Page 35 – Practical Gastro

The aim of Case Reports is to provide challenging yet clinically relevant and informative cases to primary care physicians.
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There should be a brief introduction/abstract, relevant presentation of the case,relevant case discussion and conclusion.
The conclusion should include one or two clinical pearls that the reader may apply to their practice or add to their knowledge set.
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FRONTIERS IN ENDOSCOPY, SERIES #67

Modifications to Duodenoscopes to Reduce the Risk of Infection Transmission

Evan Daugherty,

Douglas G. Adler

Duodenoscopes are complex and sophisticated medical devices which are used for a variety of procedures involving the pancreatic and biliary ducts. They incorporate a side-viewing camera which provides proceduralists with the ability to directly visualize the major and minor duodenal papillae and perform complex pancreaticobiliary interventions. Duodenoscopes incorporate a moving elevator lever that provides fine control of instruments placed through the instrument channel and allows for biliary or pancreatic duct cannulation and instrumentation during endoscopic retrograde cholangiopancreatography (ERCP).

ERCPs are associated with various adverse events, including pancreatitis, bleeding, perforation, and infections – including cholecystitis and cholangitis. Over the last 20 years, duodenoscopes from all of the major duodenoscope manufacturers have been implicated in a number of contamination and infectious outbreak events.¹² Organisms involved in outbreaks have involved multidrug-resistant (MDR) Pseudomonas aeruginosa, carbapenemresistant Enterobaceriaceae (CRE), extendedspectrum beta-lactamase (ESBL)-producing Klebsiella pneumonia, and ESBL-producing Enterobacteriaceae.¹³ These outbreaks have gained widespread national attention, including that of the Food and Drug Administration (FDA) and Center for Disease Control (CDC), and have prompted further research into contamination and disinfection of duodenoscopes.

Duodenoscopes require disinfection between patient procedures. Various methods have been explored, including increased reprocessing quality control, repeated cleaning, forced air drying, or the use of sterilizing agents such as ethylene oxide.²⁴ The FDA has called for duodenoscope designs to incorporate infection mitigating features, including disposable components or endoscopes intended for single-use.² This review will focus on the technical aspects of duodenoscope design and reprocessing which relate to contamination, and new duodenoscope models and their contaminationmitigating design features.

Review of Current Issues

During routine use, duodenoscopes are heavily exposed to oral and gastrointestinal flora. Normal handling, cleaning, drying, and storage may also expose endoscopes to skin or water-borne flora. Inadequate cleaning and inadequate drying are possible causes of duodenoscope contamination.¹ Common sites of contamination include the instrument channel, suction channel, forceps elevator, and the elevator wire channel.^1,3,5 Residual body fluids and debris in the vicinity of the elevator have been specifically recognized as a critically important cause of potential infection transmission.^1,3,5 The complexity of this elevator mechanism makes it difficult to fully access and can be challenging to clean fully.^1,3 Other potential locations of contamination exist, as any site of wear or surface breakdown may allow for bacterial biofilm accumulation.^6,7Normal duodenoscope use may damage the surface of the endoscope sheath or endcap.^4,5 The instrument channel may be subjected to abrasion with the passage of a variety of endoscopic accessories.¹ Even the elevator wire channel, despite its sealed design in newer duodenoscopes, often shows micro abrasions.⁶

In 2015, the FDA ordered manufacturers to carry out post marketing surveillance studies examining duodenoscope contamination rates.2,8 Surveillance result updates were released in 2018 and 2019, with higher than expected rates of contamination following reprocessing. Up to 6% of devices were colonized with organisms of concern, while up to 3.6% were found to have low- or moderate-concern organisms.^9,10 Other studies have reported duodenoscope contamination rates following disinfection, with results ranging between 4% and 22%.^3,4,11,12

The CDC first warned the FDA regarding a potential association between MDR infections and duodenoscopes in 2013.² Further investigation revealed cases of infectious transmission occurring despite following manufacturer-directed disinfection protocols.² Duodenoscope reprocessing involves pre-cleaning, leak testing, and manual cleaning immediately following usage. These manufacturer-directed procedures are relatively complicated with many possible points of human error. This is followed by high-level disinfection (HLD) in an automated manufacturer-specific endoscope reprocessor. Finally, duodenoscopes are rinsed then dried in a hanging cabinet with filtered circulating air.¹

In 2015, the FDA suggested measures to reduce duodenoscope contamination rates in addition to standard reprocessing.² Repeated HLD is the most popular of these strategies; however, even this may leave residual bacterial colonization.^4,8,13 Sterilization with liquid chemicals or ethylene oxide is utilized by some institutions, but may be no more effective.13 These are time-consuming processes and may necessitate the purchase of extra duodenoscopes depending on the volume of procedures at an institution. Forced air drying, either manually or via automated drying cabinets, is utilized by many institutions, and results in significantly shorter drying times and may prevent growth of hydrophilic organisms.^14,15 Reprocessing can also be followed by routine surveillance culture collection, with devices withheld from use until cultures are confirmed to be negative. While it is a resource- and staff-intensive practice, routine surveillance has also been shown to help identify endoscopes with mechanical damage.^4,5,12

Endoscope manufacturers have recently begun recommending annual duodenoscope inspections.^9,16,17 This may help identify damaged or excessively worn components, which may serve as a nidus for infection. Little data exists to support when to perform inspection and preventative maintenance.⁹ Other methods to decrease transmission of bacteria during procedures have also been explored.

Changes to device design have been offered as the best solution to the problem of duodenoscoperelated infections.^4,6,9,14 Following a 2015 advisory committee meeting, the FDA called for manufacturers to design duodenoscopes with removable or disposable parts to facilitate more effective cleaning.^2,8

New Duodenoscopes Designs and Developments

To date, the FDA has approved multiple duodenoscopes with disposable components which facilitate improved reprocessing. These include models from Olympus Medical Systems (Japan), Pentax Medical (Japan), and Fujifilm Corporation (Japan). They have also approved two fully disposable duodenoscopes from Boston Scientific (Massachusetts, USA) and Ambu (Denmark), and one single-use distal cover from GI Scientific (Virginia, USA) for an existing standard duodenoscope.

The Olympus TJF-Q180V, introduced in 2010 prior to the FDA direction to use removable parts, featured a new sealed elevator wire channel.¹⁸Its FDA approval was based on similarity to the preceding XTJF-Q160VF1 endoscope, which was approved in 2008.¹⁹ Through 2014, multiple duodenoscope-related outbreaks were associated with use of the Q180V endoscope. Olympus voluntarily recalled the device worldwide after its sealed elevator wire channel mechanism was identified as an infection risk.²⁰ The duodenoscope was reintroduced in 2016 following elevator wire channel modification and received subsequent FDA approval.²¹

An accompanying sterile, single-use distal duodenoscope cover, the GI Scientific ScopeSeal, was FDA approved in October 2019 (Figure 1).²² It seals the distal end of the device and includes a working channel extension, which provides a protective barrier around the elevator area and channel during use.^23,24 The Q180V device with ScopeSeal was assessed by Pasricha et al.²⁵The first portion of the study involved dye immersion testing, with no leakage occurring during immersion while articulating the endoscope elevator and suction mechanism. The second portion of the study assessed for endoscope contamination. The ScopeSeal device was placed on the distal end of the endoscope, the exterior was inoculated with E. coli, and the endoscope was repeatedly maneuvered to simulate use. After removal of the device, cultures were collected from the distal portion of the endoscope. In a separate test, the area around the elevator was inoculated, an instrument brush was passed repeatedly through the channel, and cultures were collected from the instrument. No contamination was detected in either test; however, this study did not include HLD of devices utilizing ScopeSeal. Of note, GI Scientific provided funding for this study and Dr. Pasricha is an equity holder in GI Scientific.²⁵

Olympus’ newest duodenoscope, the TJFQ190V, was approved in January 2020. It features a single-use, sterile endcap which interfaces with the distal ring of the duodenoscope (Figure 2A).^26–28 This cap is removed at the beginning of reprocessing to allow for improved access to the elevator area for manual cleaning and disinfection. This duodenoscope also has a proprietary distalend flushing adapter for cleaning the elevator mechanism and a sealed elevator wire channel (Figure 2B).^26,27,29 No duodenoscope infection studies have utilized the Q190V endoscope thus far.

The Pentax ED34-i10T was FDA approved in September 2017 and features a single-use, non-sterile, distal endcap (Figure 3A).^30–32 This cover allows for improved access for reprocessing and should be steam sterilized prior to use. It also features a sealed elevator wire channel.³⁰There has been one study reporting endoscope contamination rates by Rauwers et al., which has included reports of contamination in the Pentax ED34-i10T.^3,9 Pentax’s most recent iteration, the ED34-i10T2, was FDA approved in November 2019. It features a sterile, disposable elevator cap which is manipulated by a steel bar at the end of the elevator wire channel (Figure 3B).³² The distal end of the channel is sealed with an O-ring.^17,33 In contrast to the other devices mentioned, the elevator mechanism is integrated into the cap, simplifying reprocessing. The Infection Control in ERCP using a duodenoscope with a disposable EndCAP (ICECAP) trial is currently enrolling and will evaluate the ED34-i10T versus the ED34- i10T2 scopes with their distal endcap and distal elevator caps, respectively.³⁴ Investigators plan to collect cultures from the instrument channel and elevator recess followed by standardized postendoscopy reprocessing. Based on the design as reported, the study will not compare fixed endcap and removable endcap duodenoscopes, but two devices with different designs of removable caps.

The Fujifilm ED-580XT was FDA approved in September 2019. It has a disposable distal endcap which allows a brush to access the back of the elevator mechanism (Figure 4).³⁵It also features a sealed elevator mechanism.^36,37 The efficacy of the 580XT distal endcap was explored by Ridtitid et al. who compared elevator site cultures and adenosine triphosphate (ATP) testing following HLD both with the removable endcap detached versus left on prior to cleaning.³⁸Residual ATP has been used as a marker of the cleaning process of various medical devices and is associated with the presence of both human and bacterial cells. The median ATP value was significantly lower for the cap off group; however, there was only one positive culture (skin flora) out of 108 post-procedural cycles.³⁸ATP testing may not be as useful of a marker of the HLD process, since it cannot distinguish between human and bacterial contamination, nor high- and low-concern organisms.³⁹Moreover, this study did not compare fixed vs detachable cap duodenoscope models, but the same device cleaned with and without its endcap. To date, manufacturers Fujifilm, Pentax, and Olympus have submitted a total of 10 reports of device malfunctions, such as removable caps falling off during ERCP. No patient injuries have been reported to the FDA.⁴⁰

The Boston Scientific EXALT Model D was the first sterile, single-use duodenoscope and was FDA approved in December 2019 (Figure 5).^41–43 The Model D was compared to devices from the three major manufacturers in a small anatomical bench model study by Ross et al.⁴⁴Various tasks were assessed in the study, including guidewire locking, plastic stent placement and removal, metal stent placement and removal, and basket sweeping. It had comparable performance to a contemporary duodenoscope in all tasks except for navigation and “pushability.” All tasks were completed by participating proceduralists.⁴⁴The duodenoscope was also assessed in a clinical setting by Muthusamy et al.⁴⁵The maneuverability of the Model D was rated by proceduralists following ERCP biliary cannulation sphincterotomy, stone clearance, placement or removal of stents, and balloon dilation of strictures. Overall, proceduralists were “satisfied” or “neutral” regarding the performance of the endoscope; however, it was noted to be harder to torque and maneuver when advanced more distally in the duodenum. The overall adverse event rate was found to be comparable to standard ERCP practice.⁴⁵

The Ambu aScope Duodeno is a sterile, singleuse duodenoscope which was FDA approved in June 2020 (Figure 6a-6e).^46–48 It has not been examined in any duodenoscope contamination or maneuverability studies thus far. As part of the manufacturer development process, it was tested for equivalence to the Olympus TJF-Q180V in a porcine upper gastrointestinal tract model.46 While single-use endoscopes prevent potential exogenous transmission of infection, they still do not eliminate the risk of translocation of patients’ own oral or gastrointestinal flora and subsequent endogenous infection, recognizing that this is a lower risk transfer. The largest barrier to adoption of singleuse devices is likely cost. Some analysis indicate that the cost of single-use duodenoscopes may be ten-times greater than that of reusable devices even when accounting for rates of infection and the cost of subsequent treatment. These costs may only be tenable by high volume institutions.⁴⁹

CONCLUSION

Duodenoscope contamination and associated infections have resulted in an increase in research into causes of device contamination and the efficacy of disinfection processes. Manufacturers’ newly designed and re-designed duodenoscopes have attempted to answer the FDA’s call by creating endoscopes with removable or disposable parts to facilitate cleaning of high-risk areas. Because these devices have only been available recently there is a paucity of information regarding the new, removable endcap duodenoscopes discussed above.

No current studies have sufficiently compared the rates of contamination between traditional fixed endcap duodenoscopes and those with removable endcaps. The existing studies, discussed above, have either lacked sufficient control groups or have been relatively underpowered to detect contamination differences between the two devices. Post marketing surveillance, utilizing a large volume of sampling events across institutions, will be essential in establishing the benefits of these new designs. Moreover, it remains to be seen if design elements of the new devices, such as the interface between the sheath and distal endcap, will serve as a novel place of wear and potential nidus for biofilm accumulation.

Following the FDA’s call for duodenoscopes intended only for single-use, there are now two single-use devices available. Further exploration of the cost of single-use duodenoscopes will be of paramount importance if they are to be more broadly adopted. These studies should seek to incorporate all of the hidden costs associated with device reprocessing, surveillance, downtime, outbreak management, and potential lost revenues.

References

^{Rahman MR, Perisetti A, Coman R, Bansal P, Chhabra R, Goyal H. Duodenoscope-Associated Infections: Update on an Emerging Problem. Dig Dis Sci. 2019;64(6):1409-1418. doi:10.1007/ s10620-018-5431-7}
^{Infections Associated with Reprocessed Duodenoscopes | FDA. https://www.fda.gov/medical-devices/reprocessing-reusablemedical-devices/infections-associated-reprocessed-duodenoscopes. Accessed August 2, 2020.}
^{Rauwers AW, Voor In ’T Holt AF, Buijs JG, et al. High prevalence rate of digestive tract bacteria in duodenoscopes: A nationwide study. Gut. 2018;67(9):1637-1645. doi:10.1136/ gutjnl-2017-315082}
^{Mark JA, Underberg K, Kramer RE. Results of duodenoscope culture and quarantine after manufacturer-recommended cleaning process. Gastrointest Endosc. 2020;91(6):1328-1333. doi:10.1016/j.gie.2019.12.050}
^{Cristina ML, Sartini M, Schinca E, et al. Is post-reprocessing microbiological surveillance of duodenoscopes effective in reducing the potential risk in transmitting pathogens? Int J Environ Res Public Health. 2020;17(1). doi:10.3390/ijerph17010140}
^{Balan GG, Rosca I, Ursu EL, et al. Duodenoscope-associated infections beyond the elevator channel: Alternative causes for difficult reprocessing. Molecules. 2019;24(12). doi:10.3390/molecules24122343}
^{Rauwers AW, Troelstra A, Fluit AC, et al. Independent rootcause analysis of contributing factors, including dismantling of 2 duodenoscopes, to investigate an outbreak of multidrug-resistant Klebsiella pneumoniae. Gastrointest Endosc. 2019;90(5):793- 804. doi:10.1016/j.gie.2019.05.016}
^{FDA warns duodenoscope manufacturers about failure to comply with required postmarket surveillance studies to assess contamination risk | FDA. https://www.fda.gov/news-events/ press-announcements/fda-warns-duodenoscope-manufacturersabout-failure-comply-required-postmarket-surveillance-studies. Accessed August 2, 2020.}
^{The FDA Provides Interim Results of Duodenoscope Reprocessing Studies Conducted in Real-World Settings: FDA Safety Communication | FDA. https://www.fda.gov/medical-devices/ safety-communications/fda-provides-interim-results-duodenoscope-reprocessing-studies-conducted-real-world-settings-fda. Accessed August 2, 2020.}
^{The FDA Continues to Remind Facilities of the Importance of Following Duodenoscope Reprocessing Instructions: FDA Safety Communication | FDA. https://www.fda.gov/medical-devices/ safety-communications/fda-continues-remind-facilities-importance-following-duodenoscope-reprocessing-instructions-fda. Accessed August 2, 2020.}
^{Snyder GM, Wright SB, Smithey A, et al. Randomized Comparison of 3 High-Level Disinfection and Sterilization Procedures for Duodenoscopes. Gastroenterology. 2017;153(4):1018-1025. doi:10.1053/j.gastro.2017.06.052}
^{TJ DW, N S, M M, et al. A Prospective, Randomized Comparison of Duodenoscope Reprocessing Surveillance Methods. Can J Gastroenterol Hepatol. 2019;2019. doi:10.1155/2019/1959141}
^{Gromski MA, Sieber MS, Sherman S, Rex DK. Double High-Level Disinfection vs. Sterilization for Reprocessing of Duodenoscopes Used for ERCP: A Prospective Study. Am J Gastroenterol. 2019;114:S1. doi:10.14309/ajg.0000000000000373}
^{Thaker AM, Muthusamy VR, Sedarat A, et al. Duodenoscope reprocessing practice patterns in U.S. endoscopy centers: a survey study. Gastrointest Endosc. 2018;88(2):316-322.e2. doi:10.1016/j.gie.2018.04.2340}
^{Perumpail RB, Marya NB, McGinty BL, Muthusamy VR. Endoscope reprocessing: Comparison of drying effectiveness and microbial levels with an automated drying and storage cabinet with forced filtered air and a standard storage cabinet. Am J Infect Control. 2019;47(9):1083-1089. doi:10.1016/j.ajic.2019.02.016}
^{FDA 510(k) Summary: EVIS EXERA II Duodenovideoscope Olympus TJF Type Q180V. https://www.accessdata.fda.gov/ cdrh_docs/pdf14/K143153.pdf. Accessed August 2, 2020.}
^{Gastroenterology | PENTAX Medical (EMEA). https://www. pentaxmedical.com/pentax/en/95/1/DEC-Video-DuodenoscopeED34-i10T2-. Accessed August 2, 2020.}
^{EVIS EXERA II (TJF-Q180V) | Olympus America | Medical. https://medical.olympusamerica.com/products/evis-exera-ii-tjfq180v. Accessed August 2, 2020.}
^{FDA 510(k) Summary: Duodenovideoscope XTJF Type Q160VF1. https://www.accessdata.fda.gov/cdrh_docs/pdf8/ K080403.pdf. Accessed August 2, 2020.}
^{FDA clears Olympus TJF-Q180V duodenoscope with design modifications intended to reduce infection risk | FDA. https://www. fda.gov/news-events/press-announcements/fda-clears-olympustjf-q180v-duodenoscope-design-modifications-intended-reduceinfection-risk. Accessed August 2, 2020.}
^{Class 2 Device Recall Evis Exera II Duodenovideoscope Olympus TJFQ180V. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfRES/res.cfm?id=142937. Accessed August 2, 2020.}
^{GI Scientific. Scopeseal [image]. Accessed October 10, 2020.}
^{ScopeSeal – GI Scientific. https://www.giscientific.com/scopeseal. Accessed August 2, 2020.}
^{FDA 510(k) Summary: ScopeSeal Duodenoscope Protective Device. https://www.accessdata.fda.gov/cdrh_docs/pdf18/ K183171.pdf. Accessed August 2, 2020.}
^{Pasricha PJ, Miller S, Carter F, Humphries R. Novel and effective disposable device that provides 2-way protection to the duodenoscope from microbial contamination. Gastrointest Endosc. 2020;92(1). doi:10.1016/j.gie.2020.03.001}
^{TJF-Q190V Duodenoscope | Olympus America | Medical. https:// medical.olympusamerica.com/products/tjf-q190v-duodenoscope. Accessed August 2, 2020.}
^{FDA 510(k) Summary: EVIS EXERA III DUODENOVIDEOSCOPE OLYMPUS TJF-Q190V. https:// www.accessdata.fda.gov/cdrh_docs/pdf19/K193182.pdf. Accessed August 2, 2020.}
^{Olympus Medical Systems. TJF-Q190V CAP ATTACH-217 [image]. Accessed October 10, 2020.}
^{Olympus Medical Systems. Manual Reprocessing Adapter-260 [image]. Accessed October 10, 2020.}
^{FDA 510(k) Summary: PENTAX Medical ED34-I10T, Video Duodenoscope. https://www.accessdata.fda.gov/cdrh_docs/ pdf16/K163614.pdf. Accessed August 2, 2020.}
^{Gastroenterology | PENTAX Medical (EMEA). https:// www.pentaxmedical.com/pentax/en/95/1/ED34-i10T-VideoDuodenoscope. Accessed August 2, 2020.}
^{Pentax Medical. Pentax ED34-i10T2 Elevator Cap [image]. Accessed October 10, 2020.}
^{FDA 510(k) Summary: Pentax Medical Video Duodenoscope ED34-i10T2. https://www.accessdata.fda.gov/cdrh_docs/pdf19/ K192245.pdf. Accessed August 2, 2020.}
^{Forbes N, Elmunzer BJ, Allain T, et al. Infection control in ERCP using a duodenoscope with a disposable cap (ICECAP): Rationale for and design of a randomized controlled trial. BMC Gastroenterol. 2020;20(1). doi:10.1186/s12876-020-01200-7}
^{Fujifilm Corporation. ED-580XT distal end cap near scope tip [image]. Accessed October 10, 2020.}
^{FDA 510(k) Summary: FUJIFILM Duodenoscope Model ED-580XT. https://www.accessdata.fda.gov/cdrh_docs/pdf18/ K181745.pdf. Accessed August 2, 2020.}
^{Fujifilm ED-580XT Duodenoscope | Fujifilm Healthcare. https:// www.fujifilmhealthcare.com/endoscopy/fujifilm-580-seriesinterventional-endoscopes/fujifilm-ed-580xt-duodenoscope. Accessed August 2, 2020.}
^{Ridtitid W, Pakvisal P, Chatsuwan T, et al. A newly designed duodenoscope with detachable distal cap significantly reduces organic residue contamination after reprocessing. Endoscopy. April 2020. doi:10.1055/a-1145-3562}
^{FDA. Duodenoscope Sampling and Culturing Protocols Duodenoscope Surveillance Sampling and Culturing Protocols.}
^{The FDA is Recommending Transition to Duodenoscopes with Innovative Designs to Enhance Safety: FDA Safety Communication | FDA. https://www.fda.gov/medical-devices/ safety-communications/fda-recommending-transition-duodenoscopes-innovative-designs-enhance-safety-fda-safety-communication. Accessed August 2, 2020.}
^{FDA 510(k) Summary: EXALT Model D Single-Use Duodenoscope; EXALT Controller. https://www.accessdata.fda. gov/cdrh_docs/pdf19/K193202.pdf. Accessed August 2, 2020.}
^{EXALTTM Model D – Boston Scientific. https://www.bostonscientific.com/content/gwc/en-US/products/single-use-scopes/exalt- -model-d.html. Accessed August 2, 2020.}
^{Boston Scientific. Exalt Model D Duodenoscope [image]. Accessed October 10, 2020.}
^{Ross AS, Bruno MJ, Kozarek RA, et al. Novel single-use duodenoscope compared with 3 models of reusable duodenoscopes for ERCP: a randomized bench-model comparison. Gastrointest Endosc. 2020;91(2):396-403. doi:10.1016/j.gie.2019.08.032}
^{Muthusamy VR, Bruno MJ, Kozarek RA, et al. Clinical Evaluation of a Single-Use Duodenoscope for Endoscopic Retrograde Cholangiopancreatography. Clin Gastroenterol Hepatol. 2020;18(9):2108-2117.e3. doi:10.1016/j.cgh.2019.10.052}
^{FDA 510(k) Summary: Ambu AScope Duodeno. https://www. fda.gov/medical-. Accessed August 10, 2020.}
^{Ambu® aScopeTM Duodeno. https://www.ambuusa.com/endoscopy/gastroenterology/duodenoscopes/product/ambu-ascopeduodeno. Accessed August 10, 2020.}
^{Ambu. AMBU aScope Duodeno Duodenoscope [image]. Accessed October 10, 2020.}
^{Bang JY, Sutton B, Hawes R, Varadarajulu S. Concept of disposable duodenoscope: At what cost? Gut. 2019;68(11):1915-1917. doi:10.1136/gutjnl-2019-318227}

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #204

Nutrition Considerations in the Cirrhotic Patient

Eric B. Martin,

Matthew Stotts

Malnutrition is commonly seen in individuals with advanced liver disease, often resulting from a combination of factors including poor oral intake, altered absorption, and reduced hepatic glycogen reserves predisposing to a catabolic state. The consequences of malnutrition can be far reaching, leading to a loss of skeletal muscle mass and strength, a variety of micronutrient deficiencies, and poor clinical outcomes. This review seeks to succinctly describe malnutrition in the cirrhosis population and provide clarity and evidence-based solutions to aid the bedside clinician. Emphasis is placed on screening and identification of malnutrition, recognizing and treating barriers to adequate food intake, and defining macronutrient targets.

INTRODUCTION

The Problem

Individuals with cirrhosis are at high risk of malnutrition for a multitude of reasons. Cirrhotic livers lack adequate glycogen reserves, therefore these individuals rely on muscle breakdown as an energy source during overnight periods of fasting.1 Well-meaning providers often recommend a variety of dietary restrictions—including limitations on fluid, salt, and total calories—that are often layered onto pre-existing dietary restrictions for those with co-existent conditions such as diabetes or renal disease. Furthermore, different underlying etiologies of liver disease, such as heavy alcohol use and chronic cholestasis, predispose cirrhotic patients to a variety of macro- and micronutrient deficiencies as a consequence of poor intake and altered absorption.

As liver disease progresses, its complications further increase the risk for malnutrition. Large volume ascites can lead to early satiety and decreased oral intake. Encephalopathy also contributes to decreased oral intake and may lead to inappropriate recommendations for protein restriction. Frequent hospitalizations and procedures can lead to periods of prolonged fasting. In combination, the physiology of liver disease and its consequences lead to a prevalence of malnutrition in the cirrhotic population that has been described as nearly universal in those awaiting liver transplantation (LT), and so high in all individuals with cirrhosis that current guidelines recommend anticipating malnutrition, protein depletion, and trace element deficiencies.^1,2

The consequences of malnutrition are wide ranging. Sarcopenia can become one of the more obvious and discouraging physical changes patients and families notice. An abundance of evidence links low body mass index (BMI), frailty, and progressive sarcopenia with poor outcomes after liver transplantation.^3,4 Micronutrient deficiencies can lead to a variety of consequences, ranging from anemia to increased bone fracture risk to altered taste. In this setting, identification of malnourished individuals coupled with targeted nutritional interventions are critical to improving quality of life and optimizing clinical outcomes in individuals with cirrhosis. ⁵

The Practical Approach to Nutrition in Liver Disease

Screen for Malnutrition

A typical clinical encounter with a patient afflicted by advanced liver disease often requires careful consideration of their primary liver disease, management of liver decompensations, ensuring that appropriate screening of esophageal varices and hepatocellular carcinoma has been completed, and determining whether liver transplantation referral or end-of-life care is appropriate. An important yet often overlooked facet of these complex encounters is consideration of the patient’s nutritional risk.

All patients with advanced liver disease should be screened for malnutrition.⁶ Decompensated cirrhotics and those with a BMI of ≤ 18.5 kg/m2 are considered high risk regardless of screening. ^6,7 If a patient does not meet either of the aforementioned criteria, multiple screening tools can be used to stratify patients according to their nutritional risk. The Royal Free Hospital-Nutrition Prioritizing (RFH-NP) tool is easy to administer, validated in the cirrhotic population, and has been shown to correlate with disease severity. ^8,9 In those identified as moderate or high nutritional risk, a comprehensive nutritional assessment should be conducted by a registered dietitian.⁶

As outlined in Table 1, a comprehensive nutritional assessment should include evaluation for sarcopenia (e.g. lean muscle mass), use of a global assessment tool (GA), and review of the patient’s self-reported dietary intake.⁶ Sarcopenia, defined as a generalized reduction in muscle mass and function due to age or illness, is likely present when low muscle strength is detected and is confirmed when low muscle quantity or quality is found.^6,10 Handgrip strength has been shown to correlate with strength in other body compartments, and is a cheap, fast, and validated method for evaluating muscle strength.¹⁰ Handgrip strength has also been shown to predict major complications and mortality in the cirrhotic population.¹¹ An accepted alternative is the chair rise test, defined as the amount of time needed for a patient to rise from a chair five times. ¹⁰ The Liver Frailty Index is an increasingly used easy tool that combines hand grip strength, chair rise time, and ability to stand in different positions into a single metric to classify patients as robust, pre-frail, and frail, and has been validated in the liver transplant population (see Table 2; https://liverfrailtyindex.ucsf.edu).^12,13 The second component of a comprehensive nutritional assessment are GA tools, which seek to diagnose varying levels of malnourishment from history and physical. The most common GA tools deployed in clinical practice are the subjective global assessment (SGA) and the Royal Free Hospital-global assessment (RFH-GA).¹⁴ Given that the RFH-GA is time consuming and requires a registered dietitian, the SGA is generally easier to administer and is a reasonable alternative despite weak validation in the cirrhotic population.¹ To complete the nutritional assessment, a review of self-reported dietary intake should be conducted. Dietary intake surveys provide insight into the amount, type, and timing of food consumption and can provide valuable insight into barriers to adequate nutrition.⁶

Barriers and Routes of Feeding

Oral intake is the desired mode of nutrient consumption for a variety of physiologic and psychologic reasons, and consistent messaging regarding the importance of adequate nutrition should be emphasized in all cirrhotic patient encounters. In general, advice should not focus on dietary restrictions, but rather healthy eating patterns that emphasize high vegetable, fruit, protein, and caloric intake.^1,6 Eating a wide variety of enjoyable foods and avoiding the addition of salt or foods with a high sodium content is a reasonable strategy to minimize the consequence of salt restriction’s typical negative impact on caloric and protein intake.^1,6 In addition, a variety of disease related barriers are important to consider when discussing nutrition with these patients, each of which has important treatment considerations that can positively impact the patient’s nutritional intake (see Table 3).

In cases where oral intake is insufficient to meet caloric demands, enteral nutrition (EN; via nasoand orogastric tubes) or parenteral nutrition (PN) may be required. The most commonly encountered scenario where oral intake is insufficient occurs in hospitalized patients. For patients who do not have evidence of gastrointestinal bleeding, naso- or orogastric tube placement should occur immediately after intubation and can be considered safe regardless of variceal history.^1,6 In those with gastrointestinal (GI) bleeding secondary to esophageal varices, it is prudent to wait 48 to 72 hours after banding prior to placing a gastric tube.¹⁵ In other types of GI bleeding, gastric tube placement is generally reasonable 24 hours after bleeding cessation. Conversion to postpyloric feeding should occur in those who cannot tolerate gastric feeding despite efforts to improve tolerance or are at high risk for aspiration.¹⁶ In the outpatient setting, if oral intake is insufficient, feeding tubes can be maintained for considerable periods of time with minimal supervision, although insurance infrequently covers tube-feeding in the pre-transplant population. Percutaneous enteral gastrostomy (PEG) tubes are generally contraindicated in cirrhosis due to bleeding risks (i.e. gastric varices) and infectious complications (especially in the setting of ascites) and should only rarely be employed.^1,6 Parenteral feeding should only be used when enteral feeding cannot meet the patient’s energy demands or is contraindicated.¹ In addition to standard trace elements and the multivitamin and mineral supplements provided with PN, all patients requiring PN should receive vitamin K and higher doses of thiamine if actively drinking.

Calorie and Protein Goals and Strategies

Once a patient is determined to be nutritionally at risk or malnourished, they should receive targeted nutritional interventions that provide tailored strategies to achieve proper caloric and protein intake.^5,6

Caloric and protein intake recommendations are ideally based on indirect calorimetry, but due to limited availability weight-based targets are typically used. Weights taken after a paracentesis or at a time of euvolemia are considered dry weight, and may be used for weight-based energy and protein provision.¹ If no dry weight is available, but the patient is near euvolemia, actual body weight may be used. In decompensated (i.e. hypervolemic) patients, current guidelines are somewhat discordant on the recommended approach. The European Association for Study of the Liver (EASL) recommends using an adjusted body weight based on the amount of ascites and peripheral edema (subtracting 5% if mild ascites, 10% if moderate, and 15% if severe, as well as an additional 5% if pedal edema is present), whereas the European Society for Clinical Nutrition and Metabolism (ESPEN) recommends using the ideal body weight (IBW), which is based on the patient’s gender and height.^1,6 When obesity is present, both societies recommend using IBW. With these different approaches in mind, weightbased caloric and protein recommendations can be found in Table 4.

Oral nutrition supplementation and attention to meal timing are important considerations when helping patients achieve recommended protein and calorie goals. Use of protein additives, frequent small meals, and ingestion of high protein foods are common tactics employed in this patient population. Importantly, a late evening snack (LES) has been shown to improve lean muscle mass and should be routinely recommended to cirrhotic patients. The LES should occur between 9pm and 11pm and contain between 500 to 700 kcal with at least 50 grams of carbohydrates.^17,18

The When and How of Micronutrients

Macronutrient deficiencies are not the only dietary shortfall in cirrhotics. Micronutrients, a broad nutrient class that includes dietary elements (minerals, trace elements) and organic compounds (vitamins) that are required in small quantities for normal physiologic function, are also commonly deficient. Assessing many of these micronutrients is challenging and not done in routine clinical practice, as guidelines recommend treating micronutrient deficiencies liberally when suspected or confirmed.^1,6 In this context, it is reasonable to recommend a daily multivitamin (without manganese, as elevated levels observed in cirrhotics may be associated with hepatic encephalopathy), and to consider individual vitamin and mineral deficiencies in the presence of malnourishment or decompensation,^6,19 Among the fat-soluble vitamins requiring consideration, vitamin D should be repleted to a level above 30 ng/ml and vitamin K repleted as needed. Among the water-soluble vitamins, vitamin B1 (thiamine) is routinely deficient and should be aggressively repleted, although other B-vitamins can also quickly become deficient in the setting of decompensation.^1,6 Lastly, zinc repletion may be beneficial in hepatic encephalopathy (HE), and while clinical use increases, data continues to be inconclusive.^20,21

Caution with Restrictions

One of the more challenging barriers to maintaining adequate nutrition occurs in response to direct advice or orders from providers caring for these patients. Given the many comorbidities commonly associated with advanced liver disease, other dietary restrictions are often present (e.g. hearthealthy, carbohydrate controlled, and renal diets), and providers should offer clear guidance for dietary strategies in these patients. Protein restrictions are never wise and should be avoided in these individuals. Historically, protein restriction was advised in cirrhotics with HE, but subsequent studies have demonstrated normal and high protein intake does not precipitate or worsen HE, and may actually improve mental status.22,23 Fluid restriction is only recommended for individuals who experience significant hyponatremia (less than 125mEq/L).24 Sodium restriction is important in managing ascites and hypervolemia, although providers should recommend a variety of strategies to ensure compliance without increasing the risk of malnutrition.1 Table 5 offers strategies to avoid poor nutritional intake in both the in- and outpatient settings.

Special Groups/Problems

Several subpopulations and groups warrant special considerations regarding nutritional recommendations. These include the following:

Acute Liver Failure (ALF)

By definition, individuals with ALF do not have underlying cirrhosis and are not malnourished at the time of disease onset. Regardless, nutritional support in this population is vital and should be initiated early to prevent metabolic derangements, namely protein catabolism, and potentially decrease risks of gastrointestinal bleeding. Nasogastric tube placement should be performed once patients are intubated to provide EN.

Alcoholic Hepatitis

Most patients with alcoholic hepatitis are malnourished and require nutritional support, with the goal to provide adequate calories and protein as well as micronutrients including vitamins (namely folate and thiamine) and minerals (namely magnesium and phosphate). Calorie counts should be initiated early and, when oral intake cannot be maintained, enteral feeding is preferred over parenteral nutrition.

Hepatic Encephalopathy

Individuals with HE should not have their protein intake restricted. To prevent a catabolic state and resultant ammonia production, these individuals should be instructed to eat small frequent meals and ensure a late-night snack. Some data suggests benefit of branched-chain amino acids (either intravenous or oral) in individuals with HE, including a metaanalysis of 16 trials showing no benefit in mortality but a beneficial effect on manifestations of HE.^6,25 Due to costs and conflicting evidence on relatively heterogeneous cohorts, IV infusions are generally not recommended and oral supplements only recommended in protein intolerant individuals.

Hospitalized Patients

Individuals with cirrhosis are commonly kept NPO in the hospital for a variety of reasons and frequently fail to meet caloric goals. Practitioners should prioritize advancing their diet as early as possible, avoiding prolonged fasting, and placing an NG tube for EN at the time of intubation.

Sarcopenic Obesity

As cirrhosis progresses, individuals with obesity are also at risk of muscle catabolism and sarcopenia. Providers must balance preserving muscle mass and function with weight loss goals. Reasonable recommendations include a calorie-restricted, but high protein diet, in combination with an exercise regimen with the goal of achieving greater than 5-10% weight loss.⁶

CONCLUSION

Malnutrition is a ubiquitous problem in the cirrhotic patient population, negatively impacting quality of life and clinical outcomes. Current guidelines recommend screening for malnutrition, and, if present or at moderate risk, providing comprehensive dietary assessments and targeted dietary interventions. These interventions should focus less on dietary restrictions and more on adequate caloric and protein intake from diverse, healthy sources. Attention to disease-specific symptoms can maximize the impact of these interventions, with an ultimate goal to prolong and improve the cirrhotic patient’s life.

References

^{Plauth M, Bernal W, Dasarathy S, et al. ESPEN guideline on clinical nutrition in liver disease. Clinical nutrition (Edinburgh, Scotland). 2019;38(2):485-521.}
^{McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.}
^{Dick AA, Spitzer AL, Seifert CF, et al. Liver transplantation at the extremes of the body mass index. Liver Transpl. 2009;15(8):968-77.}
^{Englesbe MJ, Patel SP, He K, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg. 2010;211(2):271-8.}
^{Iwasa M, Iwata K, Hara N, et al. Nutrition therapy using a multidisciplinary team improves survival rates in patients with liver cirrhosis. Nutrition (Burbank, Los Angeles County, Calif). 2013;29(11-12):1418-21.}
^{EASL Clinical Practice Guidelines on nutrition in chronic liver disease. Journal of hepatology. 2019;70(1):172-93.}
^{Cederholm T, Bosaeus I, Barazzoni R, et al. Diagnostic criteria for malnutrition – An ESPEN Consensus Statement. Clinical nutrition (Edinburgh, Scotland). 2015;34(3):335-40.}
^{Borhofen SM, Gerner C, Lehmann J, et al. The Royal Free HospitalNutritional Prioritizing Tool Is an Independent Predictor of Deterioration of Liver Function and Survival in Cirrhosis. Digestive diseases and sciences. 2016;61(6):1735-43.}
^{Arora S, Mattina C, Catherine M, et al. PMO-040 The development and validation of a nutritional prioritising tool for use in patients with chronic liver disease. Gut. 2012;61:A90-A.}
^{Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(4):601.}
^{Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients. Nutrition (Burbank, Los Angeles County, Calif). 2005;21(2):113-7.}
^{Lai JC, Covinsky KE, Dodge JL, et al. Development of a novel frailty index to predict mortality in patients with end-stage liver disease. Hepatology. 2017;66(2):564-74.}
^{Wang CW, Lebsack A, Chau S, et al. The Range and Reproducibility of the Liver Frailty Index. Liver Transpl. 2019;25(6):841-7.}
^{Morgan MY, Madden AM, Soulsby CT, et al. Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis. Hepatology. 2006;44(4):823-35.}
^{McClave SA, Chang WK. When to feed the patient with gastrointestinal bleeding. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2005;20(5):544-50.}
^{McClave SA, DiBaise JK, Mullin GE, et al. ACG Clinical Guideline: Nutrition Therapy in the Adult Hospitalized Patient. The American journal of gastroenterology. 2016;111(3):315-34; quiz 35.}
^{Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. Journal of gastroenterology and hepatology. 2012;27(3):430-41.}
^{Plank LD, Gane EJ, Peng S, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology. 2008;48(2):557-66.}
^{Hauser RA, Zesiewicz TA, Martinez C, et al. Blood manganese correlates with brain magnetic resonance imaging changes in patients with liver disease. Can J Neurol Sci. 1996;23(2):95-8.}
^{Takuma Y, Nouso K, Makino Y, et al. Clinical trial: oral zinc in hepatic encephalopathy. Alimentary pharmacology & therapeutics. 2010;32(9):1080-90.}
^{Katayama K, Saito M, Kawaguchi T, et al. Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial. Nutrition (Burbank, Los Angeles County, Calif). 2014;30(11-12):1409-14.}
^{Gheorghe L, Iacob R, Vădan R, et al. Improvement of hepatic encephalopathy using a modified high-calorie high-protein diet. Rom J Gastroenterol. 2005;14(3):231-8.}
^{Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. Journal of hepatology. 2004;41(1):38-43.}
^{Runyon BA. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-3.}
^{Gluud LL, Dam G, Les I, et al. Branched-chain amino acids for people with hepatic encephalopathy. The Cochrane database of systematic reviews. 2017;5(5):Cd001939.}

CASE REPORT GUIDELINES FOR AUTHORS

Practical Gastroenterology Case Report Guidelines for Authors

The aim of Case Reports is to provide challenging yet clinically relevant and informative cases to primary care physicians.

The Case should center around one (1) to three (3) high quality images that are completely described in the report. Images should be endoscopic, pathologic, and/or radiographic (without any patient identifiers) with clear labeling as appropriate.

The Case must be a concise report submitted as a Word document consisting of no more than 1250 words.

The images must be submitted as .jpg files separate from the Word document.

There should be a brief introduction/abstract, relevant presentation of the case, relevant case discussion and conclusion.

The conclusion should include one or two clinical pearls that the reader may apply to their practice or add to their knowledge set.

References should be limited to 8. References should follow AMA style and journal names should be abbreviated according to Index Medicus practice. Inclusive page ranges should be indicated.

Authors should be limited to 3 on each submission. No author photographs are necessary. All authors must provide their names, addresses, phone numbers, complete titles and affiliations.

Case Reports must not have been published previously. Each Case Report is subject to review by members of our Editorial Board. Case Reports are subject to final editing. Upon publication, Case Reports will be copyrighted by Practical Gastroenterology Publishing, Inc.

Please submit your Case Report to:

Adrien Mahl, Editor
Practical Gastroenterology
practicalgastro@aol.com

A CASE REPORT

Metastatic Urothelial Bladder Cancer Involving the Rectum

Chung Sang Tse,Yousef Elfanagely,

Sean Fine

INTRODUCTION

Urothelial carcinoma of the bladder (UBC) accounts for 90% of all primary bladder tumors. ¹ Although 75% of newly diagnosed UBCs are noninvasive, they have a high rate of recurrence despite treatment. ² Recurrence most often occurs locally in the bladder or remaining upper tract with <1% involving the colon. ³ We present a case report of a patient whose initial presentation of metastatic UBC to the rectum was bright red blood per rectum and acute anemia.

Case Report

An 85-year-old man, former smoker, with a history of stage IIIA (pT3aN0M0) urothelial carcinoma of the bladder status post radical cystectomy and ileal loop conduit eight years prior was admitted to the hospital for 3-4 days of progressive scrotal pain and swelling that had not responded to outpatient ketoconazole topical ointment. Physical examination revealed a swollen and erythematous scrotum, which was tender to palpation. Initial laboratory work-up was notable for normocytic anemia with hemoglobin 8.0 g/dL (normal 13.5- 16.0 g/dL), mean corpuscle volume 83 fL (normal 80-98 fL) without leukocytosis (white blood cell count 6.9 x 109 /L). His scrotal cellulitis was treated with piperacillin-tazobactam.

Over the course of two hospital days, he developed hematochezia and acute chronic anemia with a down-trending hemoglobin of 6.2 g/dL. Gastroenterology was consulted. His abdominal exam was soft, non-tender, and non-distended with blood noted on rectal exam. Flexible sigmoidoscopy revealed a large rectal ulcer (Figure 1) with oozing. Adjacent to the ulcer was impacted stool. A diffuse area of erythematous mucosa was also found in the rectum. Given the appearance of the ulcer and the adjacent impacted stool, a stercoral ulcer was the suspected source of the bleed. Biopsies of the ulcer bed and surrounding tissue revealed rectal mucosa with urothelial carcinoma with positive immunohistochemical staining of cytokeratin 7 (CK7) (Figure 2), keratin 20 (CK20), and GATA3. For the remainder of the patient’s hospital stay, his bleeding subsided and hemoglobin stabilized. Palliative immunotherapy was pursued per the patient’s and family’s requests but was not tolerated. Hospice services were requested for comfort care; he ultimately died six months later.

Discussion

Bladder cancer is the second most common genitourinary malignancy. In the United States, approximately 70,000 patients are newly diagnosed with bladder cancer annually. ⁴ Risk factors for bladder cancer include smoking and exposure to aromatic amines. 2 Urothelial bladder cancer (UBC), a subtype of bladder cancer, comprises 90% of all primary bladder cancers. ³ Approximately 75% of newly-diagnosed UBCs are noninvasive while the remaining 25% invade the muscular layers and require radical surgery or radiotherapy. ² Radical cystectomy is the current gold standard for muscle invasive UBC. ⁵ Common distal recurrence and metastasis sites are lungs, liver, and lymph nodes (nonpelvic). ⁶ However, local recurrence is more common in the bladder or remaining urinary tract. ³ The clinical presentation of recurrent UBC varies depending on the site of recurrence, most commonly with no symptoms, venous status, or localized pain. ⁷

Gastrointestinal tract involvement of metastatic UBC is rare. ³ Literature review has identified 34 reported cases, with 16 involving rectal metastases. 8 Five cases presented with hematochezia. ^3,8 Four cases of metastatic UBC involving the rectum occurred after radical cystectomy. 8 Recurrence of bladder cancer after radical cystectomy occurs in up to 40% of patients and has been attributed to potential occult metastasis and/or seeding during surgical intervention.⁵

Unique to this case was its endoscopic finding. Colonoscopy has confirmed metastases to rectum in three other cases. However, the tissues biopsied were of fixed masses or thickened rectal wall.⁸ In our case report, the tissue biopsied was a single ulcer. Because of the appearance of the ulcer, a stercoral ulcer was thought to be the source of the bleeding. This circumstance highlights the importance of obtaining biopsies from an ulcer bed during colonoscopy for histological examination in the appropriate clinical setting.

CONCLUSION

Gastrointestinal tract involvement of metastatic UBC is rare. In this case report, a patient presented with hematochezia, found to be secondary to metastatic UBC involving the rectum. An ulcer was identified on endoscopy, and initially was suspected to be secondary to a stercoral ulcer. Biopsies were taken and consistent with metastatic disease, highlighting the importance of obtaining biopsies from an ulcer bed.

References

^{Kaufman DS, Shipley WU, Feldman ASJTL. Bladder cancer. 2009;374(9685):239-49}
^{Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. 2013;63(2):234-41}
^{El Douaihy Y, Krzyzak M, Barakat I, Deeb LJAcrj. Recurrence of Urothelial Bladder Carcinoma in the Colon Presenting as Hematochezia. 2016;3(4)}
^{Ploeg M, Aben KK, Kiemeney LAJWjou. The present and future burden of urinary bladder cancer in the world. 2009;27(3):289-93}
^{Lotan Y, Gupta A, Shariat SF, et al. Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. 2005;23(27):6533-39}
^{Wallmeroth A, Wagner U, Moch H, Gasser TC, Sauter G, Mihatsch MJJUi. Patterns of metastasis in muscle-invasive bladder cancer (pT2–4): an autopsy study on 367 patients. 1999;62(2):69-75}
^{Cornu J-N, Neuzillet Y, Hervé J-M, Yonneau L, Botto H, Lebret TJWjou. Patterns of local recurrence after radical cystectomy in a contemporary series of patients with muscleinvasive bladder cancer. 2012;30(6):821-26}
^{Aneese AM, Manuballa V, Amin M, Cappell MSJWjoge. Bladder urothelial carcinoma extending to rectal mucosa and presenting with rectal bleeding. 2017;9(6):282}

FROM THE LITERATURE

Necrotizing Enterocoliltis:Is Care Getting Better?

Necrotizing enterocolitis (NEC) is a devastating intestinal condition typically associated with premature infants in neonatal intensive care units (NICUs). NEC is associated with both a high mortality rate as well as a high rate of neurodevelopmental disability (NDD).

As survival of premature infants increases, the risk of NEC also has increased, and the authors of this study looked at current outcomes of NEC in the medical literature. In particular, a review of the literature occurred using the PRISMA Statement (http:// www.prisma-statement.org/PRISMAStatement/ PRISMAStatement). PubMed also was searched for the following terms: “NEC,” “mortality,” “morbidity,” “neurodevelopmental outcome,” “outcomes”, and “intestinal failure.” Included articles had to be in English and had to be published after January 2010 with reported NEC outcomes (mortality) from international/national/regional/multi-center studies from high-income countries.

Initially, 1371 articles were included, but only 31 articles met the criteria of studying mortality that could be included in a meta-analysis. Mortality from NEC (Bell stage 2A or higher) was 23.5% (95% confidence interval 18.5% to 28.8%) with low birthweight and history of NEC surgery being risk factors. In particular, the mortality of infants less than 1000 grams who underwent surgery for NEC was 50.9% (95% confidence interval 38.1% to 63.5%). The meta-analysis demonstrated that mortality from NEC in premature infants ranged from 10% to 21%. Five studies meeting criteria for evaluating NDD in the setting of NEC, and severe NDD ranged between 24.8% and 59.5% although the definition of “severe” varied between studies. Finally, only three studies described the association between intestinal failure (defined as intestine loss preventing normal intestinal absorption and growth) and NEC with intestinal failure rates of 15.2% in all infants with NEC and 35.4% in infants with NEC requiring surgery.

This meta-analysis provides convincing evidence that NEC still is extremely problematic in NICUs, and further research is necessary to decrease associated morbidity and mortality. Further research should be aimed towards understanding potential associated genetic mechanisms involved in NEC as well as considering the possibility of new types of pre-/pro-/ symbiotic strains to reduce the complications of this devastating disease.

^{Jones I. and Hall N. Contemporary outcomes for infants with necrotizing enterocolitis – a systemic review. Journal of Pediatrics 2020; 220: 86-92.}

FROM THE LITERATURE

Collagenous Colitis Shares Genetic Risk with Other Immune-Mediated Diseases

An array-based, genetic association study was carried out in a cohort of patients with collagenous colitis (CC) and the common genetic basis was investigated between that and Crohn’s disease (CD), ulcerative colitis (UC), and celiac disease.

DNA from 804 CC formalin-fixed, paraffinembedded tissue samples were genotyped with Illumina Immunochip. Matching genotype data was carried out on control samples and CD, UC, and celiac cases were provided by the respective consortia.

A discovery association study followed by metaanalysis with an independent cohort, polygenic risk score calculation and cross-phenotype analyses were performed. Enrichment of regulatory expression, quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells.

Three HLA alleles (HLA-B08:01, HLADRB103:01 and HLA-DQB1*02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. An independent protective effect on HLADRB04; 01 was noted on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CCI risk.

An enrichment of expression quantitative trait loci was detected among the CC susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases.

It was concluded in this largest genetic study of CC to date, with histologically confirmed diagnosis, this strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. A shared genetic risk was also detected between CC, celiac disease, CD and UC, supporting clinical observations of comorbidity.

^{Stahl, E., Roda, G., Dobbyn, A., et al. “Collagenous Colitis is Associated with HLA Signature and Shares Genetic Risks with Other Immune-Mediated Diseases.” Gastroenterology 2020; Vol. 159, pp. 549-561.}

FROM THE LITERATURE

Peripheral Eosinophils and Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease associated with mucosal infiltration of the esophagus. EoE incidence appears to be increasing, especially in children, and repeat esophagogastroduodenoscopy (EGD) often is needed to confirm therapeutic response to EoE (typically topical mucosal steroid therapy or dietary changes directed at preventing allergic disease). Since clinical symptoms of EoE are not a good indicator of clinical response to therapy, one of the current goals in EoE research is to find non-invasive biomarkers to monitor disease activity. In that regard, the blood eosinophil count has the potential to be such a marker

The authors of this study performed a retrospective chart review of all pediatric patients (less than 18 years of age) diagnosed with EoE over a 7-year period. Patients with coexisting GI disease were excluded, and EoE was defined as an eosinophil count greater than or equal to 15 eosinophils per highpower field (HPF) in biopsies in any of 3 regions of the esophagus (lower, mid, upper). All patients in this group had been on a proton pump inhibitor for at least 4 weeks prior to EGD. The primary study endpoint was determination of a possible correlation between absolute peripheral eosinophil count and esophageal eosinophilic infiltration. The secondary study endpoint was to see if esophageal eosinophils correlated with biopsy findings of basilar hyperplasia, spongiosis, and the presence of neutrophils and lymphocytes.

A total of 57 patients with EoE, 91 EGDs, and 279 biopsy specimens were included in the study. The oldest patient in the study was 17.9 years while the youngest patient was 1.6 years. The age of participants ranged from 1.6 years to 17.9 years of age, and white study subjects comprised 80% of the study population. A total of 66 procedures (71%) had biopsies consistent with EoE while the other 29% had less than 15 eosinophils per HPF or had no disease noted on biopsies. A significant correlation was seen between absolute eosinophil counts in blood samples and highest esophageal counts in biopsy specimens (P=0.0009). There was a significant correlation between absolute eosinophil counts in patients with active EoE compared to patients with biopsies showing less than 15 eosinophils per HPF or no eosinophilic infiltration. An absolute eosinophil count less than 500 correlated well with patients with inactive disease although an absolute eosinophil count greater than 500 did not correlate well with active EoE. However, when using a logistic regression model for race, sex, weight, height, and body mass index (BMI), none of these factors correlated with absolute eosinophil counts in relation to EoE activity.

It was noted that 58.1% of patients with EoE had allergic rhinitis, 50.5% of patients had food allergies, 38% had asthma, 29 % had eczema, and 14% had all of these conditions together. The most common symptoms included odynophagia (6.5%), food impaction (7.5%), chest pain (11.8%), nausea (23.7%), gastroesophageal reflux symptoms (24.7%), emesis (24.7%), dysphagia (25.8%), and abdominal pain (33.3%). The most common endoscopic finding in patients with EoE included esophageal furrowing (43%). Basilar hyperplasia, spongiosis, and microabscesses were significantly more common in patients with EoE compared to patients with no EoE although the presence of lymphocytes and neutrophils in biopsies did not differ between groups.

Although absolute eosinophil count may be a marker for inactive EoE which has the potential to be used for disease response, this study showed that it was difficult to correlate such findings with worsening EoE. Basilar hyperplasia, spongiosis, and microabscesses (potential early markers of the development of fibrosis) did seem to correlate with EoE although infiltration of other cell types (neutrophils, lymphocytes) did not. The authors state that the patients with EoE in this study were all treated with swallowed budesonide, and we have no data on other interventions such as swallowed fluticasone or dietary therapy. It appears that absolute eosinophil count is not a good marker for following EoE activity over time.

^{Choudhury S., Kozielski R., Hua J., Wilding G., Baker S. Do histological features of eosinophilic esophagitis in children correlate with peripheral eosinophils? Journal of Pediatric Gastroenterology and Nutrition 2020; 70: 604-607.}

FELLOWS’ CORNER

A Case of Small Bowel Lipoma Presenting with Intussusception

Luisa Recinos,Chiranjeevi Gadiparthi,

Arkady Broder

CASE PRESENTATION

A 55-year-old female was referred to gastroenterology service with severe and intermittent epigastric abdominal pain of 2 weeks duration. She had unintentional weight loss of 15 lbs. The pain was not associated with food intake. She had no prior abdominal surgeries. Her medical history was significant for arterial hypertension and diabetes mellitus. Physical examination revealed normal vital signs and epigastric tenderness with no palpable mass.

A complete blood count and chemistry panel were normal. An upper endoscopy and colonoscopy revealed no apparent cause of her symptoms but were remarkable for mild gastritis, diverticulosis, and small hemorrhoids. A contrastenhanced CT scan of the abdomen and pelvis showed small bowel intussusception in the right lower quadrant in mid-ileum as shown in Figure 1. For better visualization of small bowel, CT enterography was done (Figure 2) which confirmed the intussusception. An anterograde single balloon enteroscopy was unsuccessful in reaching the site of the intussusception. Surgical resection was arranged.

QUESTIONS

What are the clinical manifestations of small bowel intussusception in adults?
What are the causes of small bowel intussusception?
What are the gastrointestinal manifestations of lipomas?
What is the radiological diagnosis?

What are the Clinical Manifestations of Small Bowel Intussusception in Adults?

Intussusception is the telescoping of a proximal segment of the intestine into an adjacent distal segment. In a retrospective study,¹ abdominal pain was the most frequently reported symptom (79%). The mean duration of acute pain was 4 hours, and 80% described an intermittent and cramping pain. Other described symptoms include vomiting and diarrhea. Bloody stool and a palpable mass are frequently seen in the pediatric population, however very uncommon in adults.

What are the Causes of Small Bowel Intussusception?

According to a recent meta-analysis,² the common causes of intussusception in adults include benign tumors, followed by malignant tumors and idiopathic causes. The most common malignancies in enteric intussusception were metastatic carcinoma, metastatic lymphoma, and gastrointestinal stromal tumor (GIST). Benign tumors that can cause enteric intussusception include hamartoma, hemangioma, polyp (inflammatory, Peutz-Jegher), lipoma, and neurofibroma. These small bowel tumors typically result in lead-point for intussusception as shown in our case.

Non-lead point intussusception has been associated with celiac disease and Crohn’s disease. Inflammation with wall thickening and decreased or dysrhythmic small-bowel motility have been the suggested underlying mechanisms of intussusception.^3,4

What are the Gastrointestinal Manifestations of Lipomas?

Lipomas are submucosal tumors that can grow in any part of the gastrointestinal tract and up to 20-25%⁵ are found in the small bowel. Most commonly lipomas are asymptomatic and found incidentally during endoscopic procedures. When symptomatic, they may have pseudopedicle that leads to intussusception. At times, they can ulcerate and cause anemia due to microscopic blood loss.

What is the Radiological Diagnosis?

The imaging modalities to assess intussusception include CT scan, ultrasound, and barium enema. The accuracy of the CT scan is varied widely, and has been reported to be 58-100%⁶ and is the preferred initial test of choice. Classic findings on CT scan include the target, bulls-eye, or sausageshaped lesions. When compared to a regular CT scan, CT enterography uses thinner sections and a large amount of low-density enteric contrast. CT enterography better depicts the small bowel wall and lumen making it a superior tool to assess small bowel neoplasms with a sensitivity of 84% and specificity of 96.9%.⁷

In our case, the CT scan of the abdomen showed small bowel intussusception involving a 12 cm segment within the right abdomen, with the characteristic sausage-shaped appearance (Figure 1). The CT enterography showed small bowel intussusception in the mid ileum and the lead point was a lipoma which measured 23 x 29 x 16 mm (Figure 2). The small bowel lipoma was not evident on the contrast-enhanced CT scan of the abdomen and single balloon enteroscopy.

References

^{Cochran AA, Higgins GL, 3rd, Strout TD. Intussusception in traditional pediatric, nontraditional pediatric, and adult patients. Am J Emerg Med. 2011;29(5):523-527.}
^{Hong KD, Kim J, Ji W, Wexner SD. Adult intussusception: a systematic review and meta-analysis. Tech Coloproctol. 2019;23(4):315-324.}
^{Gonda TA, Khan SU, Cheng J, Lewis SK, Rubin M, Green PH. Association of intussusception and celiac disease in adults. Dig Dis Sci. 2010;55(10):2899-2903.}
^{Lopez-Tomassetti Fernandez EM, Lorenzo Rocha N, Arteaga Gonzalez I, Carrillo Pallares A. Ileoileal intussusception as initial manifestation of Crohn’s disease. Mcgill J Med. 2006;9(1):34-37.}
^{Thompson WM. Imaging and findings of lipomas of the gastrointestinal tract. AJR Am J Roentgenol. 2005;184(4):1163-1171.}
^{Marsicovetere P, Ivatury SJ, White B, Holubar SD. Intestinal Intussusception: Etiology, Diagnosis, and Treatment. Clin Colon Rectal Surg. 2017;30(1):30-39.}
^{Ilangovan R, Burling D, George A, Gupta A, Marshall M, Taylor SA. CT enterography: review of technique and practical tips. Br J Radiol. 2012;85(1015):876-886.}

MEDICAL BULLETIN BOARD

Research Update: Icureceliac Patient Registry Leads to New Research Findings

With your generous support, we invest heavily in celiac disease research to accelerate diagnosis, the development of treatments, and a cure. One of our most important research investments over the last several years has been in iCureCeliac®, the nation’s leading celiac disease patient registry. Again and again, iCureCeliac® has helped researchers from around the world develop a greater understanding of celiac disease, leading to investment in promising interventions and therapeutics.

In October, researchers published three important studies about celiac disease that used the iCureCeliac® patient registry database as the data source. I am pleased to be able to share these studies with you.

The first study was published in the Journal of American Medical Association (JAMA) and is titled Prevalence of Dermatitis Herpetiformis Within the iCureCeliac Patient-Powered Research NetworkPatient Characteristics and Dietary Counseling. Results of the University of Pennsylvania study showed patients with dermatitis herpetiformis (DH) were less likely to recall receiving counseling on a gluten-free diet at the time of diagnosis when compared with patients with celiac disease but without DH. This is likely because only 20% of patients diagnosed with DH present with classic GI symptoms associated with celiac disease at the time of diagnosis. As well, most DH diagnoses are made by dermatologists who may lack appreciation of the need to offer counseling on the gluten-free diet. As a result, DH patients who fail to adopt a strict glutenfree diet within the first 5 years of diagnosis may have an increased risk of mortality from lymphoma in this period of time.

The second study, Disease burden and quality of life impacts in patients with celiac disease on a gluten-free diet: an analysis of the iCureCeliac registry, was presented as a poster at the United European Gastroenterology Week Virtual 2020 Congress, October 11-13, 2020 and at the American College of Gastroenterology 2020 Virtual Annual Scientific Meeting, October 23-28. Authored by researchers from Takeda Pharmaceuticals and the Celiac Disease Foundation, the study presents compelling evidence that, ‘despite gluten-free diet adherence, many patients with celiac disease still have symptoms that substantially impact their lives. This was seen for all patients but was most pronounced for those with higher symptom burden, highlighting the heterogeneity of celiac disease burden and need for further therapies beyond a gluten-free diet.’ Takeda currently has two celiac disease drugs in development, TAK-101, which is designed to promote immune intolerance, and TAK062, which works by enzymatically digesting gluten. Findings from iCureCeliac® continue to substantiate the need for treatment alternatives to a gluten-free diet.

Probiotics Use in Celiac Disease: Results from a National Survey, the third study, is also currently being presented at ACG 2020 Virtual and is an Outstanding Poster Presenter recipient. Led by Andrew Joelson, MD, Gastroenterology Fellow at the Celiac Disease Center at Columbia University, the study examined probiotic use in the Foundation’s iCureCeliac® patient registry population finding that about one-third of patients reported using probiotics to treat persistent symptoms. Patients on a gluten-free diet who were still experiencing symptoms were twice as likely to use probiotics as patients who reported controlled symptoms. This is the Celiac Disease Foundation’s fifth collaboration with Dr. Joelson and his team at Columbia University since 2017 with iCureCeliac® data demonstrating the serious burden of celiac disease.

As always, we thank you for your generous support that makes our work possible.

To Our Health
Marilyn G. Geller, Chief Executive
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