Fundamentals of ERCP, Series #12

Bile Leaks

August 2024 • Volume XLVIII, Issue 8
Abdul Kouanda,Andrew Ofosu

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Introduction

Bile duct leaks (BDL) are characterized by a mural defect in the intrahepatic and or extrahepatic biliary tree leading to leakage of bilious fluid into the abdominal cavity.1 Post-surgical causes of bile leak after laparoscopic cholecystectomy and orthotopic liver transplant (OLT) occur in 1% and 26% of cases, respectively.2

Other non-surgical procedures that potentially lead to iatrogenic bile leak include liver biopsy, trans-jugular intrahepatic portosystemic shunting (TIPS) procedures, and hepatic tumor ablation therapies.2 Most non-iatrogenic bile leaks are due to trauma. These include penetrating injuries, such as gunshot or knife wounds, or blunt trauma, such as falls or motor vehicle accidents.3

The clinical presentation of bile leaks ranges from asymptomatic bile drainage to life-threatening conditions such as biliary peritonitis. Typical presentation symptoms include abdominal pain, fever, ascites, and jaundice.4 Regardless of the etiology and clinical presentation, bile leaks can cause significant morbidity and, rarely, mortality in afflicted patients.5 Early diagnosis is critical, with various diagnostic imaging modalities that have been described. Ultrasound and Computed Tomography (CT scan) can detect intra-abdominal collections or biliary dilation, suggesting common bile duct (CBD) obstruction.6 Hepatobiliary iminodiacetic acid (HIDA) scan can be useful in detecting biliary leaks, particularly when ultrasound and CT scan are equivocal; however, they cannot anatomically localize the site of leak.7 Magnetic resonance cholangiopancreatography (MRCP) can also detect a bile leak if transabdominal ultrasound is nondiagnostic. However, its use is limited by its inability to offer therapeutic interventions.8

Endoscopic   retrograde      cholangiopancreatography (ERCP) provides a minimally invasive technique that replaces surgery as the preferred treatment in most patients with biliary leaks. The benefits of ERCP include identifying the leak site in real time coupled with the ability to perform direct therapeutic interventions to treat the patient and heal the leak directly. 

ERCP-based approaches to patients with bile leaks include performing a biliary sphincterotomy, with or without placement of a trans papillary biliary stent. Endoscopic therapy aims to eliminate the trans-papillary pressure gradient, which promotes trans-papillary bile flow and potentially bridges or covers the leak, promoting healing.2 I.e., in a normal patient, the only route for bile to exit the biliary tree is the Sphincter of Oddi/Ampulla of Vater. In the setting of a bile leak, the leak site itself becomes the path of least resistance for bile to flow. Endoscopic therapy aims to make the path of least resistance for bile flow to be towards the duodenum. Once this situation is established, bile flow through the site of the leak itself will diminish greatly and the leak will heal.

ERCP is highly effective for treating bile leaks; however, in the presence of a perihepatic bile collection, percutaneous drainage is an adjunctive therapy that should be considered to achieve symptom relief and to reduce the risks of abscess formation and bile peritonitis. Surgical management of bile leaks is performed very rarely in modern practice and is reserved for therapeutic failures or bile leaks from high-grade injuries, or for patients who cannot undergo ERCP due to anatomic constraints i.e. postsurgical anatomy.2 This article focuses on the different etiologies of bile leaks, clinical presentation and diagnosis, and the role of ERCP in the management of bile leaks. 

Classification of Bile Leak

There are several classification systems for bile duct injury post-cholecystectomy, including the Bismuth classification, The Strasberg classification, and the Amsterdam classification.10,11 Of these, the Amsterdam classification is the most straightforward. It characterizes bile duct injuries and leaks into four types: A: cystic duct or aberrant hepatic duct leak, B: major bile duct leak with or without concomitant stricture, C: bile duct stricture without leakage, D: complete transection of the duct. Among patients with Amsterdam type A leaks, the most common type of bile duct injury encountered after cholecystectomy, success rates for ERCP-based techniques approach 100%, whereas Amsterdam type D leaks generally require surgery.12 

Sandha et al. proposed a two-category system of grading bile leak severity.13 They sub-categorized bile leaks into two major categories:

Low-grade (LG, i.e., a leak identified only after opacification of the intrahepatic biliary duct) 

High-grade (HG, i.e., a leak observed fluoroscopically before intrahepatic opacification.)

This classification aimed to provide a practical endoscopic classification system for bile leak after cholecystectomy for optimal endoscopic management. 

Role of ERCP in the Management of Bile Leaks 

ERCP has emerged as a preferred minimal invasive approach for biliary leaks’ primary treatment.

Binmoeller et al., in 1991, first reported a case series on the endoscopic management of postoperative biliary leaks. In their study, endoscopic treatment was technically successful in 95% of cases and resulted in healing of the leak itself in 82% of cases.14 Modern rates of technical and clinical success have only improved over time.

Despite favorable outcomes of ERCP, there is still an ongoing debate on the principles of endo-therapy regarding the optimal time to intervene, and which technique to use (sphincterotomy with or without placement of stents), the size of stents, and the type of stent (metal versus plastic).15

I. Timing of ERCP

There is no consensus on the appropriate timing of ERCP for biliary leaks, with variability in the timing of ERCP between different centers. In general, most patients with bile leaks can be treated electively, especially if a biliary fluid collection (i.e. biloma) has been percutaneously drained already. 

A retrospective multicenter study of patients with bile leaks showed that there was no statistically significant difference in BDL healing among patients who underwent ERCPs performed within 1 day compared with those performed on day 2 or 3 or after 3 days of bile duct injury (91.2%, 90%, and 88.5%, respectively; P = .77). Overall, adverse event (AE) rates were similar among the 3 groups (21.1%, 22.9%, and 24.6%, respectively; P = .81). However, the 90-day mortality rate was lower in the group who underwent ERCP on day 2 or 3 than in those admitted for ERCP within 1 day or after 3 days, but this difference was not statistically significant.16 The findings of this study demonstrated that the overall success rates and AEs after ERCP were not dependent on the timing of the procedure on the discovery of the bile leak. This study has also been used to demonstrate that most bile leaks do not warrant emergent ERCP. It is important to note that the relationship between the ERCP’s timing and outcomes in patients with an undrained or infected biloma were not evaluated in this study.16

Similarly, Abbas et al. performed a retrospective, nationwide, inpatient analysis of 1,028 patients who underwent ERCP for a bile leak. ERCP was classified as emergent, urgent, and expectant if it was performed within 1 day, after 2 or 3 days, or after 3 days after the biliary leak occurred, respectively. Their results showed that post-ERCP AEs were similar (11%, 10%, and 9% for emergent, urgent, and expectant ERCP, respectively (P = .577). This study further promoted the notion that most bile leaks do not need to be treated emergently via ERCP. However, in-hospital mortality showed a U-shape trend of 5%, 0%, and 2% for emergent, urgent, and expectant ERCP, respectively (P < .001).17 The authors suggested the apparent high mortality in patients who underwent an emergent ERCP was likely to a selection bias; patients with initial clinical severity were more likely to undergo emergent ERCP. 

Nevertheless, while consensus guidance on the timing for endoscopic therapy for BDL is lacking, limited data from the above studies demonstrate that the timing of ERCP is not a significant predictor of post-ERCP outcomes. It is conceivable that ERCP should not be delayed for more than 3 days, particularly if evidence of a persisting bile leak. More large prospective studies are warranted to determine the timing of ERCP in patients with bile duct leaks.

II. Sphincterotomy versus stent placement without sphincterotomy and combination therapy

Currently, there is no consensus on the optimal endoscopic intervention for the management of bile leaks regarding sphincterotomy (EST) versus bile stent placement (BS) without sphincterotomy or combination therapy (EST+BS). Any or all of these approaches should decompress the biliary tree and promote drainage to the duodenum with subsequent bile leak healing. Multiple studies have compared the efficacy of sphincterotomy versus biliary stenting with sphincterotomy with conflicting results. 

In a prospective study of patients with post-cholecystectomy bile leaks undergoing EST+10 Fr BS placement versus a 7 Fr BS without EST, resolution occurred in100% of patients in both groups, arguing against the need for EST at all in this setting. The authors concluded that endoscopic therapy with small diameter biliary stents without endoscopic sphincterotomy is effective and safe as endoscopic sphincterotomy followed by insertion of large-diameter stents in treating biliary leaks after laparoscopic cholecystectomy.18

In contrast, Abbas et al., in a nationwide analysis database, demonstrated that combination therapy of EST+BS or BS monotherapy had lower failure rates of 3% and 4%, respectively, compared with EST monotherapy which had a failure rate of 11% (P <.001). On multivariate analysis, both combination (EST+BS) and BS monotherapy were less likely to fail than sphincterotomy monotherapy.17 It should be noted that EST monotherapy may be suitable in patients who are felt to be at risk for poor follow-up, as it does not involve stent placement and subsequent ERCP for removal.

More recently, Vlaemynck et al. conducted a network meta-analysis comprising 11 studies to compare EST vs. BS vs. combination (EST+BS) treatment in treating bile leaks. Stenting was further stratified into leak-bridging and short stenting (i.e. stenting only across the ampulla and not the leak site itself).19 Compared with EST monotherapy, the combination therapy with leak-bridging stenting had a significantly higher success rate.19 Interestingly, there was no significant difference between biliary stent monotherapy (either leak-bridging or short stents) and EST monotherapy.19 It is worth noting that a leak-bridging stent was inserted, when possible, whereas, in patients with leaks that were located too peripherally within the biliary tree, a short stent was used.

In general, it is not necessary to bridge the leak site, although it could be considered technically feasible. Some endoscopists prefer to place the proximal end of the stent into the affected system in hepatic, intrahepatic, and sub vesical bile duct (duct of Luschka) leaks. There is often a perception that bridging the leak site will promote healing more rapidly, but data to support this notion is lacking. 

In the absence of consensus guidelines focusing on endoscopic management of biliary leaks, limited data suggest stenting with or without sphincterotomy has better outcomes than sphincterotomy alone. It is conceivable that the selection of endoscopic intervention (e.g., sphincterotomy alone, stenting alone, combination therapy) should be based on multiple factors, including the presence of a retained CBD stone, severity of the bile leak, and patient’s risk for complications of sphincterotomy (e.g., bleeding, perforation).

III. Large diameter stents versus small diameter stents

The optimal size of the stent introduced during ERCP is still debatable. In general, 10 F plastic biliary compared to 7 Fr stents have potentially more durable patency and are likely to improve downstream flow; however, limited data suggests so. 8.5 Fr stents are also widely available and can be placed without the need to perform a biliary sphincterotomy and may be a good option for many patients as they offer patency rates comparable to that of 10 Fr stents.

In a randomized trial of 7 Fr vs. 10 Fr stents for post-cholecystectomy bile leaks, there was no difference in success rates between the two groups.20 The stent size also did not affect the outcome of the endoscopic intervention in their cohort of patients. It is important to note that most patients included in this study had minor biliary leaks. Therefore, generalizability to the treatment of more significant biliary leaks cannot be confirmed.

Types of Bile Duct Leaks and Treatment Post-Cholecystectomy Bile Leaks

Bile leaks are reported in up to 1.1% of patients undergoing cholecystectomy and are usually associated with complex operations, technical problems, or conversion to open cholecystectomy.21-23 Post-cholecystectomy bile leaks make up more than 80% of all post-surgical bile leaks.16 Leaks can occur from the cystic duct remnant (“stump”) in up 77% of cases.21 Cystic duct remnant leaks may occur due to failure of clip ligation or iatrogenic injury during surgery. Cystic duct remnant leaks can also occur in the absence of any surgical error. 

Patients usually present with increased bilious output from the surgical drain within days of the procedure, but delayed presentations up to 30 days postoperative can also occur.24 Drain fluid bilirubin greater than three times the serum bilirubin is commonly used to support the diagnosis of a bile leak, but in practice this is rarely checked. If the drain output is obviously bilious, a leak is likely present. 

In patients with severe bile leaks, abdominal pain, fevers, distension, and jaundice may also occur. Additional workup may include abdominal ultrasound to assess for fluid collection or biliary tree caliber. MRCP with a biliary contrast agent such as Eovist or Cholescintigraphy using 99mTC-hepatic iminodiactic acid (HIDA scan) can be used to confirm the presence and location of post-cholecystectomy bile leaks and assess for concomitant choledocholithiasis prior to any interventions being performed, but is not required in most cases as once the presence of a leak is established ERCP is performed.

ERCP is the mainstay of therapy for post-cholecystectomy bile leaks. Endoscopically placed biliary stents are typically left in situ for 4-6 weeks. Percutaneous drains, if present, should be removed once drain output has resolved or is less than 10cc per day. In most patients with bile duct leaks, drains are typically removed by the time of the follow-up ERCP. At follow-up ERCP, an occlusion cholangiogram is generally performed to confirm that the site of the leak has healed. If the leak persists, a new stent can be placed and the patient can be scheduled for a follow up ERCP in another 4-6 weeks. ERCP is highly successful in treating post-cholecystectomy leaks, with success rates ranging from 90-95% of cases.25,26

In patients with biloma collections, percutaneous drainage is usually required in addition to ERCP. However, if the patient is not symptomatic from the biloma, a reasonable strategy is to perform endoscopic therapy of the leak and allow spontaneous reabsorption of the biloma. If the biloma persists despite endoscopic therapy, then percutaneous drainage can always be performed at a later date.  

In up to 10% of bile leak cases following cholecystectomy the leak may persist despite endoscopic therapy.27 In these cases, one must consider the possibility of transection of an aberrant right hepatic duct, which can cause leakage from both the proximal and distal aspects of the transection. An MRCP with or without Eovist or a HIDA scan can be performed if suspicion remains high prior to performing ERCP. 

In patients with refractory bile leaks, fully covered self-expanding metal stents (FCSEMS) or multiple plastic stents are attractive options. In a prospective series of patients who failed conventional ERCP with plastic stents, FCSEMs resulted in the resolution of the bile leaks in 94% of patients.28 In a retrospective study of patients with post-cholecystectomy bile leaks that were unsuccessfully treated with a combination of biliary sphincterotomy and the placement of a 10F trans-papillary biliary stent, the subsequent placement of a FCSEM led to much higher success rates than multiple plastic stents (100% vs. 65% respectively, p<.004).29 

It is plausible that the large metallic stent diameter diverts more flow away from the leak site, causing a significant decrease in the pressure gradient at the papilla. Additionally, the FCSEMS directly covers the leak site and exerts expansile pressure along the bile duct wall, increasing the potential for sealing/occluding the leak leading to the healing of the bile leak. FCSEMS placement for bile leaks is fully within the standard of care at this time.

Bile Leak Post-Liver Transplant

The incidence of bile leak after liver transplantation (LT) ranges from 2% to 25% and usually occurs within 1 to 3 months post-transplantation.30 Bile leaks are the second most common biliary adverse event following liver transplant and are a cause of significant morbidity for liver transplant recipients.31 Moreover, bile leaks are considered an independent risk factor for developing early or late anastomotic biliary strictures, highlighting the importance of timely diagnosis and management.32 Bile leaks post liver transplant are classified as being anastomotic or non-anastomotic.31

Anastomotic bile duct leaks occur due to technical challenges in reconstruction, such as excessive dissection of periductal tissue at the anastomosis or ischemic necrosis at the bile duct anastomosis, or may simply be due to impaired healing following surgery.30 Non-anastomotic bile leaks originate from either failed ligation of the cystic duct remnant, elective or inadvertent T-tube removal, the cut surface of a partial liver in recipients of living donor allografts, or deceased donor split-liver transplants.33

Post-transplant bile leaks can be classified as early when they occur within 4 weeks of liver transplant and late when they occur beyond 4 weeks. Early bile leaks usually arise from the anastomosis and may be related to insufficient blood flow from the hepatic artery to the anastomosis.34 Late bile leaks tend to be rare and occur due to recurrence or persistence of early complications, delayed removal of T-tubes or biliary stent migration and perforation, and hepatic artery thrombosis.30

The clinical presentation of a bile leak post liver transplant varies with the extent of the leak. A bile leak should be suspected in any patient who develops abdominal pain, fever, or any sign of peritonitis following liver transplant, especially after T-tube removal. Some patients, especially those on corticosteroids, may be asymptomatic, with no symptoms of pain or fever. In asymptomatic patients, bile leak should be suspected if there are unexplained elevations in serum bilirubin, fluctuation in cyclosporine levels, or bilious ascites.35

The role of transabdominal ultrasound (US) is limited to early detection of biliary leaks, as it lacks sufficient sensitivity to detect small but clinically significant ductal changes and more delayed leaks.36 MRCP has also been studied to detect biliary complications after OLT but has not been effective in identifying the location of the site of the leak itself unless hepatobiliary contrast is used.37 Small anastomotic leaks can be diagnosed with a T-tube cholangiogram in recipients with a T-tube, although the use of a T-tube following liver transplant is becoming uncommon. 

ERCP remains the gold standard for the diagnosis and therapy of bile leaks following liver transplant.34 Individualized endoscopic management of bile leaks is determined by the type of biliary anastomosis and the severity of the bile leak. In a retrospective study of patients with bile leak after liver transplant, BS+/-EST had a much higher resolution rate than EST monotherapy (94% vs. 58%, p<.001). This study demonstrated that ERCP with plastic stent placement is highly successful and more effective than sphincterotomy alone for post-LT bile leak treatment.31

Simple biliary defects including the T-tube exit site, the cystic duct remnant, or small anastomotic leaks typically heal within 2 to 6 weeks; hepatic surface leaks that may take up to 8 weeks to resolve.38 However, stents can be left in place for as long as needed clinically as some patients may experience delayed healing due to the use of immunosuppression.39 Small anastomotic leaks can be managed in recipients with a T-tube by leaving the tube open to drainage without further intervention.39 If symptoms persist, ERCP (with or without sphincterotomy) with biliary stent placement may be indicated.39

There is limited data on the safety and the formal efficacy of partially or, more commonly, fully covered self-expanding metal stents for the treatment of post-liver transplant bile leaks that have not been established, although in practice the use of FCSEMS in this context is widespread. In a retrospective series of 31 patients with post-liver transplant bile leaks, endoscopic therapy was performed with the placement of SEMS (3 partially CSEMS, 18 FCSEMS with fins, and 10 FCSEMS with flare ends). Clinical success was achieved in 100%, 77.8%, and 70%, respectively. Postplacement complications included cholangitis (1) and proximal migration (1), both of which occurred among patients treated with FCSEMS with fins. Large studies with long-term follow-up data regarding the safety, efficacy, and cost-effectiveness of CSEMS are needed.40

Anastomotic leaks are less common among liver transplant patients with Roux-en-Y hepaticojejunostomy anastomosed. However, for such patients with a bile leak, ERCP is technically challenging and may often not be feasible due to anatomic difficulties in reaching the biliary anastomosis. Management of these patients usually involves percutaneous biliary drainage and decompression, often with an internal/external catheter.41 Surgery or a percutaneous transhepatic approach is reserved for patients in whom ERCP is unsuccessful or, more commonly, not technically feasible, particularly when biliary extravasation is major, or the anastomosis is significantly disrupted.41 Large or infected bilomas should be drained percutaneously by placing an indwelling catheter and administering intravenous antibiotics.41

Post-traumatic bile leaks 

Bile leaks can result from penetrating injuries, such as gunshot (GSW) or knife wounds, or from blunt trauma, such as bicycle, motor vehicle (MVA) or motorcycle accidents (MCA).3 The incidence of bile leaks following hepatobiliary trauma ranges from 0.5 to 21%, depending on the criteria and methods used to diagnose the bile leak itself.3 The clinical presentation of traumatic bile duct injury is often nonspecific and can include right upper quadrant pain, fever, nausea with vomiting, and/or jaundice. Traumatic biliary leaks can lead to organized collections or unorganized intra-abdominal bile spillage with subsequent bile peritonitis. The presence of bilious output from a surgically placed percutaneous drains or at the surgical incision site should be considered evidence of a bile leak. 

There is limited data on the endoscopic management and outcomes of biliary injury after blunt or penetrating abdominal trauma due to a low frequency of presentation of traumatic bile duct injuries. Endoscopic management of traumatic biliary leaks is extrapolated from data on iatrogenic leaks after cholecystectomy. The treatment is often based on the injury’s extent and the mechanism of the injury itself, associated organ injuries, and local expertise. 

ERCP is a valuable tool for diagnosing and treating post-traumatic bile leaks, mainly when repeat surgery is deemed a substantial risk and control of post-traumatic BL is incomplete. 

In a retrospective series of 10 patients with traumatic bile leaks over a three-year period, ERCP resulted in resolution in 90% of patients. The majority of patients in this study had a penetrating injury from a GSW (5 patients), blunt injuries from a MVA (4 patients), and injury secondary to a fall in 1 patient. There were no ERCP-related adverse events.42 In a retrospective series of 14 patients who underwent ERCP for traumatic bile leaks over a 5-year period, the success rate of endoscopic therapy was 100%. The etiologies included blunt trauma from MVA in 8 patients, motorcycle accident in 3 patients, and penetrating injury from a GSW in 3 patients. The mean duration of follow-up was 85.6 days (range 54-175 days). There were no ERCP-related adverse events.43

The aforementioned studies highlight the role of ERCP in managing traumatic bile duct leaks. If an extrahepatic biliary fluid collection is present, percutaneous drainage of intra-abdominal fluid is an adjunctive treatment modality of choice to decrease the high risk of infection.

Bile leaks after liver resection

Bile leakage post liver resection (LR) is associated with an increased rate of sepsis, liver failure, and higher postoperative mortality.44 The frequency of bile leaks after hepatectomy ranges from 3.6 to 10%.45 Bile leaks following LR can be classified as central bile leaks if they occur from the hilum or common hepatic duct or peripheral bile leaks if they arise from the resection surface.46 Central bile leaks after LR tend to manifest as larger volumes of bile spillage into the peritoneum and have been associated with a worse prognosis than peripheral leaks.46 Risk factors for bile leaks after LR are related to technical aspects of the surgery, including longer operative time, left hemi-hepatectomy, segment IV resection, and advanced age.47

Options for managing post-LR leaks include surgical repair, percutaneous drainage, and endoscopic therapy. The majority of post-LR can be managed with ERCP with stent placement with or without biliary sphincterotomy. Compared to peripheral leaks, placement of stents spanning the area of the leak in central leaks is preferred. ERCP is typically repeated after 2–6 weeks, and the stents are removed if the leak has healed and replaced if additional treatment is indicated.

Dechene et al. evaluated the efficacy of ERCP in treating bile leaks after liver resections in a series of 60 patients. In 46 patients (77%), endoscopic therapy successfully resolved the bile leak without further surgical interventions. The logistic regression model identified only endoscopic sphincterotomy without stent insertion (P =.002) as highly significant for the failure of endoscopic therapy.48

Refractory bile leaks

ERCP effectively resolves 70 % – 100 % of post-cholecystectomy bile leaks and up to 84 % of bile leaks after cadaveric liver transplant.49,50 Despite the safety and efficacy of endo-therapy for bile leaks, refractory bile leaks do occur, leading to multiple endoscopic interventions and, rarely, surgery.51 The optimal approach for refractory/complex leaks has not been clearly defined but is approached similarly to post-cholecystectomy leaks with FCSEMS or simultaneous placement of multiple plastic stents, depending on the clinical scenario. 

Other innovative endoscopic treatments of refractory biliary leakage include n-butyl-2 cyanoacrylate glue occlusion during ERCP and endoscopic coil placement. Currently, the safety and success of these techniques are based on limited case reports. Large cases series are currently warranted to determine the role of these therapies.52,53

Conclusion

Bile leaks are a common and well-described complication of hepatobiliary and gallbladder surgery, and with early and prompt recognition treatment usually results in excellent outcomes. Post-cholecystectomy bile leaks are the most common post-surgical leaks. Bile leaks also occur after liver transplant, liver resection, traumatic injury, and iatrogenic bile duct injury during an unrelated intraabdominal surgery, a liver biopsy, or other interventions. With the advent of endoscopic therapy, the surgical treatment of bile leaks is no longer commonplace and reserved for rare refractory leaks. Endoscopic therapy is generally performed using the combination of endoscopic biliary sphincterotomy and biliary stent placement. Although endoscopic biliary sphincterotomy monotherapy has been advocated in the past, the preponderance of the literature seems to favor the addition of a biliary stent for improved outcomes. The data also suggest that the stent should bridge the leak if feasible, but this is not mandatory. Among patients with refractory leaks, fully covered metal stents and multiple plastic stents represent an attractive option that has been shown to improve resolution rates. Further large and randomized studies are needed to study topics such as the timing of ERCP and management of refractory leaks. 

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29. Canena J, Liberato M, Meireles L, Marques I, Romão C, Coutinho AP, Neves BC and Veiga PM. A non-randomized study in consecutive patients with postcholecystectomy refractory biliary leaks who were managed endoscopically with the use of multiple plastic stents or fully covered self-expandable metal stents (with videos). Gastrointestinal endoscopy. 2015;82:70-8.

30. Pascher A and Neuhaus P. Bile duct complications after liver transplantation. Transpl Int. 2005;18:627-42.

31. Sendino O, Fernández-Simon A, Law R, Abu Dayyeh B, Leise M, Chavez-Rivera K, Cordova H, Colmenero J, Crespo G, Rodriguez de Miguel C, Fondevila C, Llach J, Navasa M, Baron T and Cárdenas A. Endoscopic management of bile leaks after liver transplantation: An analysis of two high-volume transplant centers. United European gastroenterology journal. 2018;6:89-96.

32. Sharma S, Gurakar A and Jabbour N. Biliary strictures following liver transplantation: past, present and preventive strategies. Liver Transpl. 2008;14:759-69.

33. Wojcicki M, Milkiewicz P and Silva M. Biliary tract complications after liver transplantation: a review. Digestive surgery. 2008;25:245-57.

34. Scanga AE and Kowdley KV. Management of biliary complications following orthotopic liver transplantation. Current gastroenterology reports. 2007;9:31-8.

35. Kochhar G, Parungao JM, Hanouneh IA and Parsi MA. Biliary complications following liver transplantation. World journal of gastroenterology. 2013;19:2841-2846.

36. Kok T, Van der Sluis A, Klein JP, Van der Jagt EJ, Peeters PM, Slooff MJ, Bijleveld CM and Haagsma EB. Ultrasound and cholangiography for the diagnosis of biliary complications after orthotopic liver transplantation: a comparative study. J Clin Ultrasound. 1996;24:103-15.

37. Fontarensky M, Montoriol PF, Buc E, Poincloux L, Petitcolin V and Da Ines D. Advantages of gadobenate dimeglumine-enhanced MR cholangiography in the diagnosis of post-liver transplant bile leakage. Diagn Interv Imaging. 2013;94:443-52.

38. Krok KL, Cárdenas A and Thuluvath PJ. Endoscopic management of biliary complications after liver transplantation. Clin Liver Dis. 2010;14:359-71.

39. Thuluvath PJ, Pfau PR, Kimmey MB and Ginsberg GG. Biliary complications after liver transplantation: the role of endoscopy. Endoscopy. 2005;37:857-63.

40. Martins FP, Phillips M, Gaidhane MR, Schmitt T and Kahaleh M. Biliary leak in post-liver-transplant patients: is there any place for metal stent? HPB Surg. 2012;2012:684172-684172.

41. Arain MA, Attam R and Freeman ML. Advances in endoscopic management of biliary tract complications after liver transplantation. Liver Transplantation. 2013;19:482-498.

42. Bridges A, Wilcox CM and Varadarajulu S. Endoscopic management of traumatic bile leaks. Gastrointestinal endoscopy. 2007;65:1081-5.

43. Spinn MP, Patel MK, Cotton BA and Lukens FJ. Successful endoscopic therapy of traumatic bile leaks. Case Rep Gastroenterol. 2013;7:56-62.

44. Yamashita Y, Hamatsu T, Rikimaru T, Tanaka S, Shirabe K, Shimada M and Sugimachi K. Bile leakage after hepatic resection. Annals of surgery. 2001;233:45-50.

45. Capussotti L, Ferrero A, Viganò L, Sgotto E, Muratore A and Polastri R. Bile leakage and liver resection: Where is the risk? Archives of surgery (Chicago, Ill : 1960). 2006;141:690-4; discussion 695.

46. Dechêne A, Jochum C, Fingas C, Paul A, Heider D, Syn W-K, Gerken G, Canbay A and Zöpf T. Endoscopic management is the treatment of choice for bile leaks after liver resection. Gastrointestinal endoscopy. 2014;80:626-633.e1.

47. Nagano Y, Togo S, Tanaka K, Masui H, Endo I, Sekido H, Nagahori K and Shimada H. Risk factors and management of bile leakage after hepatic resection. World journal of surgery. 2003;27:695-8.

48. Dechêne AMD, Jochum CMD, Fingas CMD, Paul AMDP, Heider DP, Syn W-KMP, Gerken GMDP, Canbay AMDP and Zöpf TMD. Endoscopic management is the treatment of choice for bile leaks after liver resection. Gastrointestinal endoscopy. 2014;80:626-633.e1.

49. Pfau PR, Kochman ML, Lewis JD, Long WB, Lucey MR, Olthoff K, Shaked A and Ginsberg GG. Endoscopic management of postoperative biliary complications in orthotopic liver transplantation. Gastrointestinal endoscopy. 2000;52:55-63.

50. Sandha GS, Bourke MJ, Haber GB and Kortan PP. Endoscopic therapy for bile leak based on a new classification: results in 207 patients. Gastrointestinal endoscopy. 2004;60:567-574.

51. Canena J, Liberato M, Meireles L, Marques I, Romão C, Coutinho AP, Neves BC and Veiga PM. A non-randomized study in consecutive patients with postcholecystectomy refractory biliary leaks who were managed endoscopically with the use of multiple plastic stents or fully covered self-expandable metal stents (with videos). Gastrointestinal endoscopy. 2015;82:70-78.

52. Dutra B, Welborn M, Thosani NC, Badillo R, DaVee T and Bhakta D. Endoscopic Coil Embolization for Refractory Intrahepatic Biliary Duct Leak. ACG Case Rep J. 2022;9:e00743-e00743.

53. Seewald S, Groth S, Sriram PV, Xikun H, Akaraviputh T, Mendoza G, Brand B, Seitz U, Thonke F and Soehendra N. Endoscopic treatment of biliary leakage with n-butyl-2 cyanoacrylate. Gastrointestinal endoscopy. 2002;56:916-9.

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HAPPITUM™ LAUNCHES NATIONWIDE IN THE GI MARKET: A NATURAL, MULTIFACTORIAL APPROACH TO  GUT WELLNESS 

HAPPITUM™ LAUNCHES NATIONWIDE IN THE GI MARKET: A NATURAL, MULTIFACTORIAL APPROACH TO  GUT WELLNESS 

Miami, FL — 5/23/24 — Happitum™, a Gastroenterologist – formulated natural gut wellness supplement, is now available nationwide after a focused launch in the New York and Florida markets. Happitum™ offers a comprehensive approach to supporting digestive health and overall well-being for Gastroenterology patients. 

Happitum™ is distributed through Gastroenterology offices and can also be purchased by patients directly from the website happitum.com. Since its launch in early 2024, the product has received an overwhelmingly positive reception amongst the GI community and patients for its natural ingredients, which support common digestive issues such as bloating, digestion, and stress.

“Our goal at Happitum™ is to provide the Gastroenterology community a natural supplement that supports gut health effectively, and can be trusted by our physician partners and consumers alike,” said Matt Kurland, Co-Founder of Happitum™. “We have combined clinically supported, natural ingredients to promote calming, along with digestive enzymes to support bloating and digestion. The multifactorial formula can benefit a variety of patients who see their  Gastroenterologist in need of a product that is safe and reliable without taking any drugs. Nearly everyone has gut issues due to their diet, lifestyle, and stress in general. The ingredients in Happitum™ directly address these root causes.”  

Happitum™ is GI-formulated, vegan, gluten-free, made in the USA, and undergoes rigorous third-party lab testing to ensure the highest standards of safety and efficacy. Happitum™ is  formulated with a blend of bioactive natural ingredients, including: 

Peppermint, Ginger, Curcumin, Artichoke Leaf: Extensively studied ingredients that promote calming of the stomach. 

Alpha Galactosidase and 5-Enzyme Blend (Amylase, Protease, Lipase, Cellulase,  Lactase): Supports bloating and digestion by breaking down food. 

Ashwagandha and Theanine: Gut-brain axis support from ingredients that promote wellness and reduce stress.  

Marshmallow Root, Slippery Elm, and Fennel Seed: Barrier protective ingredients supporting a strong digestive tract lining. 

Happitum™ is committed to supporting healthcare providers in delivering the best care to their patients. We invite Gastroenterologists to become a Happitum™ Sample Partner and offer complimentary samples to their patients. Additionally, we offer QR code discounts for medical offices, as well as a wholesale program for our Physician Partners should they choose to distribute products at their office.

About Happitum™ 

Happitum™ is based in Miami, Florida. We are dedicated to promoting gut health through GI-formulated, natural supplements. The Happitum™ Vision is to harness the power of clinically studied, natural ingredients to support multi-factorial benefits for gut wellness, create an enhanced sense of trust between consumers and wellness benefits from their gut-balancing supplement, and create a stronger gut-health community of physicians and consumers. The Happitum™ Mission is empowering individuals to achieve digestive harmony for a healthier and balanced lifestyle.

For more information or to join one of our Partner Programs,  please contact us at:

info@happitum.com

or visit: happitum.com

MORE THAN ONE-HALF OF PATIENTS WITH CROHN’S DISEASE TREATED WITH LILLY’S MIRIKIZUMAB ACHIEVED CLINICAL REMISSION AT ONE YEAR, INCLUDING PATIENTS WITH PREVIOUS BIOLOGIC FAILURE 

Nearly one-half of patients on mirikizumab achieved endoscopic response at 52 weeks; most of these patients were also in clinical remission 

INDIANAPOLIS, May 21, 2024 /PRNewswire/ – In Eli Lilly and Company’s (NYSE: LLY) pivotal Phase 3 VIVID-1 study, patients with moderately to severely active Crohn’s disease, with or without previous biologic failure, achieved statistically significant and clinically meaningful improvements across multiple clinical and endoscopic endpoints at one year with mirikizumab compared to placebo. Data from this study – the first Phase 3 treat-through data reported for an IL23p19 antibody – was presented at Digestive Disease Week® (DDW), held in Washington, D.C. from May 18-21. 

“Crohn’s disease is a complex condition that, if untreated, may result in irreversible damage to the digestive tract. Mirikizumab patients achieved high rates of combined clinical remission and endoscopic response, two important treatment targets that are difficult to achieve in the same patient, at one year. This is particularly impressive for patients with previous biologic failure who are generally considered hard-to-treat,” said Bruce Sands, M.D., M.S., Dr. Burrill B. Crohn Professor of Medicine and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai.* “Consistent results across patient populations underscore the potential impact of mirikizumab in individuals living with this condition.” 

Crohn’s disease is a chronic, inflammatory bowel disease associated with progressive bowel damage, disability and decreased health-related quality of life. If not adequately controlled, it may lead to complications that require hospitalization and surgical intervention. A substantial proportion of patients do not experience adequate treatment outcomes, have secondary loss of response to maintenance therapy or do not tolerate existing  therapies, including biologic agents. Patients with previous biologic failure may be more difficult to treat.

As previously reported,  mirikizumab achieved both co-primary endpoints and all major secondary endpoints at Week 52 compared to placebo (p<0.000001), including: 

Proportion of participants achieving clinical response by patient reported outcomes (PRO)** at Week 12 and clinical remission (defined as a Crohn’s Disease Activity Index [CDAI] Total Score <150) at Week 52 compared to placebo

 Proportion of participants achieving clinical response by PRO at Week 12 and endoscopic response (defined as ≥50% reduction from baseline in Simple Endoscopic Score – Crohn’s Disease [SES-CD] Total Score) at Week 52 compared to placebo 

Consistent response rates and treatment effects were observed in patients with no prior biologic failure (bio-naïve) and harder-to-treat patients with previous biologic failure: 

39.3% of bio-naïve and 36.7% of bio-failed patients taking mirikizumab achieved composite Week 12 PRO clinical response and Week 52 endoscopic response compared to 11.8% and 6.2% of placebo, respectively 

47.3% of bio-naïve and 43.4% of bio-failed patients taking mirikizumab achieved composite Week 12 PRO clinical response and Week 52 clinical  remission by CDAI, compared to 26.5% and 12.4% of placebo, respectively 

At one year, clinical remission and endoscopic response were achieved by 54.1% and 48.4% of patients on mirikizumab, respectively. Notably, of the patients who received mirikizumab, 56.7% of bio-naïve and 51.2% of bio-failed patients achieved clinical remission at Week 52.

Patients taking mirikizumab achieved combined Week 52 clinical remission and endoscopic response at nominally statistically significant higher rates compared to patients on ustekinumab (34.4% versus 27.9%), with greater difference among those patients with previous biologic failure. At multiple time points, including Week 52, mirikizumab also achieved nominal statistical significance compared to ustekinumab in decreasing fecal calprotectin and C-reactive protein, two key biomarkers for inflammation. Superiority to ustekinumab was not achieved for endoscopic response.

Additionally, in the population with previous biologic failure, numerically greater rates were observed with mirikizumab compared to ustekinumab for endoscopic response, endoscopic remission (SES-CD total score ≤4, a ≥2-point reduction from baseline and no subscore >1 in any individual variable), and corticosteroid-free CDAI clinical remission at Week 52. These observed differences were not statistically significant.

The overall safety profile of mirikizumab in patients with moderately to severely active Crohn’s disease was consistent with the known safety profile in patients with ulcerative colitis. The frequency of serious adverse events was greater in placebo than mirikizumab. The most common adverse events were COVID-19, anemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis and injection site reaction. 

“After one year of treatment, more than one-half of patients treated with mirikizumab achieved clinical remission and nearly one-half achieved endoscopic response. Remarkably, the majority of patients who achieved either of these endpoints, achieved both together,” said Mark Genovese, M.D., senior vice president of Lilly Immunology development. “Lilly is committed to developing innovative treatments, like mirikizumab, that may improve upon the standard of care for people impacted by inflammatory bowel disease and immune-mediated diseases.” 

Lilly submitted a supplemental Biologics License Application for mirikizumab in Crohn’s disease to the U.S. Food and Drug Administration and European Medicines Agency  this year. Additional global regulatory submissions are planned.  

Lilly is committed to finding solutions to elevate care and improve treatment outcomes for people living with inflammatory bowel diseases. Lilly has ongoing  studies to evaluate the efficacy and safety of mirikizumab in other populations with Crohn’s disease, including a Phase 3 study in pediatric patients (NCT05509777)  and a long-term extension study of patients with moderately to severely active Crohn’s disease (NCT04232553). Omvoh™ (mirikizumab-mrkz) is approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults and has additional ongoing trials in UC, including a study in pediatric patients (NCT05784246) and a study to evaluate the long-term efficacy and safety of mirikizumab in adults (NCT03519945). Lilly is continuing to lead the science with an open-label UC trial studying two new endpoints in the assessment of bowel urgency with frequency and deferral time, both of which impact the quality of life for patients (NCT05767021). 

*
Disclosure: Dr. Sands is a paid consultant for Lilly. He has not been compensated for any media work.

About the VIVID-1 Clinical Trial Program 

VIVID-1 was a Phase 3, randomized, double-blind, treat-through study that evaluated the safety and efficacy of mirikizumab compared with placebo and an active control (ustekinumab) in adults with moderately to severely active Crohn’s disease. Patients randomized to mirikizumab were administered 900 mg of mirikizumab intravenously every four weeks from Week 0-12, then 300 mg subcutaneously every four weeks from Weeks 12-52. In this study, 49% of patients taking mirikizumab or placebo had experienced a prior biologic failure.

 **
Clinical response by PRO is defined as ≥30% decrease in stool frequency and/or abdominal pain, and neither score worse than baseline. 

Indications and Usage for Omvoh™ (mirikizumab-mrkz) (in the United States)

Omvoh™ is indicated for the treatment of moderately to severely active ulcerative colitis in adults. 

Important Safety Information for Omvoh (mirikizumab-mrkz)

CONTRAINDICATIONS

Omvoh is contraindicated in patients with a history of serious hypersensitivity reaction to mirikizumab-mrkz or any of the excipients. 

WARNINGS AND PRECAUTIONS 

Hypersensitivity Reactions 

Serious hypersensitivity reactions, including anaphylaxis during intravenous infusion, have been reported with Omvoh administration. Infusion-related hypersensitivity  reactions, including mucocutaneous erythema and pruritus, were reported during induction. If a severe hypersensitivity reaction occurs, discontinue Omvoh immediately and initiate appropriate treatment. 

Infections 

Omvoh may increase the risk of infection. Do not initiate treatment with Omvoh in patients with a clinically important active infection until the infection  resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing Omvoh. Instruct patients to seek medical advice if signs or symptoms of clinically important acute  or chronic infection occur. If a serious infection develops or an infection is not responding to standard therapy, monitor the patient closely and do not administer Omvoh until the infection resolves. 

Tuberculosis 

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Omvoh. Do not administer Omvoh to patients with active TB infection. Initiate treatment of latent TB prior to administering Omvoh. Consider anti-TB therapy prior to initiation of Omvoh in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and  symptoms of active TB during and after Omvoh treatment. In clinical trials, subjects were excluded if they had evidence of active TB, a history of active TB, or were diagnosed with latent TB at screening. 

Hepatotoxicity 

Drug-induced liver injury in conjunction with pruritus was reported in a clinical trial patient following a longer than recommended induction regimen. Omvoh was discontinued. Liver test abnormalities eventually returned to baseline. Evaluate liver enzymes and bilirubin at baseline and for at least 24 weeks of treatment. Monitor thereafter according to routine patient management. Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction. 

Immunizations 

Avoid use of live vaccines in patients treated with Omvoh. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or non-live vaccines in patients treated with Omvoh. 

ADVERSE REACTIONS 

Most common adverse reactions (≥2%) associated with Omvoh treatment are upper respiratory tract infections and arthralgia during induction, and upper respiratory tract infections, injection site reactions, arthralgia, rash, headache, and herpes viral infection during maintenance.

NEW MULTILINGUAL TOOL, SPEECHMED+GI, REVOLUTIONIZES COLONOSCOPY PREPARATION AND ENHANCES COLON CANCER SCREENING EFFORTS 

Enhancing Colonoscopy Prep with Technology: SpeechMED+GI Supports Early Detection and Expands Access in High-Risk Communities 

MIAMI, Florida (June 13, 2024) – SpeechMED™, a pioneer in health literacy solutions, is excited to announce the launch of SpeechMED+GI, a groundbreaking multilingual audio tool designed to significantly improve the preparation process for colonoscopies. This innovative platform is tailored to not only streamline pre-procedure instructions but also to bolster colon cancer screening efforts, particularly in underserved communities with historically low screening rates but high risks of colon cancer. 

SpeechMED+GI enhances the traditional patient preparation experience by replacing outdated paper-based instructions with an adaptive, user-friendly mobile app that communicates in the patient’s native language. This approach ensures that patients fully understand their pre-procedure requirements, which is crucial for effective screening and early detection of colon cancer. 

Key Features and Community Impact:

Enhanced Accessibility: Multilingual capabilities make vital pre-procedure information accessible to diverse patient populations, promoting higher screening rates among communities at increased risk of colon cancer.

Improved Compliance and Understanding: Gastroenterologists have reported that despite distributing pre-procedure instructions, many patients arrive unprepared, often unaware of dietary restrictions essential for a successful colonoscopy. SpeechMED+GI addresses this gap by providing clear, engaging instructions with reminders that patients can easily follow.

Supporting Gastroenterologists: Amidst a growing shortage of gastroenterology specialists, SpeechMED+GI helps maximize the efficiency of existing providers by reducing the number of repeat procedures and patient no-shows due to inadequate preparation.

Benefits for Colonoscopy Facilities:

Reduce Inadequate Prep Rates: SpeechMED+GI addresses the common issue of inadequate bowel preparation, which can lead to repeated procedures, wasted resources, and increased healthcare costs.

Enhanced Patient Adherence: Patients can easily switch the instructions in multiple languages and with information presented in an easy-to-understand format, SpeechMED+GI significantly boosts patient compliance.

Improved Detection Rates: Proper preparation improves visibility during colonoscopies, increasing the likelihood of detecting anomalies at an early stage.

“Our commitment at SpeechMED is to bridge the communication gap in healthcare,” says Susan Perry, CEO of SpeechMED. “SpeechMED+GI is specifically designed to ensure that all patients, regardless of their language skills or literacy level, receive the best possible preparation for colonoscopies. We are proud to offer a tool that not only enhances patient experience but also supports the critical work of gastroenterologists.”

SpeechMED+GI expands on SpeechMED’s proven platform, which facilitates communication by allowing patients to receive medical instructions in their preferred language, both verbally and visually.  

SpeechMED+GI is now available and can be integrated into healthcare systems immediately. Demonstrations and more detailed information about the product are available upon request by contacting GI@SpeechMED.com. 

About SpeechMED 

Taylannas, Inc. is a minority woman-owned and women-led health tech company on a mission of inclusion to make healthcare information understandable to everyone regardless of their language, vision, or ability to read. Their award-winning SpeechMED™ language and audio patient engagement platform is available for enterprise and personal use.

Learn more at:

speechmed.com

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Best Practices for Dysplasia Detection, Surveillance and Management in IBD

July 2024 • Volume XLVIII, Issue 7
Fernando Velayos

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Introduction

The epidemiology of inflammatory bowel disease (IBD) related colorectal cancer (CRC) has changed significantly since publication of the first case report nearly a century ago. These changes have only accelerated in the past decade or two due to the widespread use of high-definition scopes to improve detection of dysplasia and advanced therapies to better control damaging and obscuring inflammation. Even so, the risk of colorectal cancer in IBD remains elevated. While strategies for describing, screening for, and managing dysplasia in IBD are much closer to general population screening than in prior years, several IBD-specific nuances exist. This article provides an updated assessment of colorectal cancer risk in IBD and summarizes some of these nuances into ten best practices for the detection, surveillance, and management of colonic dysplasia in inflammatory bowel disease. 

The Biologic Risk of Colorectal Cancer in IBD – Then and Now

Inflammatory bowel disease has historically been a high-risk condition for developing colorectal cancer.1 Inflammation is a key driver of neoplasia via a cycle of chronic cellular damage and repair.1 To define the true biologic risk of colorectal cancer it is helpful to look at epidemiologic studies performed before the widespread use of advanced therapies and high definition colonoscopes.

Ekbom et al. published two seminal studies evaluating the risk of colorectal cancer in a population-based cohort diagnosed with ulcerative colitis or Crohn’s disease between 1922 to 1983 and followed through 1984.2,3 Compared to expected incidence, the incidence of colorectal cancer in ulcerative colitis was increased nearly sixfold (standardized incidence ratio (SIR)= 5.7, 95% confidence interval (CI): 4.6-7.0), with a clear risk gradient based on the extent of inflammation in the colon.2 In Crohn’s disease, the relative risk of colorectal cancer in Crohn’s disease of the colon alone was also nearly sixfold (SIR=5.6, 95% CI: 2.1-12.2).3 Less extensive disease was associated with a lower risk, and ileal disease alone did not harbor any increased risk (SIR= 1.0, 95% CI: 0.1-3.4).3

Fortunately, more recent cohorts have shown a reduction in colorectal cancer, although the risk still appears higher than the general population. A community based cohort from Northern California (1998 to 2010) reported an increased incidence of CRC for both ulcerative colitis (SIR=1.6, 95% CI: 1.3-2.0 ) and Crohn’s disease (SIR=1.6, 95% CI: 1.2-2.0).4 Similar findings were seen in a Scandinavian population-based study (1969-2017) with a numerically comparable risk in UC (Hazard ratio (HR)=1.7, 95% CI: 1.6-1.8) and Crohn’s HR=1.4, 95% CI: 1.3-1.5).5,6 Thus, despite advances in reducing colorectal cancer risk in IBD, IBD-specific CRC screening strategies are still needed. While the strategies for describing, screening for, and managing dysplasia in IBD are much closer to the general population than in prior years, several IBD-specific nuances exist. 

Society (Year)Intervals
British Society of Gastroenterology (2019)17Annual:
PSC, FH CRC <50, dysplasia or stricture < 5 years, extensive colitis with severe inflammation 3 years: PIP, FH CRC >50 years, extensive colitis with mild inflammation 5-year:
Extensive colitis with no active inflammation or left-sided colitis
or Crohn’s colitis <50% colon
American College of Gastroenterology (2019)141-3 years:
based on combined risk factors for CRC findings on previous colonoscopy
American Gastroenterology Association (2021)9
Annual:
PSC, FH CRC <50, dense PIP, high-risk dysplasia <5 years, moderate-severe inflammation (any extent) 2 or 3 years:
PIP, extensive mucosal scarring, FH CRC >50, low-risk dysplasia <5 years, prior dysplasia > 5 years, mild inflammation (any extent) 5 years: continued disease remission, mucosal healing current exam AND >= 2 consecutive exams without dysplasia OR Minimal historical colitis (proctitis, < 1/3 colon CD) Average risk: isolated small bowel Crohn’s
European Crohn’s and Colitis Organization (2022)11Annual:
PSC, FH CRC <50, dysplasia or stricture < 5 years, extensive colitis with severe inflammation 2-3 years:
PIP, FH CRC >50 years, extensive colitis with mild-moderate inflammation 5-year:
Colon affecting <50%, extensive colitis with minimal inflammation
Table 1. Recommended surveillance intervals in inflammatory bowel disease
Abbreviations: PSC- primary sclerosing cholangitis; FH- family history; CRC- colorectal cancer; PIP- post-inflammatory polyp

These nuances are relevant because screening, discerning precancerous lesions, and removing them in an inflamed, ulcerated, or scarred colon can be challenging and quite different from general population screening. These nuances are summarized into ten best practices for the detection, surveillance, and management of colonic dysplasia in inflammatory bowel disease and designed to facilitate this endeavor. 

Ten Best Practices for Screening and Dysplasia Detection and Management in IBD

1. Use the modified Paris classification to describe dysplasia.

Previously, the characterization of dysplasia in inflammatory bowel disease was quite distinct from general population screening.7 A consensus guideline workshop from 2014 recommended abandoning this nomenclature, which characterized dysplastic lesions as either adenomatous polyps, adenoma like polyps, dysplastic associated lesions or masses, or flat dysplasia.8 In its place, a more standard morphologic naming system, the Paris classification, was recommended with slight modifications for use in IBD. The workshop endorsed naming visible dysplastic lesions the same as in general population screening, specifically as either polypoid (subcategories sessile and pedunculated) or non-polypoid (subcategories elevated, flat or depressed). A third category, called invisible dysplasia, was meant to capture the phenomenon unique to IBD whereby dysplasia is unexpectedly detected in what was thought to be non-dysplastic, but inflamed colonic mucosa.8

Besides using the modified Paris classification, a best practice is to report when possible other key features of dysplasia, as these features may become relevant for determining feasibility of endoscopic resection at a second opinion.9 These additional features include size, border clarity, location, if within an area of colitis, if any ulceration present, and any special techniques used to visualize, such as dye spray chromo endoscopy or narrow band imaging. In addition, if a resection is attempted, perceived completeness of resection should be noted.

2. Perform the first surveillance colonoscopy 8 to 10 years after symptom onset and immediately after a diagnosis of primary sclerosing cholangitis.9

Historic studies have shown a significant increase in dysplasia and cancer risk beginning around 10 years after disease onset.10 Most current guidelines recommend a surveillance colonoscopy around 8 to 10 years after symptom or disease onset, depending on the guideline, even in patients with very limited disease.9,11 Given patients with limited or minimal disease are most likely to not have had a colonoscopy since diagnosis, colonoscopy in these patients can help assess both the degree of current inflammation and whether there has been any progression of colitis. Patients with a diagnosis of primary sclerosing cholangitis should undergo screening immediately, given the association between subclinical inflammation and colon cancer.9,11 

3. Focus on the fundamentals of dysplasia detection; recall that 90% of dysplasia is visible, even if subtle.9

It was only a generation ago, that only 5% of dysplasia in IBD was considered visible.12 Thus, began the practice of random biopsies in an effort to detect otherwise invisible dysplasia.7 Over time, enhanced dysplasia detection techniques such as dye spray chromoendoscopy were used to improve detecting subtle or atypical lesions. In fact, a more recent meta-analysis suggested a benefit for chromoendoscopy when using standard definition scopes, though interestingly not when using more modern high-definition scopes.13

The most recent American Gastroenterological Association Clinical Practice Updates on this topic emphasized focusing on the fundamentals of dysplasia detection, given that advances in both high-definition scopes, and better control of obscuring inflammation, has made dysplasia more visible, albeit still subtle.9 These fundamentals include use of a high-definition scope for screening, screening when inflammation is quiescent, washing and carefully inspecting all fully visible mucosa, and taking targeted biopsies of suspicious mucosal abnormalities or sites of prior dysplasia.9 

4. Enhanced dysplasia detection techniques should have a secondary, not primary role in dysplasia detection.

As a corollary of the above principle, enhanced dysplasia detection techniques, including non-targeted biopsies, dye spray chromoendoscopy, and “virtual chromoendoscopy” (narrow band imaging or iScan) have a complementary role in dysplasia detection, but their use should not be at the expense of the above fundamentals.9 In fact, the efficacy of these supplementary techniques will likely be low if the above fundamentals are not present (meticulous inspection of the mucosa using a high-definition scope with a good bowel preparation in the setting of quiescent inflammation).

5. Take the randomness out of the random biopsy.

It was just slightly over a decade ago that taking up to 30-40 “random” biopsies throughout the colon was the standard for dysplasia detection in inflammatory bowel disease.7 More recent guidelines have abandoned the term “random” biopsy for the preferred term “non targeted” biopsy, in part to emphasize the importance of context when interpreting the findings of biopsies.

The most recent AGA Clinical Practice Update on this topic categorized biopsies in IBD patients into three contexts help interpret results.9 The first is targeted biopsies, defined as biopsies of a suspicious mucosal abnormality to rule out subtle dysplasia. The second category is non-targeted biopsies, defined as biopsies of non-suspicious areas to rule out invisible dysplasia. The third is staging biopsies, defined as biopsies of microscopically inflamed or uninflamed mucosa to assess histologic disease activity and extent. Beyond “forcing” context with these three categories, it is important to reflect and be aware any specific individual biopsy patterns which may give additional information beyond these categories. Thus, when possible, describing the appearance of the underlying mucosa where biopsies are taken can further assist in decision making, should biopsies reveal dysplasia.

6. Proactively look for signs of dysplasia. 

Inflammation, ulceration, scarring of the mucosa, and post-inflammatory pseudopolyps can obscure subtle and sometimes not so subtle clues indicating dysplasia. Therefore, it is important to proactively look for findings suggesting possible dysplasia within this background abnormal mucosa. These findings include any inexplicable or ill-defined mucosal irregularity or subtle change in mucosal color, vascularity, nodularity, elevation, or ulceration.9 This process can be simplified even further by looking for any mucosa that looks different than its neighbor and spending additional time examining it to determine if it merits biopsy. 

7. Know that narrow band imaging is among several accepted enhanced dysplasia techniques.

Dye spray chromoendoscopy, the process by which methylene blue or indigo carmine is applied to the mucosa during colonoscopy to better accentuate subtle changes in elevation or pit pattern, has been shown to increase dysplasia detection in inflammatory bowel disease.13 A recent meta-analysis reported a greater benefit when using older standard definition colonoscopes compared to high-definition scopes.13 Virtual chromoendoscopy, whereby technologic processing in the scope produces accentuated pictures meant to highlight the same changes as dye spray chromoendoscopy, are often proprietary technologies including Narrow Band Imaging (Olympus) and iScan (Pentax), among others. 

While initial studies showed no benefit to “virtual” chromoendoscopy, more recent studies have shown either a benefit of virtual chromoendoscopy over white light colonoscopy or equivalent performance compared to dye spray chromoendoscopy, leading several societies to endorse virtual chromoendoscopy as a reasonable alternative to dye spray chromoendoscopy.9,11,14 While non-targeted biopsies typically are not recommended when virtual or dye spray chromoendoscopy are used, a French study suggested some additional benefit in the setting of primary sclerosing cholangitis, prior dysplasia, or a tubular colon.15 

8. Manage visible dysplasia in IBD patients like in the non IBD population with a caveat: Endoscopic resection may be more challenging because of scarring from underlying colitis.

Advances in disease management and experience in removing large and complex lesions using endoscopic mucosal resection or endoscopic surgical dissection, has changed how most visible dysplastic lesions in IBD are managed.9,16 Instead of surgery, which was commonly recommended in the past, most lesions can now typically be managed with endoscopic resection, similar to the general population.8 Even so, depending on the lesion, endoscopic resection may be challenging due to scarring from underlying colitis, thus necessitating consultation from an interventional endoscopist.

Most lesions less than 2 cm in size with clear border, without features of submucosal invasion or fibrosis and no histologic features of invasive cancer can typically undergo endoscopic resection with standard polypectomy techniques, followed by regular surveillance. In contrast, lesions that are larger than 2cm or complex based on a highly regular or indistinct borders or are laterally spreading, may be appropriate for endoscopic resection by an interventional endoscopist or may require surgery. Often this decision is based on local expertise, but it is reasonable to get a second opinion from an interventional endoscopist and IBD specialist. Finally, lesions that appear unresectable due to size, location, or where there are endoscopic features of invasive cancer should be referred for surgery.9 

9.  Treat invisible dysplasia as a special situation in IBD.

Invisible dysplasia, where dysplasia is incidentally diagnosed on biopsies taken from seemingly non-dysplastic mucosa, is a challenging and special situation in inflammatory bowel disease.9 These situations are best managed by first, confirming the diagnosis of dysplasia with a second pathologist. Then, repeating the colonoscopy using dye spray chromoendoscopy, to unmask subtle dysplasia and determine resectability. If no lesion is found, then extensive biopsies in the area of prior dysplasia are recommended. 

10. Determine surveillance intervals based on 3 factors and avoid yearly surveillance except in those with the highest risk factors.

Determining screening intervals after a normal colonoscopy, regardless of whether someone has IBD or not, can be challenging, however there are three important factors to help guide this decision. The first is the inherent biology and natural history of the underlying condition or findings regarding future cancer risk. The second is the presence of any genetic or environmental modifiers. The third is other factors that can obscure the detection of precancerous lesions at that colonoscopy.

Based on these factors, most surveillance guidelines have categorized follow up into either a 1 year, 2-3 year, and 5 year option.9,11,14,17 A 5-year surveillance is new to US-based guidelines, but designed for a very select subset of patients with minimal inflammation, evidence of mucosal healing, and a history of exams without dysplasia and minimal colitis. In fact, most patients likely are appropriate for two or three years. Annual colonoscopy is typically reserved for those at highest risk for dysplasia or cancer, such as primary sclerosing cholangitis, recent dysplasia, or evidence of severe inflammation. As a reminder, these are intervals for surveillance. There may be other reasons to perform a colonoscopy before a screening exam is indicated, such as evaluation of symptoms, abnormal biomarkers, or assessment of mucosal healing.

Summary

The epidemiology of inflammatory bowel disease (IBD) related colorectal cancer (CRC) has changed significantly since publication of the first case report nearly a century ago. Despite advances in reducing colorectal cancer risk in IBD, IBD-specific CRC screening strategies are still needed. While the strategies for describing, screening for, and managing dysplasia in IBD are much closer to the general population than in prior years, discerning precancerous lesions, and removing them in an inflamed, ulcerated, or scarred colon can be challenging and thus some differences remain compared to general population screening. 

References

1. Clevers H. At the crossroads of inflammation and cancer. Cell. Sep 17 2004;118(6):671-4. doi:10.1016/j.cell.2004.09.005

2. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. Nov 1 1990;323(18):1228-33. doi:10.1056/NEJM199011013231802

3. Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large-bowel cancer in Crohn’s disease with colonic involvement. Lancet. Aug 11 1990;336(8711):357-9. doi:10.1016/0140-6736(90)91889-i

4. Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology. Aug 2012;143(2):382-9. doi:10.1053/j.gastro.2012.04.054

5. Olen O, Erichsen R, Sachs MC, et al. Colorectal cancer in Crohn’s disease: a Scandinavian population-based cohort study. Lancet Gastroenterol Hepatol. May 2020;5(5):475-484. doi:10.1016/S2468-1253(20)30005-4

6. Olen O, Erichsen R, Sachs MC, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. Jan 11 2020;395(10218):123-131. doi:10.1016/S0140-6736(19)32545-0

7. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. Feb 2010;138(2):738-45. doi:10.1053/j.gastro.2009.12.037

8. Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastroenterology. Mar 2015;148(3):639-651 e28. doi:10.1053/j.gastro.2015.01.031

9. Murthy SK, Feuerstein JD, Nguyen GC, Velayos FS. AGA Clinical Practice Update on Endoscopic Surveillance and Management of Colorectal Dysplasia in Inflammatory Bowel Diseases: Expert Review. Gastroenterology. Sep 2021;161(3):1043-1051 e4. doi:10.1053/j.gastro.2021.05.063

10. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. Apr 2001;48(4):526-35. doi:10.1136/gut.48.4.526

11. Gordon H, Biancone L, Fiorino G, et al. ECCO Guidelines on Inflammatory Bowel Disease and Malignancies. J Crohns Colitis. Jun 16 2023;17(6):827-854. doi:10.1093/ecco-jcc/jjac187

12. Tytgat GN, Dhir V, Gopinath N. Endoscopic appearance of dysplasia and cancer in inflammatory bowel disease. Eur J Cancer. Jul-Aug 1995;31A(7-8):1174-7. doi:10.1016/0959-8049(95)00133-4

13. Feuerstein JD, Rakowsky S, Sattler L, et al. Meta-analysis of dye-based chromoendoscopy compared with standard- and high-definition white-light endoscopy in patients with inflammatory bowel disease at increased risk of colon cancer. Gastrointest Endosc. Aug 2019;90(2):186-195 e1. doi:10.1016/j.gie.2019.04.219

14. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. Mar 2019;114(3):384-413. doi:10.14309/ajg.0000000000000152

15. Moussata D, Allez M, Cazals-Hatem D, et al. Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy? Gut. Apr 2018;67(4):616-624. doi:10.1136/gutjnl-2016-311892

16. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet. Jan 8 1994;343(8889):71-4. doi:10.1016/s0140-6736(94)90813-3

17. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. Dec 2019;68(Suppl 3):s1-s106. doi:10.1136/gutjnl-2019-318484

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Nutrition Reviews in Gastroenterology, SERIES #15

Recognizing Thiamine Deficiency: Keeping Patients Safe and Clinicians Out of Court

July 2024 • Volume XLVIII, Issue 7
Carol Rees Parrish,Neeral Shah,Kate Willcutts

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Considerable effort has gone into identifying and diagnosing malnutrition in recent years, and along with that, recognizing those at risk for refeeding syndrome (RS). Less attention has been given to Wernicke’s Encephalopathy (WE) despite the rising number of cases, not only reported in the literature, but court cases as well. Court cases have revealed that clinicians are failing to identify malnutrition, and as a result, missing the signs and symptoms of WE with devastating consequences. The purpose of this review is to discuss those at risk for both RS and WE, and, by definition, the malnutrition that overlaps both entities. In addition, frequent findings in court cases will be shared to help clinicians better identify and treat patients at substantial risk for malnutrition, RS, and WE in order to keep patients safe and clinicians out of court.

Introduction

Refeeding Syndrome (RS) and Wernicke’s Encephalopathy (WE) are serious complications that can occur with the initiation and consistent delivery of nutrients in malnourished individuals without adequate guardrails (attention to appropriate practice guidelines). RS is the metabolic response to consistent nutrient provision in a malnourished patient leading to hypokalemia, hypophosphatemia, and hypomagnesemia and the potentially severe consequences those electrolyte shifts can bring.1,2 WE is a severe neurological syndrome due to thiamine deficiency that too often goes unrecognized, underdiagnosed, and undertreated (Table 1).3,4

First, however, one must identify the malnourished patient that should subsequently trigger concern for RS and WE. Court cases have repeatedly found that registered dietitian nutritionists (RDN) in particular have failed to meet the American Society of Parenteral Nutrition (ASPEN) / The Academy of  Nutrition and Dietetics (AND)’s consensus standards for nutritional assessment 5-7 by not:

Documenting an adequate nutritional history. 

Documenting an adequate anthropometric evaluation with weight loss history over time and/or physical assessment.

Reviewing prior admission/emergency department (ED) records that demonstrate persistent, or ongoing decline of nutritional health. 

Identifying the risk for developing micronutrient deficiencies.

Nervous System Involvement (Dry Beriberi)
Wernicke’s Encephalopathy – (acute phase & reversible): Classic triad: altered mental status (delirium, confusion, drowsiness), gait ataxia, ocular signs (nystagmus) – only 16% – 30% of patients with Wernicke’s present with all three Also, fatigue, irritability, decreased reflexes, tingling sensation (arms & legs), blurred vision, change in mobility Consider WE in any patient with unexplained delirium in the ICU Korsakoff Syndrome – (chronic phase & irreversible) Permanent mental impairment (memory loss, amnesia, tremor, coma, disorientation, and vision problems)
Cardiac involvement (Wet Beriberi)
Acute high-output cardiac failure with peripheral edema
Gastrointestinal involvement (GI Beriberi)
Abdominal pain (potential clue: elevated serum lactate), nausea, emesis
Major barrier to pt diagnosis → a low index of suspicion by clinicians
Table 1. Signs and Symptoms of Wernicke’s Encephalopathy (“Thiamine-Deficient Encephalopathy”)32,33,34
Absorption Duodenum and proximal jejunum (will your patient be affected based on anatomy?) Active alcohol consumption may alter oral thiamine absorption26
Excretion Losses are significantly increased up to 2 times baseline by loop diuretics9 Renal replacement therapies also significantly decrease plasma thiamine
Treatment considerations Short half-life – 1-12 hours8 Note: Oral gummy multivitamins rarely contain thiamine due to its offensive taste (Table 5) IV thiamine has a 2-hour half-life, hence, to maintain blood levels to treat Wernicke’s,
2-4 doses per day are needed to achieve rapid correction by steep plasma: CNS gradient35 Administer IV thiamine slowly (over 30 minutes), diluted in 100mL of normal saline
as it is very painful otherwise4
Table 2. Thiamine Considerations for the Clinician

Second, malnutrition which generally implies macronutrient “deficiency,” regardless of etiology, rarely appears in isolation from micronutrient deficiency, particularly thiamine (due to its short half-life and limited body stores). Although clinicians are aware of the need for thiamine in the setting of RS, many clinicians have a low index of suspicion for thiamine deficiency in other settings, delaying necessary treatment that can result in the development of WE and its potentially devastating consequences, or worse, Korsakoff’s Syndrome (Table 1). The importance of the clinician’s role in early identification and treatment of patients at risk for both RS and WE cannot be overstated and is the focus of this article in order to avoid serious complications and subsequent malpractice claims.  

About Thiamine

Thiamine (vitamin B1), a renally excreted, inexpensive water-soluble vitamin, has limited body stores of approximately 30 mg and a short half-life of 1-12 hours.8 Thiamine will last only 9-18 days in well-nourished individuals,9 but will deplete sooner if stores are insufficient or have been drawn upon without replenishment (e.g., 5% dextrose [D5W] infusion or parenteral nutrition [PN] administration without added thiamine or multivitamin infusion [MVI]). As thiamine is primarily absorbed in the upper jejunum, and to some extent the duodenum, consideration of the patient’s anatomy will be important when supplementing via the oral/enteral route.

Thiamine is a critical, rate-limiting cofactor to several enzymes involved in carbohydrate metabolism and can be rapidly depleted when carbohydrate is infused or ingested as the need for thiamine pyrophosphate (TPP) increases (such as in refeeding a malnourished patient). Thiamine deficiency exhausts supply to these enzymes, resulting in decreased adenosine triphosphate (ATP) synthesis, oxidative damage, and cell death; metabolic acidosis can also occur, reflected by an elevation in serum lactate concentration.8,10 For thiamine considerations for clinicians, see Table 2.

Refeeding Syndrome and Wernicke’s Encephalopathy: A Continuum

While several national and international nutrition societies have focused on identifying and preventing RS in recent years, WE has not garnered such attention. Unfortunately, too many clinicians are under the impression that WE is limited to those with alcohol use disorder, yet a myriad of other patient populations are also at risk.11-17 In fact, RS and WE often share the same high-risk groups and may occur concurrently 4,11-17 (Table 3). Two major warning signs present in almost all reported WE cases are extreme weight loss and vomiting.16 Many associations have published guidelines recommending thiamine repletion for RS;1,18,19 however, clinicians seldom realize that beyond carbohydrate metabolism, if WE is lurking, much higher thiamine doses are required (Table 4). 

Wernicke’s Encephalopathy (“Thiamine-Deficient Encephalopathy”)

WE is an acute medical neurological emergency, that if left untreated, can progress to chronic Wernicke–Korsakoff syndrome, leading to impaired memory and cognitive functions, and coma and death in severe cases. It has been estimated that 80% of WE cases go undetected,3 likely due to the fact that the classic signs and symptoms may not all be present (Table 1). In fact, WE classically presented as a triad of global confusion, gait ataxia, and ophthalmoplegia, yet this triad is only seen in 16%-20% of cases.14 The current dominant paradigm that WE only appears in those who have alcohol use disorder needs to change in order to prevent the rising cases and consequences of WE. Extensive case reports in patients with conditions other than alcohol use disorder highlight this fact, in particular, the post bariatric surgery patient population.15 Similar case examples from these and other populations resulting in lawsuits due to inadequate early treatment for WE will be addressed later in this article. 

Why Does Thiamine Deficiency (and Wernicke’s) Elude Clinicians:10

Thiamine deficiency is often missed for several reasons: 1) signs and symptoms of thiamine deficiency can vary and mimic those of unrelated disorders; 2) patients may have micronutrient deficits including a thiamine deficiency in the setting of a secondary medical issue that steers the clinician in a different direction; 3) results of serum thiamine testing take up to 7-10 days, delaying not only the diagnosis, but timely treatment; 4) the best biomarker, as well as normal range cutoffs, have yet to be determined; 5) controversy exists regarding the best treatment regimen for WE as the best universal treatment guidelines have yet to be established.20

Diagnosing and Preventing Wernicke’s Encephalopathy

Patients at Risk for Refeeding and/or Wernicke’s
Nutrient deficit/significant weight loss: Chronic, poor oral intake for ANY reason Food insecurity, homelessness, refugees Eating disorders/malnutrition/ underfeeding Malabsorption syndromes Dysphagia/esophageal disorders Prolonged fasting/NPO post-op for > 7 days Chronic alcohol or drug use disorder  Morbid obesity with significant weight loss Oncology patients  Persistent diabetic ketoacidosis, or non-ketotic, hyperosmolar state  Alcohol misuse/withdrawal Head & neck cancer patients (high alcohol misuse) Anyone with nausea/vomiting x 2 weeks or greater Recurrent visits to emergency departments for dehydration from nausea/vomiting and
D5-containing IV solutions started @ high infusion rates without MVI or thiamine added Hyperemesis gravidarum Bariatric surgery with excessive diarrhea/vomiting/weight loss Gastroparesis Esophageal or pyloric stricture, gastric outlet obstruction, etc. PN-dependent patients not infusing MVI due to intolerance or supply shortages Unexplained heart failure or lactic acidosis Chronic congestive heart failure on diuretics Psychiatric illness with weight loss
Table 3. Patients at Risk for Refeeding Syndrome and/or Wernicke’s Encephalopathy 2,16,36-38

Diagnosing WE begins with a high level of suspicion in the right clinical context: i.e., a patient who has lost a significant amount of weight, persistent vomiting for 2 weeks or more, or consumes an excessive amount of alcohol. Significant or severe weight loss has been defined as:5,7

Significant (1-2%) / severe (>2%)
over 1 week

Significant (5%) / severe (>5%)
over 1 month

Significant (7.5)% / severe (>7.5%)
over 3 months

Significant (10%) / severe (>10%)
over 6 months

Significant (20%) / severe (>20%)
over 1 year

However, clinical judgment must also be used and not rely on the numbers alone. For example, if a patient unintentionally loses 4.8% in 3 weeks, it is still considered a significant loss of weight.

Laboratory Testing

Laboratory testing for a serum thiamine level should never delay thiamine treatment – if a thiamine assay is drawn, thiamine dosing should follow immediately after. If laboratory testing is pursued, use whole blood thiamine (direct measurement of thiamine and its phosphate esters). Results can take up to 7 – 10 days, therefore, if Wernicke’s is suspected, it is important to start treatment with thiamine right after the lab draw. Serum or plasma thiamine testing suffer from poor sensitivity and specificity; < 10% of blood thiamine is contained in plasma and is affected by recent oral intake or IV infusion. Therefore, whole blood thiamine should be ordered instead. Of note, there is no established lab value at which WE is diagnosed.

Imaging

Use of magnetic resonance imaging (MRI) to detect WE has a sensitivity of only 53%, hence, MRI scans can only reliably rule-in suspected cases of WE.21 CT imaging is not suitable to use in patients with suspected WE.22 Brain abnormalities are quickly reversed after thiamine treatment, so an MRI should be performed prior to thiamine administration, but only if the MRI can be done right away, or precious time can be lost as treatment is of the highest priority in these cases. It has been suggested that the brain injury is related to focal lactic acidosis, blood–brain barrier disruption, neural cell excitotoxicity, inflammation, or inadequate ATP at the cellular level.3

Due to the alarming lack of recognition of WE, clinicians must change their differential diagnosis to not only include RS, but also note that WE may also be present in order to prevent the negative clinical, and potentially legal consequences.23  In order to improve identification and subsequent treatment of WE, clinicians must have a high level of suspicion for thiamine deficiency when at risk patients present for care (see examples below).

What do the following cases have in common?

42-year -old male presents with ongoing nausea and vomiting post gastric sleeve bypass surgery; frequent ED admissions treated with intravenous (IV) antiemetics and D5W at 100mL/hour; 

27-year-old pregnant female presents with persistent hyperemesis for the past 5 weeks; 

58-year-old male presents with almost daily nausea and vomiting due to a pyloric stenosis;

36-year-old female admitted with ongoing nausea and vomiting over 2 months due to diabetic gastroparesis;

32-year-old female admitted for an endoscopic retrograde cholangiopancreatography (ERCP) to remove gallstone complicated by acute pancreatitis, unable to eat despite attempts over the course of 5 weeks; D5W initiated, then peripheral parenteral nutrition, then central PN, all without thiamine supplementation;  

63-year-old male with daily excessive alcohol intake and 20 lb. weight loss over past month is admitted for mandibular resection due to carcinoma 

Author/AssociationRecommended Supplementation/Dosing Guideline
European (EFNS) Wernicke’s Guidelines (Galvin 2010)At risk: 200mg IV, TID before any carbohydrate is given Signs of WE: 500mg IV TID x 3 days, then 250mg daily x 5 days
Mechanick 2019Repletion dose for thiamine deficiency varies based on route of administration and severity of symptoms: Oral therapy: 100 mg 2-3 times daily until symptoms resolve IV therapy: 200 mg 3 times daily to 500 mg once or twice daily for 3-5 d, followed by 250 mg/d for 3-5 d or until symptoms resolve, then consider treatment with 100 mg/d orally, indefinitely, or until risk factors have been resolved  IM therapy: 250 mg once daily for 3-5 d or 100-250 mg monthly  Magnesium, potassium, and phosphorus should be given simultaneously to patients at risk for refeeding syndrome.
ASPEN Refeeding Consensus  (da Silva 2020)100mg before feeding or initiating IV dextrose in pts at risk 100mg/day x > 5–7 days in pts with severe starvation/chronic alcoholism/other high-risk/signs of deficiency
Dingwall 2022No clear benefit between 100mg, 300mg, 500mg IV, TID in at risk vs. symptomatic for WE
Wijnia 2022250mg IV or IM, daily x 3-5 days
Note: Guidelines are based on expert opinion, not randomized, controlled trials

The unifying presentation in all of the above cases was one or more of the following: ongoing vomiting for > 2 weeks, inability to eat normally over an extended period of time, and significant, unintentional weight loss. Weights were often not obtained or just “self-reported” by patients, thus frequently inaccurate. ED visits were common, and subsequent hospitalizations were just long enough to relieve the symptoms of nausea/vomiting, but not long enough to generate a nutrition consult from an admission nutrition screen (if one was even done, especially in an ED), or one directly from a provider. Nor was empiric thiamine treatment given. If a nutrition consult was completed in these cases, the focus was on getting the patient to consume adequate calories and protein, rather than exploring the patient’s micronutrient adequacy. It is worth noting that rare is the patient who was previously taking a vitamin/mineral supplement, whether as part of standard post bariatric care or for other reasons, who continues vitamin/mineral supplementation when they stop eating. Further perpetuating the potential for WE, treatments often include a carbohydrate containing hydration fluid such as D5W in response to dehydration from ongoing vomiting. D5W is usually ordered at 100mL/hour, without additional IV micronutrients, thus consuming any serum thiamine remaining along with other micronutrient stores.22,24

Of note, the expected weight loss in the post bariatric surgery patient is often quoted as 2-4 lb/week, or 8-16 pounds per month. The American Society of Metabolic and Bariatric Surgery 2019 guidelines list expected weight loss post-surgery based on the type of bariatric surgery.25 They cite the target weight loss from the original total body weight (not excess weight) as: 20-25% for laparoscopic adjustable gastric banding; 25-30% for sleeve gastrectomy; 30-35% for Roux-en-Y gastric bypass and 35-45% for biliopancreatic diversion with duodenal switch. However, limited literature exists addressing what constitutes an “excessive” loss of weight (too much, too fast) after bariatric surgery that would spark a warning to clinicians to investigate further for possible malnutrition, RS, and WE. One systematic review of bariatric surgical procedures found that those patients admitted with WE had a median weight loss from surgical procedure to admission of 35 kg and a weight loss rate of 0.44 kg/day (~ 1 lb/day).22 Hence, if this amount of weight loss is associated with WE, until further data is available, to prevent WE in the first place, a weight loss less than this amount should prompt further assessment at this time.

Contains small amount of thiamine  Smarty Pants® Women’s Formula
(only 0.12 mg in 6 gummies)

Vitamin or vitamin/mineral gummy combinations that do not have thiamine:
KirklandTM Adult multivitamin Gummies
VitafusionTM MultiVites
VitafusionTM Men’s Multi
VitafusionTM Women’s Multi
KirklandTM Children’s Daily Multivitamin Gummies
Smarty Pants® Kids formula Gummies
L’ilCrittersTM Gummy Vites
One A Day® Women’s VitaCraves
One A Day® Women’s Prenatals
Centrum® Adults Multigummies
Centrum® Men 50+ Multigummies
Nature’s Promise® Prenatal Multivitamin
Nature’s Promise® Men’s Multivitamin
Nature’s Promise® Women’s Multivitamin
Table 5. Thiamine Content of a Few Selected Gummy Vitamins (DRI = 1.2 mg)

Treatment

WE prevention is simple. It is repletion of thiamine, an inexpensive water-soluble vitamin. Advantages of prompt administration of thiamine, in adequate doses (Table 4), are that it leads to improvement in ocular signs within hours to days, vestibular function and gait ataxia during the second week, and confusion subsides over days to weeks.26 However, based on the findings reported in this article, it behooves clinicians to use thiamine judiciously, especially in the IV form, to prevent shortages already experienced at individual facilities as well as nationally vs. treat every patient “just in case.”

Other Nutrients Required for Thiamine Utilization

Magnesium, a necessary cofactor in carbohydrate metabolism, if depleted, impedes conversion of thiamine to TPP, further accelerating thiamine deficiency. Folate, similarly, is required to regenerate TPP. Although it is not consumed in the process, additional folate may be required.27 The examples of the role of magnesium and folate demonstrate that in caring for the malnourished patient, it is important that the clinician presume pan-nutrient deficiency and ensure that all vitamins and minerals are adequately provided in the repletion process. This can be achieved by providing a complete vitamin and mineral supplement. Additional thiamine should also be given in the case of RS and WE (Table 4). Of importance for the clinician and patient, popular chewable gummy multivitamin supplements, rarely contain thiamine due to the objectionable taste (Table 5). 

1. Nutrition Screening – Is It Working? Ensure that there are proper institutional triggers for timely evaluation and follow up by a registered dietitian nutritionist (RDN) when a pt is admitted with persistent nausea/vomiting, oral nutrition intolerance, and significant weight loss history.  

2. Failing to Identify Malnutrition: By not meeting ASPEN/AND’s consensus standards5-7 for nutritional assessment including failure to:
Document an adequate nutritional history. 
Document an adequate anthropometric evaluation including weight loss history and physical assessment.
Look at prior admission/ED records that may show nutritional decline.
Document risk for development of permanent neurological impairments of micronutrient deficiencies.

3. Relying on other providers’ review of nutrition progress notes rather than communicating and collaborating directly with other providers when orders for vitamin levels and empiric vitamin repletion are warranted to prevent adverse outcomes. 

4. NOT Relying on other providers’ progress notes that document patient showing signs of micronutrient deficiencies such as acute neurological symptoms.

5. Failing to: Acknowledge Ongoing Problems with Poor Oral Intake
Nutrition interventions which repeatedly recommend supplements that the patient either cannot, or will not tolerate, i.e.: 
Ensure, Boost, or oral multivitamins and minerals without confirming the patient has been able to take or tolerate them when nausea and vomiting persist.  Nutrition notes that continue to recommend:
“Advance diet as tolerated,”  “Honor food preferences,” or  “Oral nutrition supplements (Ensure or Boost) as tolerated.”  In such cases, the RDN has failed to confer with physicians and recommend the addition of enteral, parenteral, or vitamin/mineral supplementation. 

6. Failing to:
Evaluate and treat micronutrient deficiencies and focus only on macronutrient deficiencies. Recommend earlier B vitamins, including IV thiamine repletion, for patients with persistent nausea/vomiting and oral nutrition intolerance.
Follow ASPEN Parenteral Nutrition Safety Consensus Recommendations stating41,42  The clinician responsible for prescribing and/or charting the PN macronutrient formulation(s) is ultimately responsible for prescribing the IV micronutrients to ensure complete nutrition is provided.  The highest risk regarding routine doses is not delivering them with PN.  Multivitamins (MVI) shall be prescribed daily in PN admixtures.  When MVI products are not available, thiamine, ascorbic acid, pyridoxine, and folic acid shall be prescribed daily.
If RDNs are only responsible for recommending macronutrients in PN at a particular facility, because “the pharmacist is responsible for electrolytes, MVI, and trace elements,” make sure this is in writing in hospital policy and procedures and consider a smart phrase for this.
Table 6. Findings from Attorneys Trying Wernicke’s that Clinicians Need to Change
Adapted from the version compiled by Steven R. Davis, J.D., Davis & Davis Law Firm, Houston, TX, and used with permission.

Legal Ramifications

As the problem of WE grows, a sub-culture of lawyers who specialize in this diagnosis has emerged. A quick internet search reveals the vast scope of law firms marketing their services to those who have suffered WE due to inadequate medical treatment. To provide optimal patient care and avoid such malpractice lawsuits, it behooves the clinician to become familiar with common errors leading to lawsuits. Informal communications with an attorney specializing in Wernicke’s cases (who has tried over 27 cases so far) resulted in a list of common errors made by clinicians (Table 6). Recognizing these errors provides a road map for change for clinicians to prevent WE and subsequent lawsuits.

Special Issue: Bariatric Vitamin/Mineral Supplementation

Post bariatric surgery patients are one of the more prevalent populations in which WE has arisen including all types of bariatric surgery, even vertical sleeve gastrectomy,15,28 prompting numerous court cases. Since post bariatric surgery patients are at high risk of micronutrient deficiency, it is incumbent upon the clinician during the assessment process to question whether they are still taking their prescribed vitamin and mineral supplements,29 which ones, and how much. If a patient has stopped taking the supplements, the clinician should determine when they stopped and for how long. It is not uncommon for some patients to stop these supplements, not recognizing their importance. Some of the documented reasons why patients stop their supplementation are listed below:30,31

I understand that I am required to take the following vitamins and minerals (dosing may vary amongst institutions) as specified for the rest of my life (or until my bariatric surgeon or PCP advises me otherwise), example:

Initials:  _________  50 mg thiamine
Initials:  _________  500mg B12
Initials:  _________  3000 units vitamin D3
Initials:  _________  Complete vitamin and mineral supplement

If there comes a time that I am not taking the prescribed vitamins and minerals for any reason, I will contact my PCP or bariatric surgeon to let them know.

Sign & Print name______________________________________ Date _________
Table 7. Sample Contract with Bariatric Patients Regarding Vitamin/Mineral Supplement Adherence29

Did not think they still needed them

Did not like taking them

Could not find them

Did not like the taste

Could not remember to take them

Could not afford them

To help keep post bariatric surgery patients safe, at every hospital or clinic encounter, clinicians should: 

Inquire about and document the following: 

What vitamins and minerals is the patient taking – how often, and in what doses?

The patient’s history of taking these supplements, including whether the intake is consistent or sporadic. If sporadic, how long do they go without taking them?

For patients not taking vitamins or minerals, inquire why this is the case, and make a new plan with the patient to ensure adherence to the prescribed regimen.

Create a smart phrase (in electronic medical record) stating what was specifically reviewed with the patient in terms of the importance of vitamin and mineral adherence and, for each vitamin and mineral, the prescribed dose and frequency of administration.  

Finally, it may be prudent to ask every patient choosing to undergo bariatric surgery to sign a contract that is kept in the patient’s chart addressing vitamin/mineral supplementation (Table 7).

1. Ensure the nutrition screening tool is working, if not, change it to better capture high-risk patients. If it is not being filled out, address that with nursing, or hire diet technicians whose sole job is to screen new admissions. Consider the use of artificial intelligence or dietetic technicians for more focused admission nutrition screening, etc.

2. Consider creating a smart phrase for both refeeding syndrome and Wernicke’s such as: 100mg thiamine daily (tab or IV) x 3-5 days (if refeeding). 500mg thiamine IV, TID x 3 days (if Wernicke’s), followed by 250mg daily vs. BID, IV
(or enteral) x 5 more days. Start a complete vitamin/mineral supplement daily x 5 days, then reevaluate. Check refeeding labs (basic metabolic, magnesium, phosphorus) BID x 3 days, then reevaluate.

3. Obtain accurate weight history, not just the current admission, but from 1, 3, and 6 months prior → ensure accurate weights are done when patient is admitted.

4. If a patient is severely malnourished, assume the patient at risk for both RS and WE (Table 3).

5. Did the patient present with nausea/vomiting for > 2 weeks? Include ED visits, outside hospital admissions, etc.

6. Be specific in your nutrition recommendations: 15-20kcal/kg to start (include ALL calorie sources including D5 drips).

7. Refeeding: start thiamine, 100mg daily (tab or IV) x 3-5 days – including with all D5 IV fluids, PN, enteral feedings.

8. Wernicke’s: 500mg thiamine IV, TID x 3 days; then, 250mg daily vs. BID, IV (or enteral) x 5 more days.

9. Ensure adequate magnesium status.

10. Start complete vitamin and mineral supplement daily x 5 days – find out the actual names in the hospital formulary EMR and recommend by name to providers for ease of ordering.  

11. Check refeeding labs (basic metabolic, magnesium, phosphorus) BID x 3 days, then reevaluate.

12. If appropriate → good glycemic control to ensure nutrient utilization and protect endogenous stores.
Table 8. Actionable Interventions the Clinician Can Do Now 

Conclusion

Much attention has been paid to identifying and diagnosing malnutrition; and in addition, recognizing those at risk for RS. WE continues to be thought of, incorrectly, as a complication solely of too much alcohol intake combined with poor nutrition. WE can be found in any patient, not just bariatric patients presenting with prolonged nausea and vomiting or those at risk for RS and should be treated with thiamine and other micronutrients accordingly. Sadly, litigation of  WE cases continues to rise displaying the fact that clinicians are failing to identify malnutrition, RS, and WE with dreadful consequences. It is clear that an evaluation of why nutritional screening practices are failing and patients with severe malnutrition and nutrient deficiencies are not being recognized is warranted.  We owe it to our patients to keep them safe, and no clinician wants to find themselves in court for malpractice. See Table 8 for actionable suggestions that can begin to start addressing this pressing issue; Table 9 provides additional resources of interest for clinicians.  

Video recording – available free:
“Advanced Practice Provider (APP) Lecture Series – Vitamin B1: The Management and Treatment in Clinical Practice – American Society for Metabolic and Bariatric Surgery”
(asmbs.org); recorded 4/20/23 presented by Emma J. Patterson, MD, FRCSC FACS FASMBS:
asmbs.org/videos/advanced-practice-provider-app-lecture-series-vitamin-b1-the-management-and-treatment-in-clinical-practice/

What nystagmus looks like: youtube.com/watch?v=HXOaRGNnijU
Table 9. Additional Resources

References

1. da Silva JSV, Seres DS, Sabino K, et al; Parenteral
Nutrition Safety and Clinical Practice Committees,
American Society for Parenteral and Enteral
Nutrition. ASPEN Consensus Recommendations for
Refeeding Syndrome. Nutr Clin Pract. 2020;35(2):178-
195.
2. Krutkyte G, Wenk L, Odermatt J, et al. Refeeding
Syndrome: A Critical Reality in Patients with Chronic
Disease. Nutrients. 2022;14(14):2859.
3. Kohnke S, Meek CL. Don’t seek, don’t find: The diagnostic
challenge of Wernicke’s encephalopathy. Ann
Clin Biochem. 2021;58(1):38-46.
4. Wijnia JW. A Clinician’s View of Wernicke-
Korsakoff Syndrome. J Clin Med. 2022;11(22):6755.
5. Malone A, Hamilton C. The Academy of Nutrition
and Dietetics/the American Society for Parenteral
and Enteral Nutrition consensus malnutrition characteristics:
application in practice. Nutr Clin Pract.
2013;28(6):639-50.
6. The Academy of Nutrition and Dietetics New Revised
2024 Scope and Standards of Practice for the Registered
Dietitian Nutritionist; pp 42-45.
7. White JV, Guenter P, Jensen G, et al. Academy
Malnutrition Work Group; ASPEN Malnutrition
Task Force; ASPEN Board of Directors. Consensus
statement: Academy of Nutrition and Dietetics and
American Society for Parenteral and Enteral Nutrition:
characteristics recommended for the identification and
documentation of adult malnutrition (undernutrition).
JPEN J Parenter Enteral Nutr. 2012;36(3):275-283.
8. Marrs C, Lonsdale D. Hiding in Plain Sight: Modern
Thiamine Deficiency. Cells. 2021;10(10):2595.
9. Frank LL. Thiamin in Clinical Practice. JPEN J
Parenter Enteral Nutr. 2015;39(5):503-20.
10. Smith TJ, Johnson CR, Koshy R, et al. Thiamine deficiency
disorders: a clinical perspective. Ann N Y Acad
Sci. 2021;1498(1):9-28.
11. Antel K, Singh N, Chisholm B, et al. Encephalopathy
after persistent vomiting: Three cases of non-alcohol-
related Wernicke’s encephalopathy. S Afr Med
J. 2015;105(6):442-3.
12. Mangione D, Vassiliadis A, Gullo G, et al. Wernicke
Syndrome: Case Report and Literature Review of
Contributing Factors-Can Malpractice Dynamics Be
Identified? J Clin Med. 2024;13(3):716.
13. Mifsud F, Messager D, Jannot AS, et al. Clinical diagnosis,
outcomes and treatment of thiamine deficiency
in a tertiary hospital. Clin Nutr. 2022;41(1):33-39.
14. Okafor C, Nimmagadda M, Soin S, et al. Non-alcoholic
Wernicke encephalopathy: great masquerader. BMJ
Case Rep 2018;11:e227731.
15. Oudman E, Wijnia JW, van Dam M, et al. Preventing
Wernicke Encephalopathy After Bariatric Surgery.
Obes Surg. 2018;28(7):2060-2068.
16. Oudman E, Wijnia JW, Oey MJ, et al. Wernicke-
Korsakoff syndrome despite no alcohol abuse:
A summary of systematic reports. J Neurol
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17. Scalzo SJ, Bowden SC, Ambrose ML, et al.
Wernicke-Korsakoff syndrome not related to alcohol
use: a systematic review. J Neurol Neurosurg
Psychiatry. 2015;86(12):1362-8.
18. Friedli N, Stanga Z, Culkin A, et al. Management and
prevention of refeeding syndrome in medical inpatients:
An evidence-based and consensus-supported
algorithm. Nutrition. 2018;47:13-20.
19. Mehanna HM, Moledina J, Travis J. Refeeding syndrome:
what it is, and how to prevent and treat it. BMJ.
2008;336(7659):1495-8.
20. Cantu-Weinstein A, Branning R, Alamir M, et al.
Diagnosis and treatment of Wernicke’s encephalopathy:
A systematic literature review. Gen Hosp
Psychiatry. 2024;87:48-59.
Table 9. Additional Resources
¨ Video recording – available free:
Ø “Advanced Practice Provider (APP) Lecture Series – Vitamin B1: The Management and
Treatment in Clinical Practice – American Society for Metabolic and Bariatric Surgery”
(asmbs.org); recorded 4/20/23 presented by Emma J. Patterson, MD, FRCSC FACS FASMBS:
asmbs.org/videos/advanced-practice-provider-app-lecture-series-vitamin-b1-themanagement-
and-treatment-in-clinical-practice/
¨ What nystagmus looks like: youtube.com/watch?v=HXOaRGNnijU
NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #15
PRACTICAL GASTROENTEROLOGY • JULY 2024 37
Recognizing Thiamine Deficiency: Keeping Patients Safe and Clinicians Out of Court
21. Antunez E, Estruch R, Cardenal C, et al. Usefulness
of CT and MR imaging in the diagnosis of acute
Wernicke’s encephalopathy. AJR Am J Roentgenol.
1998;171(4):1131–1137.
22. Aasheim ET. Wernicke encephalopathy after
bariatric surgery: a systemic review. Ann Surg.
2008;248(5):714-720.
23. Hershkowitz E, Reshef A, Munich O, et al. Thiamine
deficiency in self-induced refeeding syndrome, an
undetected and potentially lethal condition. Case Rep
Med. 2014:2014:605707.
24. Li L, Shin J-H, Sharma K, et al. Wernicke encephalopathy
after sleeve gastrectomy. AIM Clinical Cases.
2024;3:e230116.
25. Mechanick JI, Apovian C, Brethauer S, et al. Clinical
Practice Guidelines for the Perioperative Nutrition,
Metabolic, and Nonsurgical Support of Patients
Undergoing Bariatric Procedures – 2019 Update:
Cosponsored by American Association of Clinical
Endocrinologists/American College of Endocrinology,
The Obesity Society, American Society for Metabolic
& Bariatric Surgery, Obesity Medicine Association,
And American Society of Anesthesiologists – Executive
Summary. Endocr Pract. 2019;25(12):1346-1359.
26. Patel S, Topiwala K, Hudson L. Wernicke’s
Encephalopathy. Cureus. 2018;10(8):e3187.
27. McLean J, Manchip S. Wernicke’s encephalopathy
induced by magnesium depletion. Lancet.
1999;353(9166):1768.
28. Tang L, Alsulaim HA, Canner JK, et al. Prevalence
and predictors of postoperative thiamine deficiency
after vertical sleeve gastrectomy. Surg Obes Relat Dis.
2018;14(7):943-950.
29. Parrott J, Frank L, Rabena R, et al. American Society
for Metabolic and Bariatric Surgery Integrated Health
Nutritional Guidelines for the Surgical Weight Loss
Patient 2016 Update: Micronutrients. Surg Obes Relat
Dis. 2017;13:727–741.
30. Ahmad DS, Esmadi M, Hammad H, et al. Malnutrition
secondary to non-compliance with vitamin and mineral
supplements after gastric bypass surgery: What can we
do about it? Am J Case Rep. 2012;13:209–213.
31. Smelt HJM, Pouwels S, Smulders JF, et al. Patient
adherence to multivitamin supplementation after bariatric
surgery: a narrative review. J Nutr Sci. 2020;9:e46.
32. Crook MA, Sriram K. Thiamine deficiency: The
importance of recognition and prompt management.
Nutrition. 2014;30(7-8):953-954.
33. Nakamura ZM, Tatreau JR, Rosenstein DL, et al.
Clinical Characteristics and Outcomes Associated
with High-Dose Intravenous Thiamine Administration
in Patients with Encephalopathy. Psychosomatics.
2018;59(4):379-387.
34. Peterson BD, Stotts MJ. Beyond the Banana
Bag: Treating Nutritional Deficiencies of Alcohol
Withdrawal Syndrome. Practical Gastroenterol.
2021;June(6):48-58.
35. Donnino MW, Vega J, Miller J, et al. Myths and
misconceptions of Wernicke’s encephalopathy: what
every emergency physician should know. Ann Emerg
Med. 2007;50(6):715-21.
36. Erick M. Gestational malnutrition, hyperemesis gravidarum,
and Wernicke’s encephalopathy: What is missing?
Nutr Clin Pract. 2022;37(6):1273-1290.
37. Marziliano A, Teckie S, Diefenbach MA, et al.
Alcohol-related head and neck cancer: Summary of
the literature. Head Neck. 2020;42(4):732-738.
38. Matz R. Parallels between treated uncontrolled diabetes
and the refeeding syndrome with emphasis
on fluid and electrolyte abnormalities. Diabetes
Care. 1994;17(10):1209-13.
39. Galvin R, Bråthen G, Ivashynka A, et al. EFNS guidelines
for diagnosis, therapy and prevention of Wernicke
encephalopathy. Eur J Neurol. 2010;17(12):1408–
1418.
40. Dingwall KM, Delima JF, Binks P, et al. What is the
optimum thiamine dose to prevent Wernicke’s encephalopathy
or Wernicke-Korsakoff syndrome? Alcohol
Clin Exp Res. 2022;46(6):1133-1147.
41. Ayers P, Adams S, Boullata J, et al. ASPEN parenteral
nutrition safety consensus recommendations. JPEN J
Parenter Enteral Nutr. 2014;38(3):296-333.
42. Blaauw R, Osland E, Sriram K, et al. Parenteral
Provision of Micronutrients to Adult Patients: An
Expert Consensus Paper. JPEN J Parenter Enteral Nutr.
2019;43(suppl 1):S16).

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Gut Inflammation in the Pediatric Patient with Cystic Fibrosis

July 2024 • Volume XLVIII, Issue 7

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Patients with cystic fibrosis (CF) have associated gastrointestinal (GI) inflammation, and such inflammation is associated with worsening pulmonary outcomes. The authors of this study evaluated clinical markers of GI inflammation in pediatric patients with CF to see if specific markers were helpful in determining clinical outcomes. Pediatric patients with CF who were between 1 and 21 years of age were recruited from a single, tertiary children’s hospital. These patients did not have any alternative cause for intestinal inflammation such as inflammatory bowel disease or celiac disease, did not have a colostomy or ileostomy, and were not on total parenteral nutrition. The pediatric study patients were compared to 20 control patients under 21 years of age who had a prior esophagogastroduodenoscopy demonstrating no GI inflammation.

Study patients with CF had blood and stool samples obtained at study entry and then 2 weeks and 3 months later. Questionnaires about GI symptoms were also obtained at these time points. Body mass index (BMI) and forced expiratory volume in 1 second (FEV1) were obtained in study patients who were 4 years of age or older. It should be noted that 90% of control patients had blood and stool samples available for analysis. Intestinal permeability on all patients was measured by testing serum E. coli anti-core lipopolysaccharide (LPS) and lipopolysaccharide-binding protein (LPB). Intestinal inflammation on all patients was measured by stool biomarkers, including fecal calprotectin (FC), fecal lipocalin-2 (FL2), and fecal neopterin (FN).

A total of 26 patients with CF completed the entire study, and these study subjects were compared to the 18 control patients who had existing blood and stool samples available.The control group was noted to be older than the study group with CF. FL2 and FN levels in patients with CF were significantly higher compared to control patients based on age-matched controls. Patients with CF who were on CF transmembrane conductance regulator (CFTR) modulators had less intestinal inflammation compared to patients with CF not on CFTR modulator therapy although the inflammation occurring with those patients on CFTR therapy was still increased compared to control patients. Increased FC and increased FL2 appeared to correlate with decreases in FEV1% predicted. No biomarker correlated with changes in BMI z-scores or weight-for-length z-scores after model adjustments for age and presence of pancreatic insufficiency. FL2 levels had statistically significant correlation with FC and FN levels, and LPS levels had statistically significant correlation with LPB levels. However, no other correlations between biomarkers were present.

This study demonstrates that FL2 may prove eventually to be a reliable marker for GI dysfunction in patients with CF. FL2 levels were increased in patients with CF compared to controls suggesting GI inflammation in the setting of CF, and FL2 levels were inversely correlated to FEV1 function while simultaneously having correlation with other serum and stool biomarkers. Further studies should look for specific microbiome signatures associated with increased FL2 levels in patients with CF while also looking for a correlation of such levels with other aspects of lung disease seen in CF.

Duckworth L, Sutton K, Shaikh N, Wang J, Hall-Moore C, Holtz L, Tarr P, Rubenstein R.  Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability. J Pediatr 2024; 265: 113800.

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Impact of Bariatric Surgery on Perianal Fistulas: A Case Report and Review of the Literature

July 2024 • Volume XLVIII, Issue 7
Uma Mahadevan,Jonathan Carter,Afshin A. Khan,Emily Finlayson

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Complex perianal fistulas can be a challenging manifestation of inflammatory bowel disease (IBD) for both gastroenterologists and surgeons. We present a patient with Crohn’s disease in endoscopic remission on monoclonal antibody therapy. Despite adequate control of her luminal disease, there was no improvement in her complex perianal fistulas with antibiotic treatment, surgical drainage, seton placement, and ultimately diversion colostomy. Bariatric surgery, which resulted in weight loss of 135-pounds, was associated with immediate control of her fistulas. Bariatric surgery in a select subset of patients may reduce the pro-inflammatory state that obesity, central or otherwise, promotes and may help IBD patients have improved health outcomes.

Case Presentation

A 28-year-old female with a BMI (body mass index) 47 kg/m2 was diagnosed with fistulizing ileocolonic and perianal Crohn’s disease 10 years ago. She was initially treated with infliximab and developed anti-drug antibodies. Upon switching to ustekinumab she achieved complete endoscopic remission but continued to have active perianal disease. Initial treatment with antibiotics were unsuccessful and she required regular exam under anesthesia (EUA) with seton placement. Within two years, the frequency of EUA with seton placement increased to five episodes in the same year. A switch to adalimumab with methotrexate was unsuccessful. She underwent diverting loop transverse colostomy to provide relief from recurrent perianal fistulas. Despite the diversion, she continued to have rectal pain, new abscesses and drainage. 

After failing non-surgical weight loss, she underwent laparoscopic sleeve gastrectomy after discussion with both colorectal and bariatric surgery. Reversal of the loop colostomy occurred a year later. Her post-operative course was complicated by a peri-gastric fistula and abscess that was endoscopically drained. Post-bariatric surgery, she lost 135 pounds and only experienced a single perianal abscess in 12 months as compared to multiple annual episodes prior to bariatric surgery. Subsequent colonoscopy showed continued normal luminal findings and significantly improved perianal disease with no active fistulas or abscess. 

Discussion 

This case highlights the impact of bariatric surgery on a patient suffering from recurrent, fistulizing, perianal Crohn’s disease previously refractory to medical and surgical management even with endoscopic remission. From a surgical perspective, she had multiple seton placements and eventually a diversion colostomy without control of her perianal disease. A multidisciplinary approach determined that obesity may be playing a key role in limiting drug efficacy, impairing wound healing from mechanical pressure, and driving inflammation with ongoing fistulas. Therefore, the risks of bariatric surgery would be outweighed by the benefit of controlling her recurrent perianal Crohn’s disease. 

Obesity, a public health epidemic, is also a concern in patients with IBD, traditionally thought to be a disease of those with low BMI. Current estimates show that 25-30% of patients with IBD have obesity, with 5-6% of them severely obese.1-4  These estimates reflect a similar trend in the general population. Until recently, Crohn’s disease has been considered a relative contraindication to Roux-en-Y gastric bypass (RYGB) surgery, according to the Guidelines for Clinical Application of Laparoscopic Bariatric Surgery of the Society of American Gastrointestinal and Endoscopic Surgeons, which is further endorsed by the American Society for Metabolic and Bariatric Surgery.5 The hesitation surrounding bariatric surgery in patients with IBD is layered. Patients with obesity have increased post-operative complications and micronutrient deficiencies become more pronounced in patients with IBD.6,7 Sleeve gastrectomy is less invasive with fewer potential complications for the patient with IBD.

Increasing evidence suggests that patients with IBD and obesity have worse clinical outcomes as they are more likely to have extraintestinal manifestations of IBD, prolonged hospitalizations and increased healthcare costs.8,9 Studies have also highlighted suboptimal response to biologic therapy in patients with obesity possibly attributed to rapid clearance of biologic agents which subsequently leads to low serum trough concentrations 10 versus increased inflammatory burden from cytokines produced by adipose cells. Additionally, significant obesity precludes ileal pouch-anal anastomosis, thus, obesity management becomes an imperative target as part of IBD management.

Prospective and retrospective studies have now suggested safety and efficacy of bariatric surgery in patients with IBD.11-13 Beyond showing that IBD should not be considered a contraindication for bariatric surgery, these studies have also exhibited an additional advantage of weight loss. Bariatric surgery reduces the number of IBD related complications including reduced corticosteroid use, IBD related surgeries, dose reduction in IBD medications, and overall improvement in quality of life.14 These benefits may be due to a decrease in the chronic pro-inflammatory state associated with obesity, including low production of C-reactive protein, tumor necrosis factor-alpha (TNF), and interleukin-6. These studies emphasize a multidisciplinary approach prior to opting for bariatric surgery and determining the best surgical approach.

Perianal fistulas cause significant morbidity including persistent drainage, fecal incontinence, scarring, and poor disease related outcomes. The desired treatment outcome is fistula closure. The Guidelines for the Multidisciplinary Management of Crohn’s Perianal Fistulas recommend the following treatment algorithm for perianal fistula management:15 simple fistulas rely on treatment with antibiotics, immunomodulators, with or without anti-TNF alpha agents. Surgical intervention (e.g., setons) in addition to the aforementioned therapies may be necessary for complex fistulas. Those with refractory fistulas may require other surgical treatments including use of fibrin glue, fistula plug, diverting colostomy, and proctectomy or protocolectomy. 

Conclusion

The potential benefit of weight loss surgery in disease management of significantly obese patients with IBD is discussed above. IBD should not be considered a contraindication for bariatric surgery. Instead, with a multidisciplinary team approach, it should be seen as an opportunity for improving overall management of IBD, particularly in a subset of patients who have disease refractory to current medical and or surgical treatments. 

References

References
1. Steed H, Walsh S, Reynolds N. A brief report of the epidemiology of obesity in the inflammatory bowel disease population of Tayside, Scotland. Obes Facts. 2009;2(6):370-2. doi:10.1159/000262276
2. Long MD, Crandall WV, Leibowitz IH, et al. Prevalence and epidemiology of overweight and obesity in children with inflammatory bowel disease. Inflamm Bowel Dis. Oct 2011;17(10):2162-8. doi:10.1002/ibd.21585
3. Flores A, Burstein E, Cipher DJ, Feagins LA. Obesity in Inflammatory Bowel Disease: A Marker of Less Severe Disease. Dig Dis Sci. Aug 2015;60(8):2436-45. doi:10.1007/s10620-015-3629-5
4. Hass DJ, Brensinger CM, Lewis JD, Lichtenstein GR. The impact of increased body mass index on the clinical course of Crohn’s disease. Clin Gastroenterol Hepatol. Apr 2006;4(4):482-8. doi:10.1016/j.cgh.2005.12.015
5. Committee SG. SAGES guideline for clinical application of laparoscopic bariatric surgery. Surg Obes Relat Dis. May-Jun 2009;5(3):387-405. doi:10.1016/j.soard.2009.01.010
6. Dogan K, Aarts EO, Koehestanie P, et al. Optimization of vitamin suppletion after Roux-en-Y gastric bypass surgery can lower postoperative deficiencies: a randomized controlled trial. Medicine (Baltimore). Nov 2014;93(25):e169. doi:10.1097/MD.0000000000000169
7. Flancbaum L, Belsley S, Drake V, Colarusso T, Tayler E. Preoperative nutritional status of patients undergoing Roux-en-Y gastric bypass for morbid obesity. J Gastrointest Surg. Jul-Aug 2006;10(7):1033-7. doi:10.1016/j.gassur.2006.03.004
8. Nguyen NH, Ohno-Machado L, Sandborn WJ, Singh S. Obesity Is Independently Associated with Higher Annual Burden and Costs of Hospitalization in Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. Mar 2019;17(4):709-718 e7. doi:10.1016/j.cgh.2018.07.004
9. Singla MB, Eickhoff C, Betteridge J. Extraintestinal Manifestations Are Common in Obese Patients with Crohn’s Disease. Inflamm Bowel Dis. Sep 2017;23(9):1637-1642. doi:10.1097/MIB.0000000000001187
10. Singh S, Dulai PS, Zarrinpar A, Ramamoorthy S, Sandborn WJ. Obesity in IBD: epidemiology, pathogenesis, disease course and treatment outcomes. Nat Rev Gastroenterol Hepatol. Feb 2017;14(2):110-121. doi:10.1038/nrgastro.2016.181
11. Aelfers S, Janssen IMC, Aarts EO, Smids C, Groenen MJ, Berends FJ. Inflammatory Bowel Disease Is Not a Contraindication for Bariatric Surgery. Obes Surg. Jun 2018;28(6):1681-1687. doi:10.1007/s11695-017-3076-9
12. Gupta R, MacIsaac M, Wright EK. Sleeve Gastrectomy in Patients with Inflammatory Bowel Disease Is Not Associated with Worsening Disease. J Crohns Colitis. Jun 24 2022;16(5):865-866. doi:10.1093/ecco-jcc/jjab195
13. Keidar A, Hazan D, Sadot E, Kashtan H, Wasserberg N. The role of bariatric surgery in morbidly obese patients with inflammatory bowel disease. Surg Obes Relat Dis. Jan-Feb 2015;11(1):132-6. doi:10.1016/j.soard.2014.06.022
14. Braga Neto MB, Gregory MH, Ramos GP, et al. Impact of Bariatric Surgery on the Long-term Disease Course of Inflammatory Bowel Disease. Inflamm Bowel Dis. Jun 18 2020;26(7):1089-1097. doi:10.1093/ibd/izz236
15. Schwartz DA, Ghazi LJ, Regueiro M, et al. Guidelines for the multidisciplinary management of Crohn’s perianal fistulas: summary statement. Inflamm Bowel Dis. Apr 2015;21(4):723-30. doi:10.1097/

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Dispatches from the GUILD Conference, Series #58

Tailoring Therapy Toward the Management of Extraintestinal Manifestations of IBD: Neurological, Ocular, Cutaneous and Musculoskeletal

June 2024 • Volume XLVIII, Issue 4
Gil Y. Melmed,Paula Prieto-Jimenez

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Extraintestinal manifestations (EIM) of inflammation are common among patients with inflammatory bowel disease (IBD), many of which have distinct etiologies and treatment approaches. In the past decade, there has been a significant expansion of treatment modalities for IBD, with distinct mechanisms of action that may allow for targeting of multiple organ systems with a single agent. We review common neurologic, dermatologic, ocular, and musculoskeletal EIMs associated with IBD, and identify opportunities to address EIMs together with IBD using specific agents or therapeutic classes in order to optimally personalize treatment toward both bowel and extraintestinal inflammation. 

Extraintestinal manifestations in patients with inflammatory bowel disease (IBD) can significantly impact health-related quality of life. Advances in pathophysiology knowledge and immunomodulatory targeted therapies bring diverse treatment options for IBD and inflammatory manifestations outside the bowel which should be considered when choosing the most appropriate approach for treating both intestinal and extraintestinal manifestations of IBD. This review provides an overview of treatment approaches of IBD and extra intestinal presentations of neurological, ocular, cutaneous, and musculoskeletal manifestations. 

NEUROLOGICAL MANIFESTATIONS

Neurological extraintestinal manifestations are relatively rare in IBD. Multiple Sclerosis (MS), optic neuritis (ON) and transverse myelitis (TM) are chronic, inflammatory, demyelinating and neurodegenerative diseases, which have a heterogeneous, multifactorial, immune-mediated background caused by complex gene–environment interactions. As MS is the most common disease, most studies between IBD and CNS have been focused on MS.

Anti-TNFα therapy has been putatively associated with demyelinating syndromes.1,2 The mechanism for which anti-TNFα might potentially cause demyelination in patients with rheumatological disease and IBD is still not fully understood. Current hypotheses include an increased influx of peripheral autoreactive T cells into the CNS, dysregulation of myelin repair, downregulation of interleukin-10 and upregulation of interleukin-12 and interferon γ; and possible increase in the risk of an underlying latent infections by anti-TNFα which could lead to demyelination.6,7

Consequently, TNF inhibitors should be avoided in patients with MS or other demyelinating diseases. Some advocate that this restriction should be applied as well to first-degree relatives of patients with MS given an increased risk of developing MS, with a sibling relative risk being as high as 18 to 36.8

In patients with MS or high risk of developing demyelinating diseases, recommendations for IBD treatment depend on the type of IBD (e.g. Crohn’s disease (CD) or ulcerative colitis (UC)). For moderate to severe CD, natalizumab may be appropriate due to its effectiveness in both CD and in MS. Natalizumab is a humanized monoclonal antibody which targets the lymphocyte adhesion molecule α4β1 integrin, disrupting the interaction of α4β1 integrin with vascular adhesion molecule (VCAM) -1 and interfering with the migration of the peripheral lymphocytes from blood vessels into the CNS and into the gut lamina propria, hence its beneficial effects for both MS and CD. It is FDA approved for the treatment of relapsing – remitting MS and for CD. However, uptake of natalizumab has been limited by increased risks of progressive multifocal leukoencephalopathy (PML) through reactivation of John Cunningham (JC) virus at a rate of approximately 1 in 1000 among individuals demonstrating antibody reactivity to JC virus, a ubiquitous virus present in large proportions of the population.9 Thus, individuals with CD initiating natalizumab should not receive concomitant immunomodulators, and steroids should be tapered off within 6 months of drug initiation. Furthermore, monitoring for JC virus every 6 months is warranted while on natalizumab maintenance therapy, with shared decision-making discussions to stop therapy for patients who seroconvert while on treatment. 

Sphingosine 1-phosphate (S1P) receptor modulators are approved as disease-modifying treatments for MS and UC based on a mechanism of limiting lymphocyte trafficking to the CNS and to the gut by trapping activated lymphocytes in lymph nodes. Ozanimod is currently approved for the treatment of both relapsing and remitting MS, as well as for moderately to severely active UC in adults. Thus, ozanimod may be an appropriate treatment option for those with UC, who also have or are at-risk for MS. 

Nonspecific white matter lesions have also been described in patients with IBD without presenting concomitant CNS degenerative diseases. It has been proposed that asymptomatic white matter lesions may be correlated with anxiety and disease duration, and that these findings may serve as a biomarker of neuropsychiatric comorbidities of CD.10 These lesions are generally asymptomatic, although their pathogenesis is unknown. Several mechanisms have been proposed for their etiology including thromboembolism, immunologic abnormalities, drug side effects, malabsorption, and infections.11,12

OCULAR

Nearly 5-7% of patients with IBD experience ocular inflammation, most commonly episcleritis, scleritis or non-infectious uveitis (NIU). 

Episcleritis, or inflammation of the episclera, is the most frequent ocular EIM. It is associated with active intestinal inflammation, and usually responds to topical steroids. On the other hand, scleritis, the inflammation of the sclera, is more challenging to treat, it usually requires nonsteroidal anti-inflammatory drugs, systemic steroids or immunosuppressants. If not controlled, scleritis can lead to necrotizing scleritis, anterior scleritis and posterior scleritis with secondary potential vision loss.14 In contrast, uveitis, the inflammation of the iris, ciliary body, and choroids, is less frequently associated with IBD flares but may precede a diagnosis of IBD by months or years. Although ophthalmological manifestations are present in any type of IBD, they are more common in CD patients. 

Infliximab and adalimumab, both anti-tumor necrosis factor (TNF)-α antibodies, are frequently used first-line in patients with ocular manifestations of scleritis or uveitis. Infliximab is effective in the treatment of NIU unresponsive to other drugs, with approximately 82% of patients achieving clinical remission in a median time of 127 days. For patient with uveitis, brain magnetic resonance imaging (MRI) is indicated to screen for demyelination before the commencement of TNFα inhibitors. TNF-alpha inhibitors were shown to significantly reduce relapses, and to control scleral inflammation both rapidly and with a long-lasting effects.15,16

Most recently, therapies targeting interleukin (IL) 23 and Janus kinase inhibitor (JAK) inhibitors have emerged as treatment options for ocular EIMs. Ustekinumab, a monoclonal antibody against human IL-12/IL-23 p40 subunit, has been described in case reports for the successful treatment of non-infectious uveitis including a patient with psoriatic arthritis and psoriasis, and 2 patients with CD, including 1 with comorbid MS.17,18

Tofacitinib, a nonselective small molecule JAK inhibitor approved for UC, has been used successfully in patients with severe refractory juvenile idiopathic arthritis (JIA)-associated uveitis,19,20 but further studies are needed to show the safety and efficacy of JAK inhibitors in larger cohorts.

SKIN MANIFESTATIONS

Cutaneous extraintestinal manifestations have been described in up to 15% of patients with IBD, often preceding their IBD diagnosis and not necessarily linked with IBD disease activity. 

Erythema nodosum (EN), affecting up to 15% of those with IBD and pyoderma gangrenosum (PG), affecting up to 5% of those with IBD are the most common skin manifestations in those with CD or UC.21 It is important to note that while PG is associated with IBD, EN may be associated with a variety of conditions such as infection, medications, sarcoidosis, pregnancy, IBD, autoimmune diseases, vaccination, malignancy, and miscellaneous causes.22 PG is also linked with some degree of colonic inflammation, in up to 50% of patients underlying active disease is present, and often requires multiple therapies to achieve complete healing.23

There is an association between psoriasis and IBD, with a risk in UC patients 1.6 times higher than in the general population. Paradoxically, psoriasis can also be triggered in up to 5% of patients using anti-TNF drugs,24 and it may present in atypical locations, including new scaly and dry plaques that may be confused for eczema; therefore requiring a high suspicion by the medical provider for medication side effects. Paradoxical psoriasis may be treated with topical steroids or oral methotrexate, but if severe may require discontinuation of anti-TNF medication. 

The IL23/IL17 axis plays a critical role in the pathogenesis of skin EIMs. IL-23 stimulates the production of IL-17, an essential proinflammatory cytokine, mainly secreted by CD4+ helper T cells (Th17); therefore, biologic therapies targeting IL-23 in IBD may play a significant role in improving cutaneous inflammation such as psoriasis.26 In a similar vein, the expression of TNFα and its receptors are increased in PG and EN lesions in skin suggesting a mechanistic explanation for the effectiveness of anti-TNF therapy for these conditions.

Anti-TNFα agents, especially infliximab and adalimumab may thus be effective for some cutaneous manifestations and IBD including psoriasis and PG, and they can also be considered as sparing agents to avoid long-term side effects from systemic corticosteroids.26 Biologics against IL-23 can also be considered in patients with IBD and psoriasis, PG or EN. Considering the role of IL23 in the pathophysiology of skin inflammation, biologics such as ustekinumab, which targets IL12/23 and is approved for moderate to severely active CD and UC; and risankizumab, a humanized immunoglobulin G1 antibody targeting the p19 subunit of IL-23 approved for moderate to severe CD, may be appropriate therapeutic options for patients with IBD and concomitant psoriasis, EN, or PG.

MUSCULOSKELETAL 

Musculoskeletal involvement is the most common extraintestinal manifestations in IBD. Arthritis may affect up to 46% of patients with IBD, and its prevalence decreases with age. Patients with IBD and concomitant musculoskeletal symptoms are typically seronegative for rheumatoid factor (RF) and anti-citrullinated peptide antibodies. Seronegative spondyloarthropathies (SpA) include ankylosing spondylitis, reactive arthritis, and psoriatic arthritis (PsA). Rheumatoid arthritis (RA) has also been linked with IBD population.


CDUCMSScleritisNIUENPGPsARASpA
Anti-TNF++x++(+)(+)+++
Anti IL12/23++

(+)(+)(+)+

Anti IL-23++

(+)(+)(+)+

JAK inhibitors++

(+)(+)(+)+++
Natalizumab+
+






Sphingosine 1-phosphate 
++






Anti IL17Ax





+
+
Table 1. Advanced Therapies used for Inflammatory Bowel Disease and Extraintestinal Manifestations

Musculoskeletal conditions associated with IBD can be mainly divided into axial and peripheral arthritis (PA). Although both are present in patients with UC and CD, they are more commonly seen in CD sub-population; and while peripheral arthritis is typically correlated with active intestinal inflammation, axial arthritis is generally independent of it.

Patients with peripheral arthritis may respond to a course of nonsteroidal anti-inflammatory drugs (NSAIDs), but chronic NSAIDs use is discouraged in patients with IBD given the possibility of intestinal ulcer development and disease exacerbation; COX-2 inhibitors have been proposed as an acceptable first line treatment option for up to 14 days.27,28

Corticosteroids, on the other hand, are well known for their anti-inflammatory effects and are used in IBD as well as for peripheral arthropathies pains and flares, however they are generally ineffective for the treatment of axial arthritis and should be limited in use due to systemic side-effects. 

Sulfasalazine may be effective for peripheral and axial inflammatory arthritis, but it may be more effective in UC and peripheral arthritis than in CD. Although methotrexate has not shown efficacy in axial arthropathy either, when treating PA and CD patients, it has provided clinical improvement and may be used to achieve higher levels of anti-TNFs.29

When biologic treatments need to be considered, anti-tumor necrosis factors including infliximab and adalimumab continue to be the first line treatment as they have shown significant efficacy in both peripheral and axial arthropathy. Additional therapeutic considerations like IL12/23 and JAK inhibitors can be alternative approaches depending on the specific rheumatologic diagnosis, PsA, RA, or SpA. (Table 1.)

Ustekinumab, has shown to be effective for peripheral arthritis, including PsA, enthesitis and dactylitis, however it does not seem to be effective for treatment of axial arthropathies as SpA nor RA.30

Jak inhibitors are fast acting, oral medications, only available after not responding to TNF blockers due to safety considerations, and are effective for the treatment of SpA, RA and PsA.

Upadacitinib, a JAK inhibitor with high selectivity for JAK1 is approved for moderate to severe CD and UC as well as for moderate to severe RA, psoriatic arthritis, ankylosing spondylitis and non-radiographical axial spondyloarthropathy. Its efficacy has been demonstrated as a monotherapy with similar efficacy that combining upadacitinib with methotrexate.31,32 Tofacitinib acts by preferentially inhibiting JAK1 and JAK3, with reduced inhibition for JAK2 and tyrosine kinase 2, it is used for moderate to severe UC as well as RA, PsA and active ankylosing spondylitis.32,33

Monoclonal IgG4 antibodies directed against IL-17A such as secukinumab and ixekizumab; or against IL-17 receptor, brodalumab, are highly effective for psoriasis, enthesitis and peripheral arthritis. However, they have not only shown to be ineffective in IBD but are associated with exacerbation and new onset of IBD and colitis and its use in patients with MSK manifestations is thus not recommended.34

Summary

IBD may present with a single or multiple extraintestinal manifestations. EIMs may affect any organ system and are chronic inflammatory diseases capable of causing a major debilitating comorbidity if left untreated or partially treated. Detailed consideration of EIMs needs to be taken into account when deciding which biologic to use when co-treating IBD and EIMs. 

References

1. Gharib MH, AlKahlout MA, Garcia Canibano B, Theophiel Deleu D, Malallah AlEssa H, AlEmadi S. Demyelinating Neurological Adverse Events following the Use of Anti-TNF-α Agents: A Double-Edged Sword. Case Rep Neurol Med. 2022 Mar 7;2022:3784938. doi: 10.1155/2022/3784938. PMID: 35296124; PMCID: PMC8920694.

2. Kunchok A, Aksamit AJ, Davis JM, et al. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77(8):937-946. doi: 10.1001/jamaneurol.2020.1162

3. Kopp TI, Delcoigne B, Arkema EV, et al. Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden. Ann Rheum Dis. 2020;79(5):566-572. doi: 10.1136/annrheumdis-2019-216693

4. Li L, Aviña-Zubieta JA, Bernstein CN, Kaplan GG, Tremlett H, Xie H, Peña-Sánchez JN, Marrie RA, Etminan M. Risk of Multiple Sclerosis Among Users of Antitumor Necrosis Factor α in 4 Canadian Provinces: A Population-Based Study. Neurology. 2023 Feb 7;100(6):e558-e567. doi: 10.1212/WNL.0000000000201472. Epub 2022 Oct 28. PMID: 36307225; PMCID: PMC9946189

5. Song J, Westerlind H, McKay KA, Almqvist C, Stridh P, Kockum I, Hillert J, Manouchehrinia A. Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study. J Neurol. 2019 Feb;266(2):481-486. doi: 10.1007/s00415-018-9163-6. Epub 2018 Dec 21. PMID: 30578428; PMCID: PMC6373346.

6. Gonzalez Caldito N. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders. Front Immunol. 2023 Jul 7;14:1213448. doi: 10.3389/fimmu.2023.1213448. PMID: 37483590; PMCID: PMC10360935.

7. Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers. Curr Neurol Neurosci Rep. 2017 Apr;17(4):36. doi: 10.1007/s11910-017-0742-1. PMID: 28337644; PMCID: PMC5364240.

8. Mansouri B, Horner ME, Menter A. Tumor Necrosis Factor-α Inhibitor Use in Psoriasis Patients with a First-degree Relative With Multiple Sclerosis. J Drugs Dermatol. 2015 Aug;14(8):876-8. PMID: 26267733.

9. Dryden GW. Natalizumab for Moderate-to-Severe Crohn’s Disease. Gastroenterol Hepatol (N Y). 2008 Apr;4(4):296. PMID: 21960916; PMCID: PMC3093736

10. Hou J, Dodd K, Nair VA, Rajan S, Beniwal-Patel P, Saha S, Prabhakaran V. Alterations in brain white matter microstructural properties in patients with Crohn’s disease in remission. Sci Rep. 2020 Feb 7;10(1):2145. doi: 10.1038/s41598-020-59098-w. PMID: 32034257; PMCID: PMC7005825.

11. Dolapcioglu C, Dolapcioglu H. Structural brain lesions in inflammatory bowel disease. World J Gastrointest Pathophysiol. 2015 Nov 15;6(4):124-30. doi: 10.4291/wjgp.v6.i4.124. PMID: 26600970; PMCID: PMC4644876.

12. Paul T. Parks, Alexander S. Easton, “Cerebral Vasculitis in Ulcerative Colitis Is Predominantly Venular: Case Report and Review of the Literature”, Case Reports in Rheumatology, vol. 2019, Article ID 9563874, 6 pages, 2019. https://doi.org/10.1155/2019/9563874

13. Hou J, Dodd K, Nair VA, Rajan S, Beniwal-Patel P, Saha S, Prabhakaran V. Alterations in brain white matter microstructural properties in patients with Crohn’s disease in remission. Sci Rep. 2020 Feb 7;10(1):2145. doi: 10.1038/s41598-020-59098-w. PMID: 32034257; PMCID: PMC7005825.

14. Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000 Oct;130(4):469-76. doi: 10.1016/s0002-9394(00)00710-8. PMID: 11024419.

15. Ferreira, Lisia Barros MD; Smith, Anthony J. FRACP, PhD; Smith, Justine R. FRANZCO, PhD. Biologic Drugs for the Treatment of Noninfectious Uveitis. Asia-Pacific Journal of Ophthalmology 10(1):p 63-73, January-February 2021. | DOI: 10.1097/APO.0000000000000371

16. Sota J, Girolamo MM, Frediani B, Tosi GM, Cantarini L, Fabiani C. Biologic Therapies and Small Molecules for the Management of Non-Infectious Scleritis: A Narrative Review. Ophthalmol Ther. 2021 Dec;10(4):777-813. doi: 10.1007/s40123-021-00393-8. Epub 2021 Sep 2. PMID: 34476773; PMCID: PMC8589879

17. Mugheddu C, Atzori L, Del Piano M, et al. Successful ustekinumab treatment of noninfectious uveitis and concomitant severe psoriatic arthritis and plaque psoriasis. Dermatol Ther 2017; 30.

18. Chateau T, Angioi K, Peyrin-Biroulet L. Two cases of successful ustekinumab treatment for non-infectious uveitis associated with Crohn’s disease. J Crohns Colitis 2020; 14:571.

19. Miserocchi E, Giuffrè C, Cornalba M, et al. JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol 2020; 39:847–851.

20. Bauermann P, Heiligenhaus A, Heinz C. Effect of Janus kinase inhibitor treatment on anterior uveitis and associated macular edema in an adult patient with juvenile idiopathic arthritis. Ocul Immunol Inflamm 2019; 27:1232–1234.

21. Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology. 2021 Oct;161(4):1118-1132. doi: 10.1053/j.gastro.2021.07.042. Epub 2021 Aug 3. PMID: 34358489; PMCID: PMC8564770.

22. Leung AKC, Leong KF, Lam JM. Erythema nodosum. World J Pediatr. 2018 Dec;14(6):548-554. doi: 10.1007/s12519-018-0191-1. Epub 2018 Sep 29. PMID: 30269303.

23. Weizman AV, Huang B, Targan S, Dubinsky M, Fleshner P, Kaur M, Ippoliti A, Panikkath D, Vasiliauskas E, Shih D, McGovern DP, Melmed GY. Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study. J Cutan Med Surg. 2015 Mar-Apr;19(2):125-31. doi: 10.2310/7750.2014.14053. Epub 2015 Mar 11. PMID: 25775631.

24. De Francesco MA, Caruso A. The Gut Microbiome in Psoriasis and Crohn’s Disease: Is Its Perturbation a Common Denominator for Their Pathogenesis? Vaccines (Basel). 2022 Feb 5;10(2):244. doi: 10.3390/vaccines10020244. PMID: 35214702; PMCID: PMC8877283.

25. Maronese CA, Pimentel MA, Li MM, Genovese G, Ortega-Loayza AG, Marzano AV. Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments. Am J Clin Dermatol. 2022 Sep;23(5):615-634. doi: 10.1007/s40257-022-00699-8. Epub 2022 May 24. PMID: 35606650; PMCID: PMC9464730.

26. Liu T, Li S, Ying S, Tang S, Ding Y, Li Y, Qiao J, Fang H. The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. Front Immunol. 2020 Nov 17;11:594735. doi: 10.3389/fimmu.2020.594735. PMID: 33281823; PMCID: PMC7705238.

27. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006; 4: 196-202

28. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006; 4: 203-211

29. Zochling J, van der Heijde D, Dougados M, Braun J. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis. 2006 Apr;65(4):423-32. doi: 10.1136/ard.2005.041129. Epub 2005 Aug 26. PMID: 16126792; PMCID: PMC1798100.

30. Ulusoy BÖ, Erden A, Güven SC, Armağan B, Yürekli ÖT, Özin YÖ, Omma A, Küçükşahin O. Ustekinumab in enteropathic arthritis. Immunotherapy. 2023 Jun;15(8):583-592. doi: 10.2217/imt-2022-0197. Epub 2023 Apr 5. PMID: 37020400.

31. Fonseca D, Nogueira M, Torres T. Upadacitinib for the treatment of psoriatic arthritis. Drugs Context. 2023 Feb 28;12:2022-11-6. doi: 10.7573/dic.2022-11-6. PMID: 36876156; PMCID: PMC9983629.

32. Wang, Wenfei MD1; Cleveland, Noa Krugliak MD2; Ollech, Jacob MD2; Rubin, David T. MD2. Use of Tofacitinib for the Treatment of Arthritis Associated with Ulcerative Colitis. ACG Case Reports Journal 6(9):p e00226, September 2019. | DOI: 10.14309/crj.0000000000000226

33. Momen Majumder MS, Haq SA, Rasker JJ. Tofacitinib for the treatment of inflammatory bowel disease-associated arthritis: two case reports. J Med Case Rep. 2023 Mar 1;17(1):71. doi: 10.1186/s13256-023-03796-2. PMID: 36855206; PMCID: PMC9976468.

34. Deng Z, Wang S, Wu C, Wang C. IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis. Front Pharmacol. 2023 Mar 23;14:1124628. doi: 10.3389/fphar.2023.1124628. PMID: 37033665; PMCID: PMC10076642.

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Nutrition Reviews in Gastroenterology, SERIES #14

Nutrition Therapies for Patients with an Ileoanal Pouch: A Moving Target?

June 2024 • Volume XLVIII, Issue 4
Elizabeth Wall

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An ileal pouch-anal anastomosis (IPAA) is the preferred surgical reconstruction for restoration of intestinal continuity after a total proctocolectomy; it obviates the need for a permanent ileostomy. The pouch, or continuity reservoir, is anastomosed to the sphincter-spared anus allowing for controlled passage of bowel movements (BMs). Patients with mature, properly functioning pouches can expect to pass 6-8 BMs every 24 hours. Diet after IPAA is empiric and patient-specific with the overarching goals to optimize pouch continence and nutrient/fluid absorption. Pouch inflammation is common and thought to be primarily related to an abnormal immune response to pouch dysbiosis.1 Diet may play an important role in mediating the dysbiosis and influence pouch function, though evidence of this is lacking. This article will review basic information regarding IPAA, pouch complications, diet for patients with IPAA, and recommendations for long-term micronutrient supplementation.

Introduction

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with refractory ulcerative colitis (UC) and familial adenomatous polyposis (FAP) who desire intestinal continuity after colectomy. The pouch is an alternative to a permanent end ileostomy. The most common pouch configuration is the J-shape (constructed from two limbs of distal ileum, Figure 1), though other configurations are possible based on the surgeon’s determination. To date there is a dearth of evidence to support specific dietary recommendations for patients with IPAA. Frequently, results of small studies with heterogeneous populations and endpoints, or recommendations based on patients’ observations of their responses to certain foods/food components, are used to make generalized dietary recommendations. This review will summarize the limited data and key expert recommendations to support nutrition therapies for patients with IPAA.

IPAA Construction and Function

The IPAA procedure is typically performed in two or three phases depending on the condition of the colon, specifically, and patient’s overall condition.2,3 Approximately 30-40 centimeters of the distal ileum is used to fashion the pouch that is then anastomosed to the sphincter-spared anus.4 The two-step procedure is most commonly performed; the first phase is the proctocolectomy and IPAA construction with a diverting ileostomy (DI) followed 6-8 weeks later by the second step of DI takedown.3 The three-step procedure is often reserved for patients with severe colitis, perforation, bleeding, or dysplasia; the first step is a subtotal colectomy with  end ileostomy, the second step is the completion proctectomy, IPAA construction with DI and takedown of the end ileostomy, and the third step is the takedown of the DI. 

Once bowel continuity is restored, patients will experience a period of intestinal adaptation during which their bowel habits and dietary tolerance evolve. The adaptation process can take 6-18 months following colectomy.6,7 After complete adaptation, patients can expect to pass an average of 6 bowel movements (BMs) per 24 hours; often 1 BM will occur overnight.6 Physical and emotional adjustments to the new pouch habits will vary between patients. Those with a history of severe colitis often pass fewer BMs and feel better with the pouch, however, patients with FAP typically do not have pre-operative gastrointestinal symptoms and must learn to cope with frequent BMs, reduced continence, and fecal urgency after the proctocolectomy. In either scenario, support from an experienced gastrointestinal registered dietitian nutritionist (RDN) will help patients to understand the relationships between diet, hydration, and pouch function to optimize their health and quality of life (QoL). 

IPAA Complications

The IPAA procedure is not without risk of complications; Table 1 lists the phenotypes of pouch disorders. In the acute post-operative phase infection/pelvic abscess, anastomotic leak, and small bowel (SB) obstruction/ileus are most commonly observed; complication rates are higher for patients who received systemic corticosteroids or smoked at the time of surgery.8 Long term complications are characterized by urgency/high frequency of BMs, continence problems (both seepage and difficult evacuation), fatigue, pouch failure, and reduced QoL.3 

Pouch inflammation (pouchitis) is the most common complication associated with an IPAA and affects 30–50% of patients.9 Acute pouchitis is defined as symptoms lasting < 4 weeks and is usually responsive to antibiotic therapy whereas chronic pouchitis lasts > 4 weeks. An approach to diagnosis and management of pouchitis was recently published in this journal.10 

The etiology of pouchitis is not fully understood and is likely multifactorial but thought to be primarily related to an abnormal immune response to pouch dysbiosis; though secondary factors such as Crohn’s disease, infection, ischemia, or radiation can also cause inflammation.1

Diet After IPAA 

The goals of nutrition therapy for patients with IPAA are to optimize SB absorption and to regulate passage of BMs. Patients may report that their pouch function and defecation frequency are directly related to meals and post-prandial gastrointestinal motility; though evidence is lacking with regard to specific dietary elements that directly affect pouch function.7,11 Therefore, patients and clinicians alike must take a flexible and empiric approach when developing meal plans because a patient’s food tolerances will likely change with pouch adaptation and in cases of dysfunction. 

PhenotypeClinical Features
StructuralAnastomotic leak Fistula Pelvic infection/abscess Obstruction Dilation Bezoar
InflammationPouchitis
(acute, chronic antibiotic-responsive, chronic antibiotic-refractory) Crohn’s disease-like pouch inflammation Cuffitis
FunctionalIrritable pouch syndrome Dysmotility Anopouch pain syndrome
Nutrition/metabolicAnemia Metabolic bone disease Micronutrient deficiencies
Table 1. Pouch Disorders Phenotypes1

Immediately after DI takedown, depending upon the surgeon’s opinion of the competence of the pouch and pouch-anal anastomosis, it may be recommended for the patient to follow a low fiber diet. Although evidence lacks for fiber restriction, of particular concern to surgeons are insoluble fibers (e.g., wheat or oat bran, vegetable/legume peels/shells, nuts, and seeds) that accelerate transit, increase stool bulk, and exert pressure on suture lines. Fiber restrictions should be limited to the least number of weeks necessary to prevent patients from indefinite adherence to a low fiber diet. 

Beyond the initial postoperative period, IPAA patients should advance their diet as tolerated to one that is balanced between all food groups. General guidelines for an “IPAA Diet” are lacking given significant variations in patients’ perceived tolerance to foods (see Table 2 for foods observed to effect pouch output; patients can include or limit foods based on their pouch function).7,12,13 After total colectomy absorption of nutrients and fluid is limited to the SB, thus application of the following generally accepted recommendations for those with an ileostomy may help to slow postprandial gastric emptying and intestinal transit for optimal absorption:14,15

Eat multiple (5-6) small meals daily to avoid excessive gastric and pouch distention

Include slowly fermented, gel-forming fiber (e.g., psyllium) with each meal

Avoid simple sugars in foods and beverages to reduce rapid gastric emptying of hypertonic fluid

May limit intake of lactose containing foods and beverages

Separate solid foods and liquids to optimize gastric digestion

Post-prandial rest for 20-30 minutes to increase gastric digestion and to reduce intestinal motility

Sip isotonic or hypotonic fluids between meals

Oral rehydration solutions (ORS) can promote SB absorption of sodium and water

Avoid eating 2-3 hours before bed to reduce nocturnal defecation 

If needed, take antimotility medications 20-30 minutes before meals and at bedtime

See Table 3 for more detailed interventions to improve absorption after IPAA.

Over time, patients with a well-functioning pouch may be able to tolerate larger, less frequent meals. Although evidence is limited, ingestion of foods with gel-forming fibers (psyllium, pectin, gums) may help to increase the consistency of stool and provide important substrate for microbial fermentation and production of important metabolites.14,16 A recent study looked at fruit consumption after IPAA and found that consumption of > 1.5 fruit servings daily reduced the risk of developing pouchitis,17 supporting the importance of dietary fiber consumption after IPAA.

The Mediterranean diet (MD) is known for its emphasis on plant-based foods, fish and olive oil while limiting intake of red meats, saturated fats, sweets, and sugary beverages. Research has demonstrated that the MD can reduce inflammation in chronic disease states.18 More recently, a study demonstrated that patients with IPAA (for UC) who followed the MD for 8 years had reduced fecal calprotectin levels and adherence was inversely associated with episodes of pouchitis.19 Although the exact mechanism is not understood, this data supports the recommendation that IPAA patients follow a MD pattern (Figure 2) to maintain optimal pouch function. 

Diet and Pouch Dysfunction

Pouch dysfunction can derail any progress a patient has made towards attaining a stable, healthy diet. In the case of pouchitis the combination of medical therapies (typically antibiotics are the first line of therapy as pouchitis is thought to result from microbial dysbiosis) and a shift of diet composition may provide patients symptomatic relief.1 A recent pilot study of 15 adults with active pouchitis identified a positive effect of the Crohn’s Disease Exclusion Diet (excludes processed and refined foods, includes resistant starch and fiber) in patients with strict adherence.20 Although the study was small, non-randomized, and uncontrolled, it seems hopeful that some cases of pouch inflammation may respond to diet therapy. As more is understood about the phenotypes of dysfunction, and the association between pouch function and the microbiome, it is likely that there will be opportunities for 1:1 counseling with a RDN to tailor the diet based on the nature of the pouch dysfunction and create more evidence-based recommendations for dietary therapies to alter active inflammation.7,14 

In patients with pouch dysfunction  that is more irritable in nature (frequent and/or urgent BMs, abdominal cramps, pelvic discomfort, and absence of inflammation),21 it may be reasonable to restrict highly fermentable and osmotically active carbohydrates with a low FODMAP diet (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols).14 Limitation of FODMAP consumption may reduce bacterial fermentation (gas production) of undigested carbohydrates, as well as decrease water delivery to the pouch, both of which can reduce symptoms of gas, bloating, and diarrhea/urgency. Patients with a positive response to the initial exclusion of FODMAPs should work intensively with a RDN to identify trigger foods and to re-introduce those foods that are tolerable. There is minimal evidence though to support FODMAP restriction in the management of pouchitis.22

Observed
Effects of Food		Foods and Beverages 
Stool thickeningApplesauce Banana Bread Pasta Potatoes Oatmeal Rice Peanut butter Soluble, low fermentable fiber (e.g., psyllium)
Stool thinningSpicy foods (capsaicin) Fruit and fruit juice Cabbage
Increased stool outputNuts Corn Chocolate Lettuce Fresh oranges Tomatoes Cow’s milk Alcohol Fried foods Spicy foods
Increased flatusFood with high FODMAPs  Onions, cabbage, and cow’s milk Spicy foods 
Perianal irritationCitrus fruits Spicy foods Nuts and seeds
Table 2. Foods Observed to Effect Stool Output and IPAA13,14

Fluids and Hydration

Hydration status after IPAA is often overlooked. Chronic low-level dehydration (characterized by low 24-hour urine volume, hypotension, chronic fatigue, dry mucous membranes, etc.) can affect a patient’s overall feeling of wellness and their ability to participate in life activities, not to mention the risk of nephrolithiasis and chronic kidney injury. It is recommended for adults with normal kidney function to produce at least 1,000-1,200 mL urine per day and kidney stone formers should make at least 1,500 mL per day.23,24 Attention to both fluid intake and urine output is imperative to gauge hydration and ensure long-term maintenance of normal kidney function. Without the colon to absorb sodium and water, those with an IPAA must rely mainly on SB sodium-glucose co-transporters to drag water across the mucosa.25 Consumption of isotonic fluids such as ORS and avoidance of hypertonic, sugary beverages should improve water absorption and hydration status.

ORS contain specific concentrations of sodium and sugar in water and are known to facilitate SB water absorption. Beverages that contain both sodium (50-70 mEq/L) and glucose (20-40g/L) are palatable options (Table 3).26 IPAA patients who pass high volume stool may find that sipping ORS between meals can help to achieve hydration goals.

Micronutrients

The IPAA consensus guidelines recommend lifelong monitoring of several micronutrients as well as for anemia and metabolic bone disease.1 Most notably, vitamin B12, vitamin D, and iron, are identified as micronutrients of potential concern (particularly in the early phase of IPAA and in the setting of pouch inflammation),1 although other fat soluble vitamins and divalent cations may become deficient in the IPAA population (see Table 4).4 Deficiencies can result from insufficient intake and with altered absorption in the setting of rapid transit or of villous atrophy associated with pouch inflammation.4 In particular, vitamin B12 deficiency can develop from reduced absorption and increased utilization by bacteria if pouch overgrowth/dysbiosis exists.4 Vitamin B12 deficiency can lead to permanent neurological deficits and therefore lifelong therapeutic dosing of cyanocobalamin (1,000 mcg by mouth daily or monthly subcutaneous injection) is safe and recommended. 

Evidence for monitoring and supplementation of micronutrients after IPAA does not exist. Data and guidelines for patients with inflammatory bowel disease and post-surgical malabsorption can guide clinicians when prescribing supplementation regimens. One important factor with respect to interpretation of serum/plasma micronutrient levels when inflammation exists is that reported levels are often perturbed making interpretation difficult.27 A RDN with experience in micronutrient repletion therapy, who is able to perform sequential nutrition focused physical exams, is the ideal team member to develop, institute, and monitor responses to micronutrient supplementation. Short of this, it is prudent for anyone unable to consume a balanced diet to take a daily multivitamin with mineral supplement that meets 100% of the Reference Dietary Intake (RDIs).

TherapyIntervention
DietEat 5-6 small meals Avoid overeating/drinking to prevent excessive pouch distention Use the Mediterranean diet pattern to structure meals Include plenty of plant foods with soluble fiber Oats, peas, carrots, beans, citrus fruits, apple, banana Slows gastric emptying, thickens stool, supports microbiome Eat at least  two fruit servings daily Limit foods with simple sugars  Cakes, cookies, pastries, ice cream, Italian ice Limit greasy foods Limit insoluble fiber, caffeine, and alcohol May increase BM frequency and cause watery stool
FluidsLimit fluids at meals to 4-8 ounces Sip remaining fluids between meals, throughout the day Focus in hypotonic and isotonic fluids for SB water absorption Hypotonic beverages – water, dilute juices, tea, coffee, diet drinks Isotonic beverages – ORS, e.g., Ceralyte®, Pedialyte®, DripDrop®, Trioral® Limit hypertonic beverages Cause osmotic shift of water into the intestinal lumen resulting in more volume to reabsorb Fruit juice, sweet tea, lemonade, sweetened beverages, and cocktails Oral nutrition supplements (Ensure®, Boost®)
Medications and supplementsUse antimotility agents such as loperamide to slow gastrointestinal transit Time antimotility medications 30-60 minutes before meals and bedtime Fiber supplements such as Metamucil® or Benefiber® may help thicken stool for improved continence
ActivitySit for 20-30 minutes after meals to allow for digestion and reduce intestinal motility Avoid eating 2-3 hours before bed to reduce nocturnal defecation
Table 3. Interventions to Optimize Food and Fluid Absorption After IPAA
MicronutrientMonitoring ParametersDaily Maintenance Dose¥ (Oral)Repletion Dose*
Vitamin B12Serum vitamin B12 Serum folate Plasma homocysteine Plasma methylmalonic acid1,000 mcg1,000 mcg subcutaneous injection for 5-7 days
Vitamin DSerum 25-hydroxy vitamin D18 – 70 yrs 15 mcg > 70 yrs 20 mcg100-125 mcg oral daily
Vitamin EPlasma α-tocopherol15 mg90 – 180 mg oral daily
Vitamin ASerum RetinolMen 900 mcg Women 700 mcg Pregnant 770 mcg Lactating 1300 mcg1,500 – 3,000 mcg
oral daily
IronHemoglobin Serum iron Total iron binding capacity Transferrin saturation Serum ferritinMen  8 mcg Women Premenopausal 18 mg Postmenopausal 8 mg50 – 200 mg oral daily (divided doses)
ZincPlasma zincMen – 11 mg Women – 8 mg50 mg oral daily
CalciumBone densityMen 19 – 70 yrs 1,000 mg >70 yrs 1,200 mg Women 19-50 yrs 1,000 mg >50 1,200 mgVariable based on
bone health
Table 4. Micronutrient Monitoring and Dosing Recommendations After IPAA

Conclusion

For patients with severe colitis or FAP the IPAA is a means to restore bowel continuity and avoid a permanent end ileostomy after total proctocolectomy. The procedure requires patients to adopt balanced dietary patterns, such as the MD, that include fruits, vegetables, and fiber to optimize pouch function, absorption, the microbiome, and overall health. Avoidance of excessive pouch distention from over-eating/drinking may help to control the frequency of BMs. Symptoms of irritable pouch syndrome (diarrhea dominant), rather than inflammation, may be controlled with elimination of some highly fermentable carbohydrates. Collaboration between the patient and a RDN is necessary to identify poorly tolerated foods and design the most balanced diet possible. Routine supplementation with vitamin B12 and close monitoring for micronutrient deficiencies, anemia, bone health, and hydration status is essential to ensuring optimal health and well-being. In summary, the IPAA can significantly improve the health and QoL for some patients but may require ongoing RDN support for optimization of nutrient uptake, hydration, and pouch function. 

References

1. Shen B, Kochhar GS, Kariv R, et al. Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol 2021;6:826-849.

2. McGuire BB, Brannigan AE, O’Connell PR. Ileal pouch anal anastomosis. Br J Surg. 2007;94(7):812-823.

3. Deputy M, Segal J, Reza L., et al. The pouch behaving badly: management of morbidity after ileal pouch-anal anastomosis. Colorectal Dis. 2021;23:1193-1204. 

4. Buckman SA, Heise CP. Nutrition considerations surrounding restorative proctocolectomy. Nutr Clin Pract. 2010;25:250-256.

5. Marulanda K, Purcell LN, Egberg MD, et al. Analysis of modified two-stage approach to ileal pouch-anal anastomosis without fecal diversion in pediatric patients. Am Surg. 2022;88(1):103-108.

6. Michelassi F, Lee J, Rubin M, et al. Long-term functional results after ileal pouch anal restorative proctocolectomy for ulcerative colitis. Ann Surg. 2003;238(3):433-445.

7. Ardalan ZS, Sparrow MP. A personalized approach to managing patients with an ileal pouch-anal anastomosis. Front Med. 2020;6:337.

8. Zittan E, Ma GW, Wong-Chong N, et. al. Ileal pouch-anal anastomosis for ulcerative colitis: a Canadian institution’s experience. Int J Colorectal Dis. 2017;32(2):281-285.

9. Turpin W, Kelly O, Borowski K, et al. Mucosa-associated microbiota in ileoanal pouches may contribute to clinical symptoms, particularly stool frequency, independent of endoscopic disease activity. Clin Trans Gastro. 2019;10:1-7. 

10. Hossain M, Kayal M. A review of the diagnosis and treatment of inflammatory pouch conditions.Pract Gastroenterol. 2023;47(4):17-21.

11. Groom JS, Kamm MA, Nicholls RJ. Relationship of small bowel motility to ileoanal reservoir function. Gut 1994;35:523-529.

12. Tyus FJ, Austhof SI, Chima CS, Keating C. Diet tolerance and stool frequency in patients with ileoanal reservoirs. J Acad Nutr Diet. 1992;92:861-863.

13. Quinn KP, Lightner AL, Faubion WA, Raffals L. A comprehensive approach to pouch disorders. Inflamm Bowel Dis. 2019;25(3):460-471.

14. Ardalan ZS, Yao CK, Sparrow MP, Gibson PR. Review article: the impact of diet on ileoanal pouch function and on the pathogenesis of pouchitis. Aliment Pharmacol Ther. 2020;52:1323-1340.

15. Bridges M, Nasser R, Parrish CR. High output ileostomies: the stakes are higher than the output. Pract Gastroenterol. 2019;9:20-33.

16. Sidebottom AM, Chang EB. IBD microbial metabolome: The good, bad, and unknown. Trends Endocrinol Metab. 2020;31(11):807-809.

17. Godny L, Maharshak N, Reshef L, et. al. Fruit consumption is associated with alterations in microbial composition and lower rates of pouchitis. J Crohn’s and Colitis. 2019 Sep 27;13(10):1265-1272.

18. Chicco F, Magri S, Cingolani A. et. al., Multidimensional impact of Mediterranean diet on IBD patients. Inflamm Bowel Dis. 2021 Jan 1;27(1):1-9.

19. Godny L, Reshef L, Pfeffer-Gik T, et al. Adherence to the Mediterranean diet is associated with decreased fecal calprotectin in patients with ulcerative colitis after pouch surgery. Eur J Nutr. 2020;59:3183-3190.

20. Fliss Isakov N, Kornblum J, Zemal M, Cohen NA, Hirsch A, Maharshak N. The effects of the Crohn’s Disease Exclusion Diet on patients with pouch inflammation: an interventional piolet study. Clin Gastro Hepatol 2023;21(6):1654-1656.

21. Shen B, Achkar JP, Lashner BA, et al. Irritable pouch syndrome: A new category of diagnosis for symptomatic patients with ileal pouch anal anastomosis. Am J Gastro. 2022;97:972-977.

22. Rabbenou W, Chang S. Medical treatment of pouchitis: a guide for the clinician. Ther Adv Gastroenterol. 2021;14:1-15.

23. Parrish CR, Wall EA. The clinician’s toolkit for the adult short bowel patient Part 1: nutrition and hydration therapy. Pract Gastroenterol. 2022;6:32-53.

24. Borghi L, Meschi T, Amato F, et al. Urinary volume, water, and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996;155(3):839-843.

25. Barrett KE. Water and Electrolyte Absorption and Secretion. In: Barrett KE. Ed. Gastrointestinal Physiology, 2e. New York, NY: McGraw-Hill; 2014. http://access-medicine.mhmedical.com/content.aspx?bookid=691&sectionid=45431404. Accessed February 25, 2024.

26. Wall E. ORS: The Solutions to Optimize Hydration in Short Bowel Syndrome. Practical Gastroenterology. 2020;3:24-31.

27. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022;41:1357-1424.

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FRONTIERS IN ENDOSCOPY, SERIES #91

Endoscopic Management of Laparoscopic Gastric Sleeve Leaks

June 2024 • Volume XLVIII, Issue 4
Kelita Singh,Douglas G. Adler,Abinash Subedi,Fathima Keshia Suhail

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INTRODUCTION

Bariatric surgery is a well-established option for patients with obesity, with over 200,000 procedures performed annually in the United States. Sleeve gastrectomy comprises 58% of these surgeries.1 Gastric sleeve leaks (GSL) can occur in 1-2% of patients following laparoscopic sleeve gastrectomy.2 Leaks occur when tissue breakdown, most commonly near the anastomosis and/or suture or staple lines and can evolve into a fistula with an epithelialized tract if they do not heal in a timely manner.3 GSL are the second most common cause of mortality in patients undergoing sleeve gastrectomy, following pulmonary embolism.4

A multidisciplinary approach is important when managing these patients and should involve surgery, gastroenterology, and interventional radiology. Prompt diagnosis, classification, and treatment of GSL is essential. Techniques for managing GSL can vary based on the patient’s clinical condition, leak classification, expert experience, and availability of resources. In the presence of hemodynamic compromise, septic shock or peritonitis, further surgical management is needed. Otherwise, endoscopic treatment is preferred, due to high perioperative morbidity with surgery.5

Classification

Classification of GSL can guide management decisions. There are several proposed classification systems that are based on timing of presentation and findings on computed tomography (CT) scan. 

The Rosenthal sleeve gastrectomy leak classification system organizes leaks based on timing of presentation.6 Acute leaks are diagnosed and treated before 7 days from the operative procedure, early leaks between 1-6 weeks, late leaks between 6-12 weeks, and chronic leaks after 12 weeks. 

Sleeve leaks can also be classified according to a CT scan classification system7 which is organized by the type of collection on CT and leak visualization. (Table 1) Johari et al. proposed a validated classification system, based on CT imaging that predicts a stepwise increased risk of complication severity, increased hospital stay and salvage resection using a 2-phase modified Delphi process.8
(Table 1)

Csendes et al.Johari et al.
Type Collection on CTClass 1 Phlegmon associated with staple line
I< 5cm in LUQClass 1aPhlegmon 
II> 5cm in LUQClass 1bPhlegmon with small localized locules of gas
IIIDiffuse abdominal collectionsClass 2Fluid collection
IV Pleural (thoracic) collectionsClass 2aFluid collection with localized locules of gas
Type Staple line localization Class 2b Extensive mixed fluid and gas collection
SSuperior part of sleeve Class 3Contrast leak 
MMiddle part of sleeveClass 3aContained contrast leak 
IInferior part of sleeveClass 3bFree intraperitoneal contrast leak 

Leak VisualizationClass 4Chronic fistula 
aNo leak

bPositive leak 

Etiology

The etiologies of GSL can be due to mechanical/tissue causes or ischemic causes. It is related to an increase in intraluminal pressure which exceeds the strength of the tissue and/or staple line.9 When creating a gastric sleeve, a long staple line anastomosis is created which extends from the antrum of the stomach to the gastroesophageal junction. Leaks can form anywhere along the staple line, although most leaks occur near the angle of His, where the gastric wall is susceptible to ischemia. Relative ischemia tends to occur in this area secondary to surgical ligation of gastric arteries, relative dysmotility and increased intragastric pressure. Distal obstructions, such as concomitant gastric sleeve stenosis, can further increase intraluminal pressure and contribute to the development of leaks. 

Risk Factors

Surgical and nonsurgical risk factors contribute to the development of GSLs. Several studies have demonstrated that male gender and higher BMI, especially in super-obese patients (BMI >50 kg/m2), increase the risk of developing a GSL.2,10

Surgical risk factors relate to stapling, ischemia, gastric stenosis, and the experience of the surgeon. Meticulous tissue handling, consideration of tissue thickness, conscious stapling, avoidance of inadvertent narrowing are methods to decrease surgical risk factors.9 Additionally, surgeons performing >43 cases per year can achieve a <1% leak rate.11

Clinical Manifestations 

Clinical manifestation of GSL can range from asymptomatic leaks diagnosed with routine imaging to signs and symptoms of perforation, peritonitis, and septic shock. Fever and tachycardia are two of the most important clinical factors in the diagnosis of GSL.5 Other clinical manifestations include abdominal pain, pain radiating to the left shoulder, vomiting and tachypnea.12

Diagnosis 

Upper gastrointestinal (UGI) fluoroscopy and CT scan of the abdomen with oral contrast are the most common tests used to diagnose GSL. In a head-to-head study comparing UGI contrast studies and CT scan with oral contrast, CT was found to be superior to UGI series in the diagnosis of GSL with a sensitivity of 95% vs. 74.9% respectively.13 Endoscopy is also useful when trying to establish the characteristics of the leak such as size of the orifice.14

Endoscopic Management 

Endoscopic treatment is feasible in most patients with GSL and have been shown to facilitate healing of GSL in 74-81%14,15 of patients, with early intervention increasing the likelihood of success.15 Predictors of successful healing with endoscopic management include acute leaks that developed ≤ 3 days from the operative procedure, early endoscopic treatment < 21 days after leak diagnosis, leak size < 1 cm, and no prior history of banded gastroplasty.15 

There are various treatment options for endoscopic management of GSL. Treatment strategy depends on the characteristics of the defect and center level of experience. The size, viability of surrounding tissue, and location of the defect can be defined endoscopically to determine which closure strategy might be best to perform. Additionally, treatment of distal stenoses and removal of foreign material is important for successful treatment of GSL.16

A retrospective review of 37 patients with GSL demonstrated that 30/37 (81%) were successfully managed endoscopically. Endoscopic techniques performed included: 44% fully covered bariatric gastric stents, 34% internal pigtail plastic stents, 11% septoplasty, 5% endoluminal vacuum therapy, and 3% over-the-scope clip (OTSC).14 Other endoscopic approaches include use of tissue sealants, endoscopic suturing, and novel techniques such as use of cardiac septal occluders. Patients may require combined endoscopic modalities for successful closure, especially in patients with refractory leaks who failed initial endoscopic intervention.17

Endoscopic Internal Drainage

The presence of an intra-abdominal collection (IAC) requires drainage as they tend to be the source of sepsis. Adequate drainage can be performed internally by endoscopy, via percutaneous drains, or, less frequently, via surgery.18,19 The reported efficacy rate when EID is used as a primary intervention is 74-86%.18-20 

Endoscopic internal drainage (EID) is accomplished under general anesthesia with fluoroscopy to identify the defect within the staple line.18 One or more double pigtail stents (DPS) with a diameter of 7 or 10 French are left in place, with one end of the pigtail in the collection and the other end of the pigtail in the stomach, for several months.18-20 Follow up endoscopy with fluoroscopy can be performed after one month for stent retrieval and to determine the presence of any residual leak. In patients with persistent leaks, stents are re-inserted.18 Adverse events of EID include stent migration, seen in 46% of cases, minor gastric mucosal trauma, minor bleeding related to stent erosion, and major bleeding from nearby vessel (i.e., splenic vessels).18,20 

Endoscopic ultrasound (EUS) can also be utilized for endoscopic drainage of IAC. EUS allows determination of collection size, location, and avoidance of any intervening vessels. Drainage is accomplished by using a 19G needle, guidewire, over the wire puncture and deployment of multiple DPS or lumen-apposing metal stents (LAMS) or can simply be done via freehand technique.21  LAMS can be exchanged at 1 month with DPS, if needed.18

Self-Expanding Metal Stents 

SEMS placed is the most common endoscopic interventions used to manage GSL.22 The objective of endoluminal stenting is to divert gastric contents from the leak site and to bypass any distal stenosis if present. The ideal stent should be long enough to cover the distal end of the sleeve, including the incisura. Predictors for success include male gender, higher pre-bariatric surgery BMI, and early stenting. (25 vs. 49 days).23 (Figure 1)

The success of endoluminal stenting for GSL is between 70%-88%.22,24,25 Additionally, successful treatment of GSL with SEMS can occur in 50% of patients after a single endoscopic session.22 The most undesired adverse effect of SEMS for treatment of GSL is migration which has been demonstrated in 30-47% cases.22,24 Anti-migratory mechanisms that can be utilized include endoscopic suturing of stents, longer stent length, and the use of endoscopic clips.22 Other adverse events include stent intolerance, bleeding, foreign body obstruction, strictures, and mucosal hypertrophy. According to one group, the optimal time for stent removal is after six to eight weeks, and they proposed that shorter intervals may lead to incomplete leak closure and longer intervals may result in stent migration or mucosal hypertrophy leading to difficulty with stent extraction.25 Still, in practice many different physicians have different opinions on the optimal stent indwell time and most patients receive individualized care. 

Fully covered self-expanding metal stents (fcSEMS) have the advantage of being easily removable compared to partially covered self-expanding metal stents (pcSEMS).26 However, fcSEMS have a high migration rate, reaching up to 26-67%.27,28 The Mega stent (Taewoong Medical, Seoul, Korea) was designed as a proposed solution to overcome the problem of migration.28 It is an ultra-large fully covered stent with braided mesh and increased flexibility which allows it to conform to post-bariatric anatomy. Its design can increase compression and coaptation against the luminal wall.  Shehab et. al has demonstrated the success rate of Mega stents to be 82% with a migration rate of 18%.28 Stenting can be combined with other treatment modalities, such as over-the-scope clips, which can directly close the wall defect.29 

Through-the-Scope-Clips 

Through the scope clips (TTSC) were initially designed for the treatment of gastrointestinal bleeding. These clips can approximate the edges of a lesion and produce mechanical compression/hemostasis without creating tissue injury seen with thermal hemostatic devices.30 TTSC have been reported as a modality for management of GSL.31,32  Once the edges of the defect are approximated, one or more clips are deployed to close the defect. In a meta-analysis of 17 studies including a total of 98 patients treated with clips for GSL, 4 studies (13 patients) utilized TTSC and successful treatment was reported in 9 of 13 patients (69.2%).32 This study is limited by the inclusion of very small number of patients. The use of TTSC can be considered in stable patients with small leaks, if the leak has failed endoscopic stenting, or is not amenable to stent placement.31  

Over-the-Scope Clips 

The over-the-scope clip (OTSC) is a mechanical clipping device designed to encircle, lift, and close endoscopic defects. These clips can achieve full thickness closure of luminal defects.29 Suction or grasping can be utilized to help ensure proper placement over the entire defect. OTSC is a wall defect closure strategy for the management of GSL.  A meta-analysis reported the use of OTSC in 85 patients across seventeen papers (98 patients) with a successful closure rate of 67.1%.32 The use of OTSC is more efficient if IAC are drained prior.33 OTSC-related adverse events occur in approximately 1.7% of cases.34 These include jejunal stenosis, clip mis-deployment, and micro-perforation or free perforation if there is an underlying ulcer.33,34

As most GSL are located at the proximal end of the staple line, using an OTSC and its mounting system to maneuver and position the clip may be difficult, due to limited space. Successful deployment of an OTSC depends on the working space, size, orientation of the defect and surrounding tissue quality.35 Using OTSC as a closure device to treat GSL should be considered for small- to medium-sized defects that can easily be accessed endoscopically. (Figure 2)

Tissue Sealants

Tissue sealants are adhesives that can be used to treat gastrointestinal leaks with initial data arising predominantly from use in Roux-en-Y gastric bypass (RYGB) patients. Such products are not readily available for endoscopists, which limit its use. The most commonly used sealant used for GSL closure is fibrin glue.32 Fibrin glue mechanically occludes the stomach wall defect and aids in wound healing. It induces a cellular response to tissue damage by forming matrix-building strands which promotes neovascularization and fibroblast proliferation.36 In a 2021 systematic review and meta-analysis, 10 case series comprising 63 patients with GSL were treated with fibrin glue. In 25 patients, the sealant was delivered endoscopically with a 100% success rate. The amount of glue ranged from 2-10 cc (median 4cc). Adverse events were reported in one study and included pain and fever in 3/24 patients.32

Another example of a tissue sealant glue is cyanoacrylate. Cyanoacrylate is a highly adhesive synthetic glue with antibacterial properties that can be utilized as a tissue sealant for GSL closure.37 Only a small amount (0.5-4cc) is needed and it can be utilized in a wet environment. Despite its advantages, it’s rapid polymerization results in poor mechanical properties such as low tensile strength and brittle nature, as well as risking damage to the endoscope.37 

SurgiSIS (Cook Biotech Inc., West Lafayette, IA) is an acellular matrix biomaterial comprising porcine small intestine submucosa. It stimulates proliferation and formation of fibroblasts in the regions of wounds.38 Strips of soaked SurgiSIS material are captured within a specially designed polypectomy snare and loaded into the endoscope outside of the patient. The scope is re-inserted after which the snare is used to place the material on the defect.38 In a 2009 clinical trial, the rate of closure of 5 to 10mm wide fistulas in patients who had undergone prior gastric bypass was achieved in 20/25  patients (80%) after 3 sessions.38 Further studies are necessary to determine the efficacy of SurgiSIS in patients with leaks from sleeve gastrectomy. 

Endoscopic Suturing 

Endoscopic suturing may be considered for closure of GSL when the defect size is large and other methods are less likely successful or have failed.39 The OverStitch (Apollo Endosurgery Inc., Austin, TX) is an endoscopic suturing system, mounted over the scope, that places full-thickness sutures endoscopically. Choosing to perform endoscopic suturing for gastrointestinal leaks depends on the condition/viability/friability/etc. of the target tissue, the feasibility of placing the suture according to the shape of the defect, distance of the margins, and absence of IAC.40  

The success of closing gastrointestinal leaks with endoscopic sutures was initially reported among RYGB patients.41 Mukewar et al. reported 100% immediate clinical success rate for gastrointestinal fistula closure with endoscopic suturing, however only 40% sustained clinical success at 4 weeks after the index procedure.39 There has been limited data which observed the use of endoscopic suturing in the management of GSL. Granata et al. reported 100% clinical success rate for gastric sleeve leak patients treated with OverStitch™ endoscopic suturing (6/6 patients).40 In a 2022 randomized controlled trial, 5/15 patients with gastric sleeve leaks were managed with endoscopic suturing alone with 100% clinical success and no cases of recurrent gastric fistula during the 18 month follow up period.3 

Septotomy 

Septotomy is a relatively new procedure which allows for fluid drainage from an abscess cavity, formed secondary to a leak, into the stomach by dividing the septum that separates the abscess from the gastric lumen.42 This division equalizes the intraluminal pressures by addressing the pressure gradient that drives gastric contents from the gastric lumen into the peri gastric collection.43 These changes can result in abscess cavity collapse and healing can occur through secondary intention and epithelialization.42,43 

This procedure is performed with a forward viewing gastroscope and the leak orifice is identified. If feasible, the abscess cavity is inspected and entered for irrigation.42 Division of the septum can be performed using a needle knife, cutting knife, or other endoscopic tools.43-45 Division of the septum is complete when the entire abscess cavity communicates with the gastric lumen, allowing drainage into the lumen of the stomach.  In a small multicenter study of 9 patients with GSL treated via septotomy, the peri-gastric collections ranged in size from 3-10cm. The mean procedure time was 87 minutes and a mean of 2.3 procedures were required to achieve radiologic resolution.43 Bleeding occurred in 3 patients and was managed successfully with TTSC. All patients achieved radiologic resolution. Diaz et al. demonstrated 5 patients with GSL who were treated with septotomy combined with sleeve dilation. Clinical success was achieved in 80% of patients (4/5), and no adverse events to the procedure were identified.42 

Endoscopic Vacuum Assisted Closure 

Endoscopic vacuum assisted closure (EVAC) is a negative pressure closure technique involving the placement of a porous polyurethane sponge in the abscess cavity at the leak site. In addition to drainage, it also increases local blood flow and promotes granulation tissue formation.46,47 The Endo-SPONGE system (B. Braun, Melsungen, Germany) allows for the insertion of an open-pored sponge into the leakage cavity using an endoscope. A drainage tube is connected to the sponge and suction is applied between 75 – 120 mm Hg depending on the size of the leak.48 The sponge can be inserted in cavities from leaks with large openings (≥ 9mm). The sponge can be exchanged every 3 days via endoscopy.48 

Studies have demonstrated 85-100% success with use of EVAC for treatment of GSL.47-49 Markus et al. demonstrated a 90% healing rate with Endo-SPONGE with a mean treatment time of 17 days. GSL healing with use of a sponge was defined as wound cavity size smaller than 1 cm in radius and 2 cm in depth, after which EVAC was terminated.48 

Cardiac Septal Occluders 

Cardiac septal occluder devices (CSDO) are a novel, off-label, treatment option for the management of GSL. CSDO Amplatzer™ (St. Jude Medical, Plymouth, Minn) is a self-expandable double disk (double umbrella) closure device, made of nitinol and interwoven polyester, which promotes tissue in-growth while sealing fistulous tracts.50 In a 2020 systematic review of 22 patients with GI fistulas, in 2 patients with GSL, technical success was 100% and clinical success (after one year of follow-up) was seen in 77%. Adverse events were reported in 5 patients and included migration and fistula enlargement. Further studies are needed prior to consideration of CSDO as the first line for treatment of GSL.50

Conclusion 

Gastric sleeve leaks are common adverse events following sleeve gastrectomy. Management of these leaks should ideally occur in a multidisciplinary setting.  An endoscopic approach should be considered as a less invasive option to surgery in patients without hemodynamic compromise, septic shock or peritonitis. The endoscopic armamentarium currently provides various options, and continues to expand, serving as a minimally invasive treatment avenue for the management of GSL. 

References

References

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2. Stroh C, Kockerling F, Volker L, et al. Results of More Than 11,800 Sleeve Gastrectomies: Data Analysis of the German Bariatric Surgery Registry. Ann Surg. May 2016;263(5):949-55. doi:10.1097/SLA.0000000000001559

3. Negm S, Mousa B, Shafiq A, et al. Endoscopic management of refractory leak and gastro-cutaneous fistula after laparoscopic sleeve gastrectomy: a randomized controlled trial. Surg Endosc. Mar 2023;37(3):2173-2181. doi:10.1007/s00464-022-09748-z

4. Souto-Rodriguez R, Alvarez-Sanchez MV. Endoluminal solutions to bariatric surgery complications: A review with a focus on technical aspects and results. World J Gastrointest Endosc. Mar 16 2017;9(3):105-126. doi:10.4253/wjge.v9.i3.105

5. Csendes A, Braghetto I, Leon P, Burgos AM. Management of leaks after laparoscopic sleeve gastrectomy in patients with obesity. J Gastrointest Surg. Sep 2010;14(9):1343-8. doi:10.1007/s11605-010-1249-0

6. Rosenthal RJ, International Sleeve Gastrectomy Expert P, Diaz AA, et al. International Sleeve Gastrectomy Expert Panel Consensus Statement: best practice guidelines based on experience of >12,000 cases. Surg Obes Relat Dis. Jan-Feb 2012;8(1):8-19. doi:10.1016/j.soard.2011.10.019

7. Nedelcu M, Skalli M, Delhom E, Fabre JM, Nocca D. New CT scan classification of leak after sleeve gastrectomy. Obes Surg. Aug 2013;23(8):1341-3. doi:10.1007/s11695-013-1002-3

8. Johari Y, Catchlove W, Tse M, et al. A 4-tier Protocolized Radiological Classification System for Leaks Following Sleeve Gastrectomy. Ann Surg. Feb 1 2022;275(2):e401-e409. doi:10.1097/SLA.0000000000003984

9. Kim J, Azagury D, Eisenberg D, et al. ASMBS position statement on prevention, detection, and treatment of gastrointestinal leak after gastric bypass and sleeve gastrectomy, including the roles of imaging, surgical exploration, and nonoperative management. Surg Obes Relat Dis. Jul-Aug 2015;11(4):739-48. doi:10.1016/j.soard.2015.05.001

10. Benedix F, Benedix DD, Knoll C, et al. Are there risk factors that increase the rate of staple line leakage in patients undergoing primary sleeve gastrectomy for morbid obesity? Obes Surg. Oct 2014;24(10):1610-6. doi:10.1007/s11695-014-1257-3

11. Varban OA, Sheetz KH, Cassidy RB, et al. Evaluating the effect of operative technique on leaks after laparoscopic sleeve gastrectomy: a case-control study. Surg Obes Relat Dis. Apr 2017;13(4):560-567. doi:10.1016/j.soard.2016.11.027

12. Li M, Zeng N, Liu Y, et al. Management and outcomes of gastric leak after sleeve gastrectomy: results from the 2010-2020 national registry. Chin Med J (Engl). Aug 20 2023;136(16):1967-1976. doi:10.1097/CM9.0000000000002499

13. Bingham J, Shawhan R, Parker R, Wigboldy J, Sohn V. Computed tomography scan versus upper gastrointestinal fluoroscopy for diagnosis of staple line leak following bariatric surgery. Am J Surg. May 2015;209(5):810-4; discussion 814. doi:10.1016/j.amjsurg.2015.01.004

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Feeding Tube Response in Esophagitis

May 2024 • Volume XLVIII, Issue 5

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Eosinophilic esophagitis (EoE) in young children can be associated with poor feeding as well as associated failure to thrive/failure to gain weight. Thus, use of nasogastric (NG) tube feeds as well as surgical gastrostomy tube (G-tube) feeds may be recommended to improve caloric intake as well as to provide elemental nutrition in this age group with EoE. There is minimal long-term data available regarding which pediatric patients with EoE would benefit most from NG/G-tube feeds.  

This retrospective study occurred at a tertiary children’s hospital in the United States. All pediatric patients with EoE and with a history of enteral tube feeds used as treatment for EoE from 2002 to 2021 were included. Basic patient demographics were obtained on all patients, and all patients were evaluated for both endoscopic and histologic response to enteral feeds. A total of 457 pediatric patients with EoE were identified, of which 39 pediatric patients with EoE required enteral tube feeds. The mean age of initial diagnosis of EoE for patients requiring enteral tube feeds was 6.3 ± 7.6 years, and the mean age for patients requiring enteral tube placement was 6.3 ± 9.3 years. The most common symptoms in this patient group were emesis and dysphagia. When compared to children with EoE who did not require enteral tube feeds, the patients with EoE and enteral tube feeds were significantly younger, had a significantly lower body mass index (BMI), and had a significantly lower initial Eosinophilic Esophagitis Endoscopic Reference Score (used to determine treatment response to EoE) and Endoscopic Severity Score.  

Most patients had enteral tube placement for failure to gain weight, and 19 patients (49%) required a transition from NG tube feeds to G-tube feeds. The vast amount of enteral nutrition provided to this patient group consisted of elemental formula (87%). Other therapeutics provided for this group included proton pump inhibitors, system steroids, and dupilumab. Enteral tubes remained in place for a mean of 6.8 ± 6.2 years. Most patients (92%) had enteral tube complications which were relatively mild, including tube displacement or granulation tissue formation. Most patients (71%) with enteral support achieved histologic EoE response. There was a significant increase in BMI-for-age z-scores in those patients with EoE requiring enteral feeds. Patients requiring enteral feeds prior to a diagnosis of EoE were significantly more likely to have autism or developmental delay, be non-white, and have no food allergies compared to patients with enteral feeding starting after a diagnosis of EoE. However, there was no difference in patient age, sex, or year in which EoE was diagnosed. Patients requiring initial enteral feeds due to a feeding problem had a delay of 2.2 ± 0.6 years prior to EoE eventually being diagnosed.

Although this is a small retrospective study, it does provide some interesting information to pursue further. For example, the finding that pediatric patients with EoE requiring enteral tube feeds having lower associated Eosinophilic Esophagitis Endoscopic Reference Scores and Endoscopic Severity Scores need further study as such patients may require more intensive feeding therapy and perhaps medical therapy. The delay in EoE diagnosis in patients with enteral feedings already in place suggests that a heightened awareness of the possibility of EoE is needed when evaluating children with feeding problems.

Borinsky S, Cameron B, Xue Z, LaFata S, Kiran A, Ocampo A, McCallen J, Lee C, Redd W, Cotton C, Eluri S, Reed C, Dellon E. Feeding Tube Placement, Complications, and Treatment Responses in a Large Eosinophilic Esophagitis.  J Pediatr Gastroenterol Nutr 2023; 77: 753-759.

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