors and malnutrition risk.

Yelencich, E., Truong, E., Widaman, A., et al. “Avoidant Restrictive Food Intake Disorder Prevalent Among Patients with Inflammatory Bowel Disease.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1282-1289.

Glucagon-Like Peptide-1 Receptor Agonist and Cirrhosis

To compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas or sodium-glucose co-transporter-2 (SGLT-2) inhibitors in reducing

decompensation events, among patients with cirrhosis and type 2 diabetes.

A population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis in a commercial healthcare database (IBM MarketScan). A 3-pair wise 1:1 propensity score (PS)matched cohorts of adults initiating GLP1RAs or a comparator medication (ie, DPP-4 inhibitors), sulfonylureas or SGLT-2 inhibitors. Patients were followed in an as-treated approach for decompensation events (ie, ascites, SBP, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios

(HRs) and 95% confidence intervals for >90 baseline characteristics.

Over 132 days of median follow-up (interquartile range 73-290 days), PS-matched ratios of any decompensation were significantly lower among GLP-1RA initiators vs. DPP-4 inhibitor initiators (105.2 vs. 144 per 1000 person-years; HR 0.68; n = 1431 pairs), and vs. sulfonylureas (97.3 vs. 144 per 1000 PY; HR 0.64; 95%, n = 1246 pairs). 

Similar, inverse associations were found for individual decompensation events, including ascites, SBP, or hepatorenal syndrome (HR 0.66; 95%; and HR 0.66, respectively; esophageal variceal hemorrhage (HR 0.62 and HR 0.59, respectively), hepatic encephalopathy (HR 0.76 and HR 0.60, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar with GLP1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR 0.89).

It was concluded that among cirrhotic patients with type 2 diabetes, there was a high rate of decompensation consistent with previous reports and those rates were substantially lower among GLP-1RA initiators, compared with DPP-4 inhibitors or sulfonylureas. 

Glucagon-Like Peptide-1 Receptor Agonist and Cirrhosis

To compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas or sodium-glucose co-transporter-2 (SGLT-2) inhibitors in reducing decompensation events, among patients with cirrhosis and type 2 diabetes.

A population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis in a commercial healthcare database (IBM MarketScan).

A 3-pair wise 1:1 propensity score (PS)matched cohorts of adults initiating GLP1RAs or a comparator medication (ie, DPP-4 inhibitors), sulfonylureas or SGLT-2 inhibitors. Patients were followed in an as-treated approach for decompensation events (ie, ascites, SBP, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios (HRs) and 95% confidence intervals for >90 baseline characteristics.

Over 132 days of median follow-up (interquartile range 73-290 days), PS-matched ratios of any decompensation were significantly lower among GLP-1RA initiators vs. DPP-4 inhibitor initiators (105.2 vs. 144 per 1000 person-years; HR 0.68; n = 1431 pairs), and vs. sulfonylureas (97.3 vs. 144 per 1000 PY; HR 0.64; 95%, n = 1246 pairs).  Similar, inverse associations were found for individual decompensation events, including ascites, SBP, or hepatorenal syndrome (HR 0.66; 95%; and HR 0.66, respectively; esophageal variceal hemorrhage (HR 0.62 and HR 0.59, respectively), hepatic encephalopathy (HR 0.76 and HR 0.60, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar with GLP1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR 0.89). It was concluded that among cirrhotic patients with type 2 diabetes, there was a high rate of decompensation consistent with previous reports and those rates were substantially lower among GLP-1RA initiators, compared with DPP-4 inhibitors or sulfonylureas.

Simon, T., Patorno, E., Schneeweiss, S. “Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients with Cirrhosis and Diabetes.”  Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1382-1393

HCC Risk with Positive HBeAg Positivity in Chronic Hepatitis B

Antiviral treatment from HBeAg-positive status may attenuate the integration of hepatitis B virus DNA into the host genome, causing hepatocellular carcinoma (HCC). An investigation was conducted in Korean patients who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative patients. The results in the cohort were validated in a Caucasian PAGE-B cohort. 

A total of 9143 Korean patients (mean age 49.2 years), were included: 49.1% were HBeAgpositive and 49.2% had cirrhosis. During followup (median, 5.1 years), 916 patients (10%), developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic cohort. However, in the noncirrhotic cohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [a-HR], 0.41; propensity score-matching (aHR 0.46), and inverse probability weighting analyses (aHR 0.44). In the Caucasian cohort (n = 719; mean age 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the noncirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR 0.21).

This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis. 

Jang, H., Yoon, J., Park, S., et al.  “Impact of HBeAg on Hepatocellular Carcinoma Risk Through an Oral Antiviral Treatment in Patients With Chronic Hepatitis B.” Clinical Gastroenterology and Hepatology 2022; Vol. 20, pp. 1343-1353.

Vitamin E as a Preventative Approach for NAFLD

Vitamin E supplementation has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD) for nondiabetic patients, but in order to evaluate its preventative effects, assessment of dietary vitamin E intake was carried out with disease phenotypes and vitamin E levels were evaluated with the development of NAFLD.

Data from greater than 210,000 participants demonstrated that increased dietary vitamin E associates with reduced rates of several gastrointestinal diseases and with reduced overall mortality. Diabetic and overweight subjects with increased vitamin E intake had fewer NAFLD diagnoses. 

The findings revealed relevance of vitamin E consumption for several gastrointestinal diseases with recommendation for further mechanistic and therapeutic investigations. 

Scorletti, E., Creasy, K., Vujkovic, M., et al.  “Dietary Vitamin E Intake is Associated with a Reduced Risk of Developing Digestive Diseases and Nonalcoholic Fatty Liver Disease.”  American Journal of Gastroenterology 2022; Vol. 117, pp. 927-930.

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