NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #3

The Infant Formula Shortage: Reasons, Responses, and Resources for Clinicians

April 2023 • Volume XLVII, Issue 4
Tegan Medico

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In the United States, regulatory and trade barriers contributed to an infant formula market dominated by a few domestic companies, such that a major recall in 2022 swiftly and profoundly reduced access nationally. Limited data points to an adverse impact broadly on households with formula-dependent infants, particularly those reliant on specialized formulas. To remedy the crisis, several federal actions aimed to augment the domestic formula supply and increase flexibility in formula purchasing by participants of the Supplemental Nutrition Program for Women, Infants, and Children. Clinicians in inpatient and outpatient pediatric care settings will benefit from an understanding of the systems that influence infant formula use and access to help provide families with safe recommendations and resources.

INTRODUCTION

In 2022, a widespread shortage of infant formula in the sociopolitical background for the recent infant the United States sent parents and clinicians into formula shortage, a review of known and theoretical a panic. An unprecedented crisis, the shortage safety concerns, the federal response, and practical aroused scrutiny of the conditions that set its stage, tips for clinicians.

History of Infant Formula
Commercialization

Commercial alternatives to human milk emerged following advances in science and technology of the Industrial Revolution.1,2 Early infant formulas were expensive, and many were complicated to prepare.3 Energy density ranged widely.1 Some products were accompanied by recipe books containing numerous preparation permutations based on a perceived clinical indication, variations were known as the “percentage method”.1,4 The percentage method largely was implemented in hospitals and specialized commercial laboratories.1 Hence, many physicians more simply recommended recipes amenable to home preparation that consisted of boiled milk or diluted evaporated milk and corn syrup or table sugar, a practice that persisted widely into the mid-20th century.1,3

Infant formulas with more straightforward preparation methods and improved nutritional compositions, achieved by the addition of cod liver or vegetable oils and vitamins, emerged in the 1920s and peaked in popularity in the early 1970s.1 Breastfeeding rates reached a low with the increased usage of formulas: 25% initiation during the first week of life.5 Homemade formula preparation was a dwindling practice as well.1,6

Regulation

Regulation of infant formula was an evolving endeavor beginning in 1938 with the Federal Food, Drug, and Cosmetic Act (FFDCA). The FFDCA established standards for food product identity, quality, and volume that were applicable to infant formulas, and it authorized oversight by the United States Food and Drug Administration (FDA).7 A 1941 amendment to the Act included infant formula labeling requirements1 and a 1966 amendment included minimums for 11 vitamin levels following cases of vitamin B6 deficiency associated with a production change to a liquid concentrate.1,8 By the time these latter changes were implemented in 1971, minimum concentrations (per 100 kilocalories of formula) for protein, fat, linoleic acid and 17 vitamins and minerals also were established.1 A later reformulation oversight that resulted in 141 cases of hypochloremic metabolic alkalosis9,10 gave way to the most comprehensive amendment to the FFDCA, the Infant Formula Act of 1980 and its 1986 amendment.

To date, the Infant Formula Act remains the most significant legislation concerning infant formula production and composition, and it is the most rigorous legislation for any food sold in the

United States. Notable provisions include:11,12

  • infants defined as less than 12 months of age mandated alerts to the FDA prior to first manufacture and with any formulation changes
  • mandated scientific evidence of safety and efficacy across product shelf-life
  • standards for good manufacturing practices and quality control procedures
  • expanded nutrient minimums and maximums
  • standards for certain nutrient forms and ratios
  • updated product labeling requirements

The International Code of Marketing of Breast-milk Substitutes is a set of policy-aimed recommendations adopted by the World Health Organization to limit the marketing reach of infant formula manufacturers. The Code has not been adopted by the United States, nor has the United States produced any legislation pertaining to one or more of the Code’s specific articles.13

Nutritional Features of Infant Formula

All infant formulas marketed and sold in the United States must meet nutrient composition requirements set by the FDA, unless designated exempt. Nutrient composition requirements for non-exempt formulas are detailed in Title 21, Chapter 1B, Part 107, of the Code of Federal Regulations and are publicly available online.12 Exempt formulas are intended to address specific medical and/or nutritional problems, such as low birth weight, cow milk protein-induced allergic proctocolitis, malabsorption, and inborn errors of metabolism.12,14 Nutrient compositions of exempt formulas vary widely depending upon their unique indications. Some exempt formulas are medically compulsory, such that unavailability could pose a significant health risk, and they often require a prescription from a medical provider. The FDA status (exempt/non-exempt) is shown in Table 1, along with primary indications for use, major nutritional features, and contemporary brand examples.

Nutrients that are not required by the FDA, but nevertheless widespread in modern options domestically and abroad, include docosahexaenoic acid (DHA) and arachidonic acid (ARA) (long-chain fatty acids); oligosaccharides (prebiotics); taurine (amino acid); lutein (carotenoid); and carnitine (amino acid derivative). These components are targets of growing research interest related to infant nutrition.15,16

Precursors to the Infant Formula Shortage Domestic Monopolies

Despite its comprehensiveness, the Infant Formula Act does not abide mutual recognition of foreign regulatory approval of infant formulas, though such provisions apply to pharmaceuticals.17 Without recognition of foreign regulatory approval, infant formulas produced in other countries must undergo FDA approval prior to legal sale in the United States. According to a report from the Congressional Research Service, few foreign companies have pursued and obtained FDA approval historically, ostensibly due to significant trade barriers—high tariffs, quota tariffs, and export caps—that threaten profitability in the United States market.18 These regulatory and trade barriers contribute to a domestic infant formula market dominated by a few companies: Abbott Nutrition (of Abbott Laboratories), Mead Johnson (of Reckitt Benckiser Group), Gerber Products Company (of Nestlé), and Perrigo. The latter is the major white label manufacturer of store-brand and boutique formulas. Although exact figures are unavailable, common estimation is that Abbott Nutrition held approximately 40% of the total infant formula market share 19 and 75% of the amino acid formula market share.20

Supplemental Nutrition Assistance Program for Women, Infants, and Children

Domestic monopolies are reinforced by contracts between infant formula manufacturers and state-level WIC (Women, Infants, and Children Program) agencies. Federally funded via the United States Department of Agriculture (USDA) Food and Nutrition Service (FNS), WIC is a nutrition assistance program that provides supplemental foods, including infant formula, to infants from lowincome families. It covers all 50 states, the District of Columbia, 33 Indian Tribal Organizations, American Samoa, Guam, the Commonwealth Islands of the Northern Marianas, Puerto Rico, and the U.S. Virgin Islands. The greatest program expense, the cost of infant formula, is contained via contracts between individual state programs or state consortia and a single infant formula company. Contracts are determined via a competitive bidding process. The winning company provides WIC with rebates for approximately 85% of retail price and in turn enjoys priority shelf space in WICparticipating retailers, thus recouping money in the non-WIC market via a “spillover effect”.21-23

In 2022, 43% of infants in the United States participated in WIC.24 An estimated 85-90% of participating infants receive formula as a program benefit.25 Thirty-four states and the District of Columbia contracted with Abbott Nutrition,23 thus directing a majority of total domestic infant formula sales toward Abbott products.

Abbott Nutrition Recall and Plant Closure

On February 17, 2022, Abbott Nutrition issued a largescale recall of its Similac® and Elecare® product lines. The recall followed troubling findings during an FDA inspection of one of Abbott’s primary plants in Sturgis, MI. The inspection was prompted by four reports of infant illness, including two deaths, from Cronobacter sakazakii infection. Additionally, a whistleblower report to the FDA in October 2021 detailed safety concerns at the Sturgis plant.26 Although evidence was insufficient to determine a direct link between the Sturgis plant and the infected infants, the plant closed production shortly after issuing the recall. Under a consent decree with the FDA, it remained closed until June 2022 but closed again soon thereafter due to storm flooding. It resumed operations in July 2022.

Consequences of the Infant Formula Shortage Medical & Nutritional Risk 

Availability of infant formulas following the Abbott Nutrition recall was largely gauged via retail data. Information Resources, Inc. (IRI) Worldwide and Datasembly reported out-ofstock figures of approximately 30-40% during the shortage peak.27,28 However, out-of-stock rates ranged widely store-by-store and state-by-state providing a limited interpretation of the crisis.

There are two big limitations of out-of-stock rates in evaluating the full extent of the infant formula shortage. Foremost, the out-of-stock rate is more a measure of product variety on the shelves rather than overall quantity. Considering the uneven demand across formula brands because of WIC participants’ restrictions to specific products, overall quantities of the most in-demand formulas is important. A major WIC-approved formula outof-stock represents lack of access for a significant portion of infants. Furthermore, retail data does not capture formulas obtained through durable medical equipment companies (DMEs), WIC-contracted special formula distribution centers, medical clinics, and hospitals. Specialized formulas, such as those for inborn errors of metabolism, renal disease, and severe allergies, are not typically available or obtained via retail channels. At this time, there is no quantitative data to confirm the many anecdotes from families and clinicians who were challenged in accessing specialized formulas, nor is there data of medical emergencies directly related to the shortage or of the impact on specific patient populations. There is, however, data supporting adverse impact broadly. The United States Census Bureau’s Household Pulse Survey was developed to assess socioeconomic impacts of the SARS-CoV-2 (COVID-19) pandemic rapidly and continually. In 2022, questions specific to the infant formula shortage were included. First results for these questions from September 202229 revealed the following:

  • Of households with infants, 50.2% reported being affected by the infant formula shortage.
  • Of households with infants who used formula, 31.8% reported difficulty obtaining formula over the last 7 days, including 32.9% using routine infant formula, 32.6% using extensively hydrolyzed infant formula, 65.1% using amino acid formula, and 65.9% using metabolic formula. 
  • Of households with infants who used formula, 6.2% reported having no formula on hand, and 18% reported having less than a week’s supply on hand. 
  • Of households affected by the infant formula shortage, irrespective of income level, 8.1% reported watering down formula or making a homemade version. The household income categories with the highest rates of watering down or using homemade formula: <$25,000 (25.5%), $35,000-$49,999 (17.8%) and ≥ $200,000 (13.9%). 

Federal Response

The impacts assessed by the Household Pulse Survey were likely mitigated by several federal actions in response to the shortage. These initiatives aimed to increase the domestic supply of infant formula and to increase flexibility in formula purchasing by WIC participants. Major actions are listed below.

Defense Production Act

On May 18, 2022, President Joseph Biden delegated authority to the Secretary of the HHS to invoke the Defense Production Act (DPA). By invoking the DPA, HHS was able to prioritize procurement of raw materials for infant formula production by

Abbott Nutrition and Mead Johnson.30

Operation Fly Formula

Along with the DPA, President Biden announced Operation Fly Formula. A coordinated effort of the USDA, HHS, and Department of Defense, Operation Fly Formula was a series of air shipments of formulas sourced from other countries. As of October 5, 2022, 26 missions were completed.31

FDA Enforcement Discretion to Manufacturers

Most formulas imported via Operation Fly Formula were products previously not approved by the FDA for domestic sale. Announced on May 16, 2022, the FDA’s Enforcement Discretion to Manufacturers was essentially an accelerated and temporary approval of foreign formulas for sale in the United States on a case-by-case basis. Among the FDA criteria for review were nutritional composition, ingredients, product label and packaging, current or anticipated inventory, microbiological testing, and facility inspection history. A stop-gap approach, the FDA Enforcement Discretion to Manufacturers expired November 14, 2022, though some products approved before that date may remain in the United States market.32

Access to Baby Formula Act

The Access to Baby Formula Act (ABFA) was passed on May 21, 2022. This amendment to the Child Nutrition Act of 1966 has two broad objectives. The first is to require state WIC agencies to include language in their infant formula rebate contracts regarding manufacturers’ plans to prevent supply disruption for WIC participants in the event of a recall.  For example, the FNS recommends that “manufacturers be required to pay rebates on both contract brand and non-contract brand formula in any available unit size, type, or form”.33

The second main objective of the ABFA is to give the USDA permanent authority to issue waivers for WIC program rules during emergencies, disasters, and supply chain disruptions.33 Prior to the ABFA, state WIC agencies submitted individual requests to implement emergency waivers. Some states had done so with the COVID-19 pandemic, and they were able to invoke their existing emergency waiver to allow participants to access non-contract formula substitutes during the infant formula shortage. The ABFA allows for a more streamlined waiver process.

Tips for Clinicians
Formula Substitutions

  • See Table 2 for emergency guidance from governmental and professional organizations.
  • See Table 3 for a formula substitution matrix.
  • Formulas marketed for sensitivity/comfort have varying degrees of lactose reduction. There is no evidence supporting lactose reduction in infants apart from rare circumstances: galactosemia, an inborn error of metabolism that requires total lactose elimination; congenital disaccharidase deficiency; and transient lactose intolerance from acute gastroenteropathy.34 Thus, the lactose contents of these formulas should not be used as a criterion for determining appropriate substitutions in most cases.
  • Toddler formulas are not regulated like infant formulas. They have varying calorie concentrations and may not be nutritionally complete. The nutritional composition of toddler formulas should be thoroughly evaluated prior to use, and use should be temporary (<1 week).

Foreign Formulas

  • Foreign formulas sold within the FDA Enforcement Discretion to Manufacturers may be used with confidence. 
  • Safety, quality, and identity cannot be guaranteed for foreign formulas imported outside the FDA Enforcement Discretion.
  • See Table 4 for an updated list of FDAapproved foreign formulas.
  • Some foreign formulas are “staged”. “Stage 1” or “first milk” is for infants up to 6 months of age. Stage 2, “second”, or “follow-on” milk is for infants 6-12 months of age. Stages vary in nutritional composition, particularly iron. Guide caregivers to use the correct stage for their infant’s age.

Accurate and Safe Formula Preparation

  • Never dilute infant formula.
  • Scoop sizes are formula-specific and may not be interchanged. The mixing instructions for specialty formulas and imported formulas may differ.
  • Imported formulas may express water measurements as milliliters instead of ounces. Ensure caregivers understand how to convert between units (one fluid ounce contains 30 milliliters).
  • Families who were instructed to mix formula to a non-standard calorie concentration using a hospital- or clinic-provided recipe should receive updated mixing instructions with every formula change.
  • If non-standard mixing instructions are not immediately available, instruct families to prepare formula per can instructions until the specialized recipes can be conveyed.
  • Reinforce safe formula mixing methods to minimize the growth of harmful pathogens. See Infant Formula Preparation and Storage on the Centers for Disease Control and Prevention website (cdc.gov) for guidance.

Homemade Formulas and Milks

  • Ask caregivers whether they are making homemade formulas, as this practice has been reported by a significant percentage of households.29
  • Discourage use of homemade formula. Although once a common practice, it was not without documented health consequences, including hypertonic dehydration, rickets, scurvy, and iron deficiency.1,6 Contemporary variations of homemade formulas available on social media have been noted to contain unsafe ingredients,35,36 and some have been implicated in cases of malnutrition, electrolyte disarray, acidosis, rickets, seizure, and cardiac arrest.37-39
  • Emergency guidance from the American Academy of Pediatrics states that pasteurized whole cow milk or fortified soy milk may be used for infants older than 6 months and for no longer than one week.40
  • Plant-based alternative milks, other than temporary use of soy milk described above, should not be used.
  • Raw milk from cows, goats, or other mammals, should never be given.

Human Milk

Select recommendations from the Academy of Breastfeeding Medicine include:41

  • Support those wishing to increase milk production by referring to a qualified lactation expert.
  • If accessible, consider pasteurized donor milk from milk banks certified by the Human Milk Banking Association of North America (visit hmbana.org for a map of milk bank locations).
  • Exercise caution with informal milk sharing. Consider the health of the donor, along with flash pasteurization methods. 
  • Discourage online purchasing of human milk, especially from unknown donors.

Collaboration

  • As applicable, be familiar with state WIC program formularies and approved substitutions.
  • Be aware of current limitations in how WIC participants may access formula. For example, formulas may only be purchased at WICapproved retailers; online purchases are not currently a feature of the program. Some states offer ship-to-home services for specialty formulas.
  • As applicable, be familiar with DME company formularies and communicate with DME personnel to stay abreast of inventory changes. • Give input to hospital stakeholders involved in facility formula contract negotiations to optimize formula access.
  • Utilize registered dietitian/nutritionists (RDNs) with expertise in infant nutrition for guidance on the features and indications of various formulas, as well as for specialized mixing instructions.

Conclusion

The evolution of the infant formula industry has shaped, and has been shaped, by scientific advances, infant feeding trends, and regulatory constraints and liberties, both. The 2022 shortage experienced in the United States may reshape the domestic market and industry at large. Notwithstanding, at the time of this writing, the major trade and regulatory structures underpinning formula access in the United States remain intact. Time will tell whether the market diversity and resiliency will improve. Clinicians in inpatient and outpatient pediatric care settings will benefit from an understanding of the systems that influence infant formula use and access to help provide families with safe recommendations and resources.

References

  1. Fomon SJ. Infant feeding in the 20th century: Formula and beikost. J Nutr. 2001;131(2).
  2. Wargo WF. The history of infant formula: quality, safety, and standard methods. J AOAC Int. 2016;99(1):7-11.
  3. Schuman A. A concise history of infant formula (twists and turns included). Contemp Pediatr. 2003; 2:91.
  4. The Mellin’s Food Method of Percentage Feeding. Press of Mellin’s Food Company; 1908.
  5. Martinez GA, Krieger FW. 1984 milk-feeding patterns in the United States. Pediatrics. 1985;76(6).
  6. Bertmann F, Dunn CG, Racine EF, Fleischhacker S. The risk of homemade infant formulas: Historical and contemporary considerations. J Acad Nutr Diet. 2022;122(4):697-708.
  7. U.S. Federal Food, Drug, and Cosmetic Act. 21 U.S.C. §§301392, 52 Stat. 1040 (1938).
  8. Nelson EM. Association of vitamin B6 deficiency with convulsions in infants. Public Health Rep. 1956;71(5).
  9. Laskin CR, Pilot LJ. Defective infant formula: The Neo–Mull– Soy/Cho–Free incident. Prev Hum Serv. 1982;1(4).
  10. Malloy MH, Willoughby A, Berendes H, et al. Hypochloremic metabolic alkalosis from ingestion of a chloride-deficient infant formula: Outcome 9 and 10 years later. Pediatrics. 1991;87(6).
  11. Infant Formula Act of 1980. 21 U.S.C. 106 §350a (2014). Accessed November 11, 2022. https://www.ecfr.gov/current/ title-21/chapter-I/subchapter-B/part-106.
  12. Infant Formula Act of 1980. 21 U.S.C. 106 §350a (1985).
    Accessed November 11, 2022. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-107.
  13. Soldavini J, Taillie LS. Recommendations for adopting the International Code of Marketing of Breast-milk Substitutes into U.S. policy. J Hum Lact. 2017;33(3).
  14. U.S. Food and Drug Administration. Exempt Infant Formulas Marketed in the United States by Manufacturer and Category. Updated December 3, 2019. Accessed November 11, 2022. https://www. fda.gov/food/infant-formula-guidance-documents-regulatory-information/exempt-infant-formulas-marketedunited-states-manufacturer-and-category.
  15. Koletzko B, Baker S, Cleghorn G, et al. Global standard for the composition of infant formula: Recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr. 2005;41(5).
  16. Alles MS, Scholtens PAMJ, Bindels JG. Current trends in the composition of infant milk formulas. Current Paediatrics. 2004;14(1).
  17. U.S. Food & Drug Administration. Mutual Recognition Agreement (MRA). Updated November 8, 2021. Accessed November 11, 2022. https://www.fda.gov/ international-programs/international-arrangements/ mutual-recognition-agreement-mra.
  18. Casey, C. Congressional Research Service. Published May 23, 2022. Accessed October 29, 2022. Tariffs and the infant formula shortage. https://crsreports.congress. gov/product/pdf/IN/IN11932.
  19. Leo L, Khandekar A. Abbott aims to recapture baby formula market share. Reuters. July 20, 2022. Accessed November 11, 2022. https://www.reuters.com/business/ healthcare-pharmaceuticals/abbott-raises-2022-profitforecast-2022-07-20.
  20. Bottemiller Evich H. “I don’t know how my son will survive”: Inside the dangerous shortage of specialty formulas. Politico. May 7, 2022. Accessed November 11, 2022. https://www.politico.com/ news/2022/05/07/i-dont-know-how-my-son-will-survive-inside-the-dangerous-shortage-of-specialty-formulas-00030787.
  21. Choi YY, Ludwig A, Andreyeva T, Harris JL. Effects of United States WIC infant formula contracts on brand sales of infant formula and toddler milks. J Public Health Pol. 2020;41(3):303-320.
  22. Rojas CA, Wei H. Spillover mechanisms in the WIC infant formula rebate program. J Agric Food Ind Organ. 2019;17(2).
  23. Neuberger Z, Bergh K, Hall L. Center on Budget and Policy Priorities. Infant formula shortage highlights WIC’s critical role in feeding babies. June 22, 2022. Accessed October 29, 2022. https://www.cbpp.org/ research/food-assistance/infant-formula-shortage-highlights-wics-critical-role-in-feeding-babies.
  24. USDA Economic Research Service. WIC Program. Updated August 10, 2022. Accessed November 6, 2022. https://www.ers.usda.gov/topics/food-nutritionassistance/wic-program.
  25. USDA Food and Nutrition Service. Fiscal Year 2020 WIC Breastfeeding Data Local Agency Report. Published June 2021. Accessed October 29, 2022. https://fns-prod.azureedge.us/sites/default/files/ resource-files/FY2020-BFDLA-Report.pdf.
  26. Bottemiller Evich H. Whistleblower warned FDA about formula plant months before baby deaths. Politico. April 28, 2022. Accessed November 11, 2022. https://www.politico.com/news/2022/04/28/whistleblowerfda-baby-formula-00028569.
  27. Snider M. Baby formula shortage continues: nearly 30% of popular brands sold out, stores ration sales. USA Today. April 9, 2022. Accessed October 29, 2022. https://www.usatoday. com/story/money/shopping/2022/04/09/baby-formula-shortage-2022-worsens/9525498002.
  28. Datasembly releases latest numbers on baby formula. Datasembly. May 10, 2022. Accessed October 29, 2022. https://datasembly.com/news/datasembly-releases-latest-numbers-on-baby-formula.
  29. U.S. Census Bureau. Week 49 Household Pulse Survey: September 14 – September 26. Published October 5, 2022. Accessed November 5, 2022. https://www.census.gov/programs-surveys/household-pulse-survey/data.html.
  30. U.S. Department of Health and Human Services. HHS Secretary Becerra Invokes Defense Production Act for Third Time to Further Increase Production of Infant Formula for American Families. Published May 27, 2022. Accessed October 29, 2022. https://www.hhs.gov/about/news/index. html.
  31. The White House. President Biden Announces TwentySixth Operation Fly Formula Mission. Published October 5, 2022. Accessed November 11, 2022. https://www.whitehouse. gov/briefing-room/statements-releases/2022/10/05/presidentbiden-announces-twenty-sixth-operation-fly-formula-mission.
  32. U.S. Food and Drug Administration. Enforcement Discretion to Manufacturers to Increase Infant Formula Supplies. Updated November 2, 2022. Accessed November 12, 2022. https:// www.fda.gov/food/infant-formula-guidance-documents-regulatory-information/enforcement-discretion-manufacturersincrease-infant-formula-supplies.
  33. U.S. Department of Agriculture Food and Nutrition Service. WIC Policy Memorandum #2022-6: Implementation of the Access to Baby Formula Act of 2022 – PL 117-129. Published June 6, 2022. Accessed November 11, 2022. https://fns-prod. azureedge.us/sites/default/files/resource-files/WPM-2022-6Access-Baby-Formula-Act-2022.pdf.
  34. Heine RG, Alrefaee F, Bachina P, et al. Lactose intolerance and gastrointestinal cow’s milk allergy in infants and children – Common misconceptions revisited. World Allergy Organization Journal. 2017;10(1).
  35. Davis SA, Knol LL, Crowe-White KM, Turner LW, McKinley E. Homemade infant formula recipes may contain harmful ingredients: A quantitative content analysis of blogs. Public Health Nutr. 2020;23(8).
  36. Aiken S, Knol L, Crowe-White K, Turner LW. A Content Analysis of Blogs Featuring Homemade Infant Formula Recipes. J Acad Nutr Diet. 2017;117(10).
  37. Vieira MA, Kube PK, van Helmond JL, et al. Recipe for disaster: Homemade formula leading to severe complications in 2 infants. Pediatrics. 2021;148(3).
  38. Calello DP, Jefri M, Yu M, Zarraga J, Bergamo D, Hamilton R. Vitamin D-deficient rickets and severe hypocalcemia in infants fed homemade alkaline diet formula — three states. August 2020-February 2021. MMWR Recomm Rep. 2021;70(33). doi:10.15585/mmwr.mm7033a4.
  39. Davydov D, Martin A, Bauerfeld C. Detrimental effects of internet-promoted “healthy” homemade formula in two infants. Pediatrics. 2021;147(3_Meeting Abstract).
  40. Abrams S. With the baby formula shortage, what should I do if I can’t find any? American Academy of Pediatrics. Updated June 28, 2022. Accessed November 11, 2022. https://www.healthychildren.org/English/tips-tools/ask-thepediatrician/Pages/Are-there-shortages-of-infant-formula-dueto-COVID-19.aspx.
  41. Kellams A. Academy of Breastfeeding Medicine Recommendations during shortage of artificial breast milk substitutes. Breastfeed Med. 2022;17(6):469-471.

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SPECIAL ARTICLE

Patient-Related Adverse Events and Clinical Device Failures Associated with the Linx Magnetic Sphincter Augmentation Device: A MAUDE Database Analysis

April 2023 • Volume XLVII, Issue 4
Alexandra McMillan,Daryl Ramai,Douglas G. Adler

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Abstract

Introduction: The Linx Medical Sphincter Augmentation Reflux Management System is a surgical option for the treatment of chronic gastroesophageal reflux disease (GERD). However, real life data regarding device failures and patient-related adverse events is lacking.

Methods

We analyzed device failures and patient-related adverse events reported to the FDA Manufacturer and User Facility Device Experience (MAUDE) database related to the Linx device from January 2011 to October 2021.

Results

We identified 499 reports describing 918 patient-related adverse events and 101 device failures with two duplicates excluded. The most reported patient-related adverse events were dysphagia in 275 patients (30%), odynophagia in 271 patients (29.5%), GERD in 135 patients (14.7%), adverse events not otherwise specified in 39 patients (4.2%) and erosion in 38 patients (4.1%). The most reported device failures were device removal for recurrence of symptoms in 61 patients (60.4%), Linx device opening unexpectedly in 14 patients (13.9%), Linx device removed without additional information reported in 9 patients (8.9%), Linx bead separation in 7 patients (6.9%) and device migration from the original site of implantation in 7 patients (6.9%).

Conclusion

Linx device implantation offers an alternative to other surgical and medical therapies in the treatment of refractory GERD; however, additional investigation of both short and long-term device failures and patient-related adverse events is necessary.

ABSTRACT

The Linx Medical Sphincter Augmentation Reflux Management System is a surgical option for the treatment of chronic gastroesophageal reflux disease (GERD). However, data regarding device failures and patient-related adverse events is lacking. We analyzed Linx device failures and patient-related adverse events reported to the FDA Manufacturer and User Facility Device Experience (MAUDE) database from January 2011 to October 2021. We describe 101 device failures and 918 patient-related adverse events in detail, providing valuable information for clinicians and patients considering Linx implantation.

INTRODUCTION

The Linx Medical Sphincter Augmentation Reflux Management System (Ethicon, Bridgewater, NJ) is a device created as a surgically-implanted option for the treatment of chronic gastroesophageal reflux disease (GERD). Linx was approved in 2012 by the U.S Food and Drug Administration (FDA) as a safe alternative to fundoplication for the treatment of patients with GERD.1 Compared to the previous surgical gold standard of Nissen fundoplication, the Linx device is designed to be implanted laparoscopically without altering foregut anatomy and is reversible via device removal.2 Prior to antireflux surgery, increasing the dose of proton pump inhibitors in patients with GERD is a common treatment option to suppress acid secretion; however, some patients continue to have insufficient symptom control after dose adjustments.2,3 The magnetic sphincter augmentation (MSA) device was developed as a long-term solution for GERD due to its specific design to augment lower esophageal sphincter length and provide support to patients with LES failure.4

The Linx device is a ring composed of interlinked titanium beads with magnetic cores that is surgically implanted around the gastroesophageal junction to reduce and/or prevent acid from entering the esophagus. The beads can temporarily separate in the context of ring expansion to allow food or liquid to pass into the stomach as well as belching and vomiting.5 The magnetic attraction between the beads allows the lower esophageal sphincter to remain closed and protect the esophagus from acid reflux and mucosal injury. The magnetic force when the beads are closed is 40 grams and when the beads are separated falls to 7 grams.6 Linx device implantation via laparoscopy occurs under general anesthesia and patients are able to return to a regular diet shortly after the procedure.7

According to Duke Health, approximately 6,000 Linx devices had been implanted globally by 2017 with the number of explants not reported.8 A study of the safety of magnetic sphincter augmentation published in 2021 noted 30,000 Linx devices have been implanted worldwide with a 7-year cumulative removal of 4.81%.9 The likelihood of removal was felt to be related to device size, with devices composed of a lower number of magnetic beads having a higher rate of removal.9 Due to the relative lack of data regarding Linx device failures and clinical adverse events, we undertook an analysis of the MAUDE database to assess these outcomes.

Methods

We performed an analysis of the FDA Manufacturer and User Facility Device Experience (MAUDE) database to report the device failures and clinical adverse events following Linx device implantation. The MAUDE database contains medical device reports submitted to the FDA by voluntary reporters, patients and healthcare professionals, or mandatory reporters, such as manufacturers; however, the medical device reports cannot be solely used to establish rate of events. The FDA works to include all reports received and updates the MAUDE database monthly. The database is available to the public at accessdata.fda.gov/scripts/ cdrh/cfdocs/cfmaude/search.cfm. We searched the MAUDE database from January 2011 to October 2021 for all reports related to the Linx device. The medical device reports were downloaded and individual reports were analyzed for device failures and clinical adverse events.

The event descriptions for each report were individually analyzed and categorized and data was collected on the type of device failure and clinical adverse events. Each device failure and clinical adverse event were assigned a number. When appropriate, some of the clinical adverse events were reclassified to correct for some differences in nomenclature. For example, pyrosis, regurgitation and heartburn were all classified under GERD. As the individual reports were analyzed, the numbers representing each device failure and clinical adverse event were assigned to the report. The total number of device failures and clinical adverse events associated with each report were calculated and organized into two tables.

Results

Our search of the MAUDE database identified 499 reports describing 918 patient-related adverse events and 101 device failures from January 2011 to October 2021 with two duplicates excluded.

Patient-related Adverse Events

Patient-related adverse events following Linx implantation are detailed in Table 1. The most reported patient-related adverse event following Linx implantation was dysphagia, which was reported in a total of 275 patients (30%). This was followed by odynophagia in 271 patients (29.5%) and GERD in 135 patients (14.7%). Thirty-nine patients (4.2%) had adverse events not otherwise specified in the event descriptions associated with the report. Erosion secondary to the device occurred in 38 patients (4.1%). Reports of erosion secondary to Linx device implantation include one or more of the magnetic beads eroding through the esophageal lumen. Thirty-eight patients (4.1%) experienced abdominal pain and 24 patients (2.6%) reported pain but the location was unspecified. Vomiting occurred in 16 patients (1.7%). Additionally, sixteen patients (1.7%) had chest pain while 14 patients (1.5%) reported a hiatal hernia. Nausea occurred in 7 patients (0.7%) and anxiety in 4 patients (0.4%). Three patients (0.3%) experienced headaches. Muscle spasms, weight change and flatus each occurred in 3 patients (0.3%). Inflammation, fatigue, allergy, aspiration, diarrhea, ulcer, infection, perforation and hemorrhage were reported for 2 patients (0.2%) each. The remaining adverse events each occurred in 1 patient (0.1%); pneumothorax, muscle weakness, eructation, abscess, laceration of the esophagus, adhesion, constipation, hypertension, obstruction, cardiac arrest, scar tissue formation, foreign body sensation and dry mouth.

Device Failures

Device failures following Linx implantation are detailed in Table 2. The most reported device failure, affecting 61 patients (60.4%), was device removal for recurrence of original symptoms such as dysphagia, odynophagia and GERD. This was followed by the Linx device opening unexpectedly through the interlinked titanium beads and/ or the locking clasp, after implantation around the lower esophageal sphincter in a total of 14 patients (13.9%). Nine patients (8.9%) had the Linx device removed without additional information reported in the event description associated with the report. Seven patients (6.9%) experienced Linx bead separation, where a magnetic bead disconnects from an adjacent wire link, after device implantation. Device migration from the original site of implantation occurred in 7 patients (6.9%). The reports include Linx device movement below the diaphragm or around the stomach leading to device removal. Unintended movement of the Linx device also occurred due to a hiatal hernia. In 1 patient (1.0%), the Linx locking device (a multi-directional locking clasp) mechanism failed. Additionally, in 1 patient (1.0%), there was a sizing tool failure during the procedure, which is used to approximate the Linx device to the circumference of the distal esophagus. Lastly, 1 patient (1.0%) experienced an implantation failure due to findings of impaired esophageal peristalsis during a motility study.

Discussion

This analysis of the MAUDE database over a 10year period reveals a variety of device failures and patient-related adverse events reported after Linx implantation. This is the first study exploring device failures and patient-related adverse events reported to the MAUDE database. One previous MAUDE analysis of the Linx device reported solely on the single and specific adverse event of erosion.10 Their study evaluated 9,453 Linx device implantations from 2007 to 2017 and included 29 reported cases of erosion with most patients experiencing newonset dysphagia.10 In our study, removal of the Linx device for recurrence of original symptoms and the Linx device opening unexpectedly were the most common reported device failures.

A study on Linx explantation in 435 devices from 2009 to 2017 from a single institution concluded that the most common reason for device removal in patients was recurrent GERD, which parallels our MAUDE database finding of removal for recurrence of the patient’s original symptoms.11 Additionally, a review on magnetic sphincter augmentation for GERD noted postoperative dysphagia is a common reason for device removal.12  In our study, dysphagia, odynophagia and GERD were the most commonly reported patient-related adverse events.

A literature review on the Linx device concluded that dysphagia was the most common patient related adverse event following MSA.13 In addition, Linx device erosion through the esophageal lumen was reported as the most significant adverse event of the device due to its potential morbidity.13 Further, a safety analysis of the first 1000 patients treated with the MSA device for GERD also concluded dysphagia was the primary reason for device removal.14 In our study, dysphagia was also the most reported patient-related adverse event in 275 patients (30%). Further, our study revealed erosion secondary to Linx device implantation was a significant adverse event, occurring in 38 patients (4.1%). MAUDE database medical device reports have limitations. Not all reports contain complete data regarding the device failure or patient related adverse event. For this reason, some of the device failures were reported without specific information on the type of device failure. Those entries were categorized in our study as devices removed

without additional information. Additionally, patient related adverse events that were reported without further details were classified as adverse events not otherwise specified. Other MAUDE database limitations include lack of information on the frequency of device use and the potential for under-reporting of events.

With 101 device failures and 918 patient-related adverse events, our study highlights the importance of awareness of the potential adverse outcomes of Linx device implantation. Early reviews assessing the efficacy of the Linx device concluded that the device is a well-tolerated option for the treatment of GERD but also note the long-term safety of the device was, at that time, undetermined.15,16,17 A more recent review stated the adverse event of esophageal endoluminal erosion was not fully appreciated in previous reviews and Linx device implantation should be used with restraint with regards to this potential injury.13 Although Linx device implantation has its own risks, laparoscopic removal of the device can be performed safely as a 1-stage procedure even within the context of esophageal erosion.18 Endoscopic removal of the Linx device is considered safe; however, potential complications from device implantation still need to be considered. A case report on esophageal penetration of the MSA device analyzed two cases of severe dysphagia due to migration of the device into the esophagus after implantation.19 The report concluded that the Linx device may migrate into the esophagus as seen in the two cases, yet the authors felt that the device was considered an effective treatment option for GERD and device removal is generally without diffculty.19 In our study, device migration from the original site of implantation occurred in 7 patients (6.9%) leading to device explantation.

The Linx device is widely used as an alternative to proton pump inhibitors. In a controlled clinical trial in 2012, the Linx device improved the quality of life in patients with GERD in 23 out of 23 patients and decreased dependence on proton pump inhibitors for refractory GERD in 20 out of 25 patients after 4 years.20 Further, the Linx procedure is minimally invasive and the device can be easily removed, making it a potentially desirable surgical option for patients with chronic GERD.21 However, the current literature and this analysis suggests that the long-term safety of the device warrants further research.22

CONCLUSION

Our study shows that the Linx device has complications which must be thoroughly discussed with patients prior to implantation. Although the Linx device offers patients an alternative to Nissen fundoplication and proton pump inhibitors for the treatment of refractory GERD, additional investigation of both the short and long-term device failures and patient-related adverse events are warranted.

References

  1. Reynolds JL, Zehetner J, Bildzukewicz N, Katkhouda N, Dandekar G, Lipham JC. Magnetic sphincter augmentation with the LINX device for gastroesophageal reflux disease after U.S. Food and Drug Administration approval. Am Surg. 2014;80(10):1034-1038.
  2. Bonavina L, Saino G, Lipham JC, Demeester TR. LINX(®) Reflux Management System in chronic gastroesophageal reflux: a novel effective technology for restoring the natural barrier to reflux. Therap Adv Gastroenterol. 2013;6(4):261- 268. doi:10.1177/1756283X13486311
  3. Fass R. Alternative therapeutic approaches to chronic pro- ton pump inhibitor treatment. Clin Gastroenterol Hepatol. 2012;10(4):338-e40. doi:10.1016/j.cgh.2011.12.020
  4. Reynolds JL, Zehetner J, Wu P, Shah S, Bildzukewicz N, Lipham JC. Laparoscopic Magnetic Sphincter Augmentation vs Laparoscopic Nissen Fundoplication: A Matched-Pair Analysis of 100 Patients. J Am Coll Surg. 2015;221(1):123- 128. doi:10.1016/j.jamcollsurg.2015.02.025
  5. Bonavina L, DeMeester T, Fockens P, et al. Laparoscopic sphincter augmentation device eliminates reflux symptoms and normalizes esophageal acid exposure: one- and 2-year results of a feasibility trial. Ann Surg. 2010;252(5):857-862. doi:10.1097/SLA.0b013e3181fd879b
  6. Schizas D, Mastoraki A, Papoutsi E, et al. LINX® reflux management system to bridge the “treatment gap” in gastro- esophageal reflux disease: A systematic review of 35 studies. World J Clin Cases. 2020;8(2):294-305. doi:10.12998/wjcc. v8.i2.294
  7. Zimmermann CJ, Lidor A. Endoscopic and Surgical Management of Gastroesophageal Reflux Disease. Gastroenterol Clin North Am.
  8. 2021;50(4):809-823. doi:10.1016/j.gtc.2021.07.005 Pittman, Tim, and Tim Pittman. “Novel Procedure Offers Resolution of Reflux Disease.” Duke Health Referring Physicians, 17 Jan. 2017, https://physicians.dukehealth.org/articles/novel- procedure-offers-resolution-reflux-disease.
  9. DeMarchi J, Schwiers M, Soberman M, Tokarski A. Evolution of a novel technology for gastroesophageal reflux disease: a safety perspective of magnetic sphincter augmentation. Dis Esophagus. 2021;34(11):doab036. doi:10.1093/dote/doab036
  10. Alicuben ET, Bell RCW, Jobe BA, et al. Worldwide Experience with Erosion of the Magnetic Sphincter Augmentation Device. J Gastrointest Surg. 2018;22(8):1442-1447. doi:10.1007/ s11605-018-3775-0
  11. Tatum JM, Alicuben E, Bildzukewicz N, Samakar K, Houghton CC, Lipham JC. Removing the magnetic sphincter augmentation device: operative management and outcomes. Surg Endosc. 2019;33(8):2663-2669. doi:10.1007/s00464- 018-6544-y
  12. Dunn C, Bildzukewicz N, Lipham J. Magnetic Sphincter Augmentation for Gastroesophageal Reflux Disease. Gastrointest Endosc Clin N Am. 2020;30(2):325-342. doi:10.1016/j.giec.2019.12.010
  13. Zadeh J, Andreoni A, Treitl D, Ben-David K. Spotlight on the Linx™ Reflux Management System for the treatment of gastroesophageal reflux disease: evidence and research. Med Devices (Auckl). 2018;11:291-300. Published 2018 Aug 31. doi:10.2147/MDER.S113679
  14. Lipham JC, Taiganides PA, Louie BE, Ganz RA, DeMeester TR. Safety analysis of first 1000 patients treated with mag- netic sphincter augmentation for gastroesophageal reflux disease. Dis Esophagus. 2015;28(4):305-311. doi:10.1111/ dote.12199
  15. Sheu EG, Rattner DW. Evaluation of the LINX antireflux procedure. Curr Opin Gastroenterol. 2015;31(4):334-338. doi:10.1097/MOG.0000000000000189
  16. Bonavina L, Attwood S. Laparoscopic alternatives to fun- doplication for gastroesophageal reflux: the role of mag- netic augmentation and electrical stimulation of the lower esophageal sphincter. Dis Esophagus. 2016;29(8):996-1001. doi:10.1111/dote.12425
  17. Skubleny D, Switzer NJ, Dang J, et al. LINX®magnetic esophageal sphincter augmentation versus Nissen fundoplica- tion for gastroesophageal reflux disease: a systematic review and meta-analysis. Surg Endosc. 2017;31(8):3078-3084. doi:10.1007/s00464-016-5370-3
  18. Asti E, Siboni S, Lazzari V, Bonitta G, Sironi A, Bonavina L. Removal of the Magnetic Sphincter Augmentation Device: Surgical Technique and Results of a Single-center Cohort Study. Ann Surg. 2017;265(5):941-945. doi:10.1097/ SLA.0000000000001785
  19. Salvador R, Costantini M, Capovilla G, Polese L, Merigliano S. Esophageal Penetration of the Magnetic Sphincter Augmentation Device: History Repeats Itself. J Laparoendosc Adv Surg Tech A. 2017;27(8):834-838. doi:10.1089/ lap.2017.0182
  20. Lipham JC, DeMeester TR, Ganz RA, et al. The LINX® reflux management system: confirmed safety and efficacy now at 4 years. Surg Endosc. 2012;26(10):2944-2949. doi:10.1007/ s00464-012-2289-1
  21. Asti E, Aiolfi A, Lazzari V, Sironi A, Porta M, Bonavina L. Magnetic sphincter augmentation for gastroesophageal reflux disease: review of clinical studies. Updates Surg. 2018;70(3):323-330. doi:10.1007/s13304-018-0569-6
  22. Halpern SE, Gupta A, Jawitz OK, et al. Safety and effi- cacy of an implantable device for management of gastro- esophageal reflux in lung transplant recipients. J Thorac Dis. 2021;13(4):2116-2127. doi:10.21037/jtd-20-3276

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #50

A Practical Approach to Diagnosis and Treatment of Barrett’s Esophagus

March 2023 • Volume XLVII, Issue 3
Abhilash Perisetti,Prateek Sharma

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Barrett’s esophagus (BE) is a condition characterized by transformation of the normal squamous epithelium of the distal esophagus with abnormal columnar epithelium. It can be detected in patients with gastroesophageal reflux disease (GERD, 2.3% to 8.3%) or without GERD (1.2% to 5.6%). Common risk factors include older age (approximately 1.1% in individuals older than 50 years and 0.3% in those 50 years or younger), Caucasian race, male gender, cigarette smoking, positive family history and longstanding GERD. BE can progress to neoplasia and if left untreated, could develop adenocarcinoma. BE increases the risk (annual rate of 0.2% to 0.5%) of developing esophageal adenocarcinoma (EAC) and it remains critical for early identification and treatment of this precancerous condition. High-quality upper endoscopy remains an essential tool for early identification, treatment and surveillance of BE. Despite advances in the endoscopic recognition, there is approximately a 20-25% rate of missed lesions and an urgent need to improve the rate of neoplasia detection. Management of BE is dependent on presence or absence of neoplasia. Non-dysplastic BE is treated with regular endoscopic surveillance (3-5 years) compared to neoplastic BE which requires endoscopic resection and ablation. In this review, we aim to describe recent updates on the screening, surveillance, diagnosis and management of patients with BE.

Introduction

Barrett’s esophagus (BE) derives its term from a British surgeon Dr. Norman Rupert Barrett1 who first described abnormal appearing esophageal lining in BE. The esophagus is normally lined by flat, stratified squamous epithelium which if exposed to chronic inflammation and tissue injury, could turn into mucus secreting tall and long columnar epithelium.2 This metaplastic change (where a differentiated flat squamous epithelium transforms into another mature differentiated columnar cell type) is triggered by inflammation and chronic acid exposure. This change remains a precursor to dysplasia, a critical step for developing esophageal adenocarcinoma (EAC).3 The natural history of BE involves a risk of transformation to full blown EAC in 3% to 5% of patients during their lifetime. This rate accelerates when an individual develops dysplasia.

Screening

Screening refers to evaluating individuals with GERD (without a prior history of BE) with upper endoscopy for BE. On the contrary, surveillance involves a prior established diagnosis of BE and to assess the progression to EAC. An algorithm approach for screening and surveillance for BE have published in prior studies (Figure 1).4

Patients with chronic gastroesophageal reflux disease with one or more risk factors (male sex, smoking history, age > 50 years, obesity and positive family history) are at risk of developing BE. A meta-analysis of 44 cross-sectional studies5 included 26,521 GERD individuals, in whom the pooled prevalence of endoscopically suspected BE (suspected columnar epithelium in the esophagus without biopsy) was 12% (95% CI, 5.5%-20.3%) while histologically confirmed BE was 7.2% (95% CI, 5.4%-9.3%), short-segment (BE affecting 1 to 3 cm of the esophagus) was 6.7% (95% CI, 4.6%9.1%) and long-segment (BE affecting more than 3 cm of esophagus) was 3.1% (95% CI, 2.0%4.6%).5 Male sex is associated with higher BE pooled prevalence of 10.8% (95% CI, 6.6%15.9%) compared to females of 4.8% (95% CI, 2.7%-7.5%).5 Although the precise reason for this difference is unclear, possible contributors include a male-predominant gender bias including GERD related esophagitis, vulnerability of esophageal epithelium to acid exposure and estrogen induced acid protection in females.6 Prevalence of BE is higher in White individuals compared to Hispanics (6.1% vs. 1.7%; P = .002).7 Older individuals (>50 years) are at higher risk than younger individuals (50 years or younger). In a cohort of 29,374 patients, prevalence of BE was higher in older patients compared to younger individuals (1.1% vs. 0.3%; P = .02).8 Further, tobacco smoking increases the risk of BE with higher prevalence noted in cigarette smokers compared to nonsmokers (12% vs. 1.1%; P < .001).9 Obesity poses a risk for higher prevalence of BE compared to lean individuals. A study of 13,434 patients (mean body mass index [BMI] of 39 to 51.2) showed for every 1-point increase in BMI, there is a 0.15% increase in prevalence of BE. This is likely attributed to adipocytokines increasing the risk of inflammation in obese individuals. Patients with positive family history (of BE or EAC) are at a higher risk of BE.10

While screening can assess for BE and need for further surveillance, an important consideration should be given to overall life expectancy. If the patient overall life expectancy is less than 10 years, the value of screening decreases significantly.

Diagnosis of BE and Related Neoplasia

BE is primarily diagnosed by high-quality upper endoscopy followed by multiple biopsies of the columnar lined esophagus to confirm intestinal metaplasia. To minimize variability in measuring the extent of BE during endoscopy, the Prague criteria with methodological inspection of the diaphragmic area, upper end of gastric folds, circumferential and maximum extent of squamocolumnar area has been introduced.11 Further, use of expert esophageal histopathologist could improve the interobserver variability for diagnosis of dysplasia in BE.12 A high-definition endoscope could improve the detection of the visible and potentially curable lesions (BE-related neoplasia [BERN]). Multiple strategies are available to improve the detection of these subtle BERN lesions on upper endoscopy.13 High-quality endoscopy requires CLEAN-adequate cleaning [C], learning [L] slow withdrawal with inspection of BE segment, use of virtual chromoendoscopy [E], acquiring [A] education to identify BERN lesions (by webbased and interactive sessions), and use of quality metrics (neoplasia detection rate [NDR]), which could potentially enhance detection of these lesions (Figure 1).13 The evaluation of the BE requires extensive cleaning of the concerned segment and slow withdrawal during the inspection. Endoscopists with a mean inspection time longer than 1 minute per centimeter of BE detected more lesions compared to those with less than 1 minute inspection time (54.2% vs. 13.3%; P = .04).14

For individuals who cannot tolerate sedation, office-based procedures such as swallowed cellcollection devices (unsedated transnasal endoscopy, esophageal capsule endoscopy) have been advocated.12 In unsedated transnasal endoscopy, an ultrathin endoscope is passed through the nose and advanced to the esophagus to evaluate for mucosal abnormalities. Non-endoscopic capsule sponge device (once swallowed, the capsule dissolves, compressed sponge emerges which is pulled out by a string for laboratory biomarker assessment) combined with biomarkers (trefoil factor 3, methylated DNA markers) can be used in individuals with chronic GERD.12

Missed Lesions

The visible lesions noted in the BE segment, also called BE-related neoplasia (BERN), are abnormalities noted on the BE surface mucosa (raised or abnormal pattern) indicative of dysplasia or invasive cancer. The prevalence of  LGD remained relatively stable at approximately 1213%, HDG increased by 148% (2.7% [1990-1994] to 10% [2010 and beyond]).15 Further, prevalence of EAC increased by 112% (3.3% [1990-1994] to 7.6% [2010 and 2016]).15 This correlated with increase in BERN lesions from 5.1% [1990-1994] to 16.3% [2010-2019]. While this increase in prevalence of HGD or EAC could be theoretically related to increase in recognition of BERN lesions, further studies are needed to corroborate these findings. On the contrary, the rate of missed BERN lesions on endoscopy is an important finding to assess for potential targets for improving lesion detection. Recent studies reported a missed rate up to 23% from Netherlands (f lat BERN from community centers had higher grade when referred to expert centers), 27% from Australia (BE referral centers identified advanced BERN lesions with a prior diagnosis of LGD). A meta-analysis of 24 studies reported a missed rate of 25.3% (95% CI, 16.4%-36.8%) for EAC.16 These studies indicate an approximate missed rate of EAC/HGD as high as up to one-quarter of all cases suggestive of an area of huge improvement.

Progression of BE to EAC

The annual rate of progression of BE to EAC is dependent on length of BE segment, and the presence or absence of dysplasia. In a study involving 4097 patients with BE,17 the annual rate of progression to EAC in short-segment BE (nondysplastic) was 0.06% (95% CI, 0.01%-0.10%), in long-segment BE 0.31% (95% CI, 0.21%-0.40%).17 Similarly, a meta-analysis of 2694 patients with BE and LGD (low-grade dysplasia) found that annual incidence of HGD/EAC was 1.73% (95% CI, 0.99%-2.47%).18 The progression of BE to HGD/EAC is critical and risk stratification tools have been developed. In a study involving 4584 patients with BE in the US and Europe, Progression in Barrett Esophagus (PIB) score was developed.19 This scoring system (composed of 30-point score, validated externally) combines data from age, sex, tobacco smoking history, BE segment length and presence of any LGD. An annual progression risk is determined based on score, 0.13% (score: 0-10), 0.73% (score: 11-20), 2.1% (score: 21-40).

Prevention

Given that GERD is a risk factor for development and progression of BE to EAC, acid exposure elimination remains an important strategy for prevention. Aspirin (given its anti-inflammatory properties) have been used as a chemo preventative agent against multiple cancer including progression of BE to EAC. This combined with a proton pump inhibitor (PPI) could potentially reduce the progression of BE. To evaluate this, a large, randomized trial published (ASPECT trial) in Lancet20 was conducted in the UK and Canada (84 centers, 2557 participants). Four groups: high-dose PPI with aspirin group, low dose PPI with aspirin group, twice-daily PPI group and daily PPI group. At 9 year follow up, the first group (high-dose PPI with aspirin) had overall reduced rates of a combination of: EAC, all-cause mortality and HGD without significant adverse events. High-dose PPI added the highest beneficial effect and combination with aspirin added another 38% benefit to the time to an event.20 Health et al.21 studied Celecoxib (n= 49, 200 mg twice daily) vs. placebo (n = 51) to evaluate for change in dysplasia progression and found no difference at 4-year follow-up (-0.08% vs. -0.06%). Despite this benefit, given the risk of non-fatal, fatal bleeding events22 and cerebrovascular events, the American College of Gastroenterology (ACG) and American Gastroenterological Association (AGA) recommend against routine use of aspirin and/or nonsteroidal anti-inflammatory drugs for chemoprevention of BE.

Surveillance of BE

Management of BE includes surveillance endoscopy and treatment interventions (endoscopic resection and ablation). Surveillance refers to assessment for progression of EAC with an established diagnosis of BE in the past. The intervals for surveillance is dependent on the length of the BE segment. Major gastrointestinal societies recommend a 5-year surveillance for short segment (<3 cm) compared to 3-year surveillance for long segment (> 3 cm). Endoscopy image technology and pixel improvement resulted in high-definition white light endoscopy (HD-WLE) and chromoendoscopy (electronic or dye-based [acetic acid]). Acetic acid chromoendoscopy meets the Preservation and Incorporation of Valuable Innovations (PIVI) thresholds. A meta-analysis of 24 studies (2304 patients) with BE patients showed a sensitivity of 97% (95% CI, 95%-98%), negative predictive value (NPV, 98%, CI, 95%99%) and specificity of 85% (95% CI, 69%-93%) for acetic acid chromoendoscopy.23 Additionally, American Society of Gastrointestinal Endoscopy (ASGE) recommended chromoendoscopy in addition to WLE for biopsy specimens. In a meta-analysis including 12 randomized trials and 2433 BE patients, a 9% (95% CI, 4.1%-14%) increase in dysplasia detection was noted with chromoendoscopy compared to WLE.23

Endoscopic Resection

The initial step in endoscopic therapy includes either mucosal or submucosal resection. Prior to these advances, many of these esophageal lesions were treated surgically. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are most commonly performed procedures when lesions are restricted to mucosa and superficial third of the submucosa respectively. EMR and ESD are both highly effective with ESD achieving a higher R0 resection at the expense of time and higher adverse events. Further, prior endoscopic therapy (mucosal resection or ablation) can lead to submucosal fibrosis which can make further endoscopic therapy challenging. In these cases, ESD could offer definitive treatment. Band mucosectomy is the most commonly performed EMR technique which could assist with resection for margin free removal. This technique involves evaluation of abnormal mucosal tissue and followed by targeted resection of visibly abnormal area. The resected area is assessed histologically for the depth and lateral margins for R0 resection. For welldifferentiated lesion restricted to mucosa, without submucosal or lymphovascular involvement, EMR could be considered curative. ESD is a technique characterized by dissecting lesions in the submucosa with ability to remove entire lesions with varying length and depth. Given the ability to target a wider area, it could theoretically lead to higher R0 resections. In a small randomized controlled trial of BE patients24 with focal area of HGD or early EAC < 3 cm undergoing either ESD (20 patients) or EMR (20 patients), R0 (margin free of HGD/EAC) resection rates were higher in ESD compared to EMR (10/17 vs. 2/17, P = 0.01), but no difference was noted in neoplasia remission, recurrence or need for surgery.24 Further, ESD was associated with longer procedure times with a mean ESD time of 83.3 minutes compared to EMR of 36.7 minutes limiting its generalizability.24

Ablation Therapies

Endoscopic ablative therapy with heat (radiofrequency ablation [RFA], argon plasma photocoagulation [APC]) or cold (cryotherapy) have been used for BE patients with HGD or visible neoplastic lesions after resection.12 RFA remains the most studied and established method of ablation for neoplastic BE and HGD.25 RFA could be used after resection (EMR/ ESD) or without resection for absolutely flat HGD. A systematic review of 20 cohort studies (9 studies with RFA post resection and 11 studies with only RFA) noted complete eradication of neoplasia (CE-N) in 93.4% (for RFA post resection) and 94.9% for RFA only groups.26 Complete eradication of intestinal metaplasia (CE-IM) was 73.1% for RFA post resection compared to 79.6% in RFA only group.26 Rates of recurrence were 1.4% (EAC), 2.6% (dysplasia) and 16.1% (IM) for RFA post resection. For RFA only group, recurrence rates were 0.7% (EAC), 3.3% (dysplasia) and 12.1% (IM). Adverse events associated with RFA were post treatment stricture formation, bleeding and perforation. The risk of adverse events with RFA have been studied in a systemic review and meta-analysis of 9200 patients in 7 studies with rates significantly higher in RFA with resection (EMR) compared to RFA without resection (22.2% vs. 5%; relative risk, 4.4; P = .015).27 For every 1-cm increase in the median BE length, there was a 25% (95% CI, 16-35%) increase in adverse events.27 Nevertheless, mucosal resection (to remove the neoplastic BE) followed by RFA remains the standard of care for patients to achieve eradication of IM. Cryoablation involves the application of a cryogen such as liquid nitrogen spray or nitrous oxide via flexible catheter to achieve a temperature as low as __196 0C. These extremely low temperatures cause ice crystallization and destruction of plasma cell membranes and denature the proteins. The tissue architecture and extracellular matrix (which are cryoresistant) are preserved reducing the underlying risk of tissue scaring, post-procedure pain and stricture formation. A multicentric nonrandomized and noncontrolled clinical trial of 120 patients using nitrous oxide cryoballoon focal ablation system achieved eradication of IM in 91% and dysplasia in 97%.28 Post-procedure pain was well tolerated with a score of 2 which was considered mild (visual analog score of 0 [no pain] to 10 [most severe pain]) which resolved within 2 days. Some reported adverse events included post-procedure chest pain, stricture formation, bleeding and perforation.29 Hybrid- Argon plasma coagulation (APC) uses injection therapy followed by heat for achieving eradication of metaplasia in BE. A randomized pilot study of 65 patients with BE showed that APC compared to RFA achieved ablation in BE patients in 55.8% vs. 48.3% (OR, 1.4 [95% CI, 0.5-3.6]) with comparable adverse events and quality of life scores.

Approach to Neoplastic BE

Endoscopic therapy remains first-line of treatment for high-grade dysplasia and early EAC (T1a and superficial T1b) lesions. In LGD, the risk of progression to EAC should determine the intensity of treatment versus surveillance. Given the variable risk of LGD patients progressing to EAC (0.02%11.4%), shared decision making based on the patient preferences, risk factors and annual progression risk could be considered. Surgical options (esophagectomy) could be considered for HGD or early EAC, however are associated with higher adverse events compared to endoscopic therapy. A systematic review of 870 patients (510 undergoing endoscopic therapy and 360 undergoing surgical esophagectomy) in 7 studies30 showed no difference in rates of CE of dysplasia (314/334 in endoscopy arm vs. 237/241 in surgical esophagectomy arm, relative risk, 0.86 [95% CI; 0.91-1.01]). Survival rates and mortality did not differ between groups at 1 year and 5 years. However, adverse events (stricture formation, bleeding, perforation) were significantly lower in endoscopic therapy (66/510) compared to esophagectomy (90/360, relative risk, 0.38; 95% CI, 0.20-0.73; P = .004).30 For lesions extending to superficial submucosa (early T1b), a multidisciplinary team approach is needed to assess the candidacy for ESD. Patients with lowrisk lesion (good to moderate differentiation), no lymphovascular invasion, and superficial submucosal lesion (up to 500-mm invasion) could be offered ESD in high-volume center with experienced advanced endoscopist. In an observational study of 61 patients with low risk T1b lesions with ESD, eradication of dysplasia was noted in 87% of patients with maintenance of eradication in 84% over a 47 month period.31

Limitations

This review aims to provide updated information on the diagnosis, treatment and management of BE. First, due to use of practice guidelines, they could be subjected to expert opinion bias. Second, since this review did not systematically search the literature, some relevant publications may have been missed. Observational data without randomized controlled trials could decrease the strength of recommendations.

The Future

Given the high miss rate of BERN lesions, artificial intelligence (AI) could be a promising tool in identifying subtle neoplastic lesions with improved sensitivity (>90%) and specificity (>80%).13 Use of machine learning with convolutional neural networks, deep learning can assess the lesion accurately for depth and precise mucosal patterns. This combined with areas in long segment BE could improve quality, blind spot assessment, could provide feedback and report quality metrics needed to reduce the missed BERN lesions. Use of highquality BE examination with CLEAN (cleaning, learning, endoscopic [virtual], acquiring and neoplasia detection metric [NDR quality metric assessment]) could further improve our ability to identify and manage these lesions effectively. Newer treatment modalities such as radiofrequency vapor therapy can generate heat therapy (vapor at 100 °C using a RF electrode) and could be used for ablation of the dysplastic segment, the efficacy and feasibility needs to be studied in the future.32

References

  1. Norman Rupert Barrett. Lancet. Jan 27 1979;1(8109):224.
  2. Kurn H, Daly DT. Histology, Epithelial Cell. StatPearls. StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.; 2022.
  3. Giroux V, Rustgi AK. Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence. Nat Rev Cancer. Oct 2017;17(10):594-604. doi:10.1038/nrc.2017.68
  4. Sharma P. Barrett Esophagus: A Review. Jama. Aug 16 2022;328(7):663-671. doi:10.1001/jama.2022.13298
  5. Eusebi LH, Cirota GG, Zagari RM, Ford AC. Global prevalence of Barrett’s oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis. Gut. Mar 2021;70(3):456-463. doi:10.1136/gutjnl-2020-321365
  6. Kim YS, Kim N, Kim GH. Sex and Gender Differences in Gastroesophageal Reflux Disease. J Neurogastroenterol Motil. Oct 30 2016;22(4):575-588. doi:10.5056/jnm16138
  7. Abrams JA, Fields S, Lightdale CJ, Neugut AI. Racial and ethnic disparities in the prevalence of Barrett’s esophagus among patients who undergo upper endoscopy. Clin Gastroenterol Hepatol. Jan 2008;6(1):30-4. doi:10.1016/j. cgh.2007.10.006
  8. Macdonald CE, Wicks AC, Playford RJ. Ten years’ experience of screening patients with Barrett’s oesophagus in a university teaching hospital. Gut. 1997;41(3):303-307. doi:10.1136/gut.41.3.303
  9. Balasubramanian G, Gupta N, Giacchino M, et al. Cigarette smoking is a modifiable risk factor for Barrett’s oesophagus. United European Gastroenterol J. Dec 2013;1(6):430-7. doi:10.1177/2050640613504917
  10. Chak A, Faulx A, Eng C, et al. Gastroesophageal reflux symptoms in patients with adenocarcinoma of the esophagus or cardia. Cancer. Nov 1 2006;107(9):2160-6. doi:10.1002/cncr.22245
  11. Sharma P, Katzka DA, Gupta N, et al. Quality indicators for the management of Barrett’s esophagus, dysplasia, and esophageal adenocarcinoma: international consensus recommendations from the American Gastroenterological Association Symposium. Gastroenterology. Nov
    2015;149(6):1599-606. doi:10.1053/j.gastro.2015.08.007
  12. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. Mar 2011;140(3):e18-52; quiz e13. doi:10.1053/j.gastro.2011.01.031
  13. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. Dec 23 2022;doi:10.1016/j.gie.2022.10.022
  14. Gupta N, Gaddam S, Wani SB, Bansal A, Rastogi A, Sharma P. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus.
    Gastrointest Endosc. Sep 2012;76(3):531-8. doi:10.1016/j. gie.2012.04.470
  15. Desai M, Lieberman DA, Kennedy KF, et al. Increasing prevalence of high-grade dysplasia and adenocarcinoma on index endoscopy in Barrett’s esophagus over the past 2 decades: data from a multicenter U.S. consortium. Gastrointest Endosc. Feb 2019;89(2):257-263.e3. doi:10.1016/j.gie.2018.09.041
  16. Visrodia K, Singh S, Krishnamoorthi R, et al. Magnitude of Missed Esophageal Adenocarcinoma After Barrett’s Esophagus Diagnosis: A Systematic Review and Metaanalysis. Gastroenterology. Mar 2016;150(3):599-607.e7; quiz e14-5. doi:10.1053/j.gastro.2015.11.040
  17. Chandrasekar VT, Hamade N, Desai M, et al. Significantly lower annual rates of neoplastic progression in short- compared to long-segment nondysplastic Barrett’s esophagus: a systematic review and meta-analysis. Endoscopy. Jul 2019;51(7):665-672. doi:10.1055/a-0869-7960
  18. Singh S, Manickam P, Amin AV, et al. Incidence of esophageal adenocarcinoma in Barrett’s esophagus with low-grade dysplasia: a systematic review and metaanalysis. Gastrointest Endosc. Jun 2014;79(6):897-909.e4; quiz 983.e1, 983.e3. doi:10.1016/j.gie.2014.01.009
  19. Parasa S, Vennalaganti S, Gaddam S, et al. Development and Validation of a Model to Determine Risk of Progression of Barrett’s Esophagus to Neoplasia. Gastroenterology. Apr 2018;154(5):1282-1289.e2. doi:10.1053/j.gastro.2017.12.009
  20. Jankowski JAZ, de Caestecker J, Love SB, et al. Esomeprazole and aspirin in Barrett’s oesophagus (AspECT): a randomised factorial trial. Lancet. Aug 4 2018;392(10145):400-408. doi:10.1016/s0140-6736(18)31388-6
  21. Heath EI, Canto MI, Piantadosi S, et al. Secondary chemoprevention of Barrett’s esophagus with celecoxib: results of a randomized trial. J Natl Cancer Inst. Apr 4 2007;99(7):545-57. doi:10.1093/jnci/djk112
  22. Perisetti A, Goyal H, Tharian B, Inamdar S, Mehta JL. Aspirin for prevention of colorectal cancer in the elderly: friend or foe? Ann Gastroenterol. 2021;34(1):1-11. doi:10.20524/aog.2020.0556
  23. Thosani N, Abu Dayyeh BK, Sharma P, et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE Preservation and Incorporation of Valuable Endoscopic Innovations thresholds for adopting real-time imaging-assisted endoscopic targeted biopsy during endoscopic surveillance of Barrett’s esophagus. Gastrointest Endosc. Apr 2016;83(4):684-98.e7. doi:10.1016/j.gie.2016.01.007
  24. Terheggen G, Horn EM, Vieth M, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. May 2017;66(5):783-793. doi:10.1136/gutjnl-2015-310126
  25. Shaheen NJ, Falk GW, Iyer PG, Gerson LB. ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus. Am J Gastroenterol. Jan 2016;111(1):30-50; quiz 51. doi:10.1038/ajg.2015.322
  26. Desai M, Saligram S, Gupta N, et al. Efficacy and safety outcomes of multimodal endoscopic eradication therapy in Barrett’s esophagus-related neoplasia: a systematic review and pooled analysis. Gastrointest Endosc. Mar 2017;85(3):482-495.e4. doi:10.1016/j.gie.2016.09.022
  27. Qumseya BJ, Wani S, Desai M, et al. Adverse Events After Radiofrequency Ablation in Patients With Barrett’s Esophagus: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. Aug 2016;14(8):1086-1095.e6. doi:10.1016/j.cgh.2016.04.001
  28. Canto MI, Trindade AJ, Abrams J, et al. Multifocal Cryoballoon Ablation for Eradication of Barrett’s
    Esophagus-Related Neoplasia: A Prospective Multicenter Clinical Trial. Am J Gastroenterol. Nov 2020;115(11):1879-1890. doi:10.14309/ajg.0000000000000822
  29. Hu SN-Y, Adler DG. Endoscopic Cryotherapy: Indications and Efficacy. Pract Gastroenterol. 2015;39:19-45.
  30. Wu J, Pan YM, Wang TT, Gao DJ, Hu B. Endotherapy versus surgery for early neoplasia in Barrett’s esophagus: a meta-analysis. Gastrointest Endosc. Feb 2014;79(2):233-241.e2. doi:10.1016/j.gie.2013.08.005
  31. Manner H, Pech O, Heldmann Y, et al. Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion. Clin Gastroenterol Hepatol. Jun 2013;11(6):630-5; quiz e45. doi:10.1016/j.cgh.2012.12.040
  32. van Munster SN, Pouw RE, Sharma VK, Meijer SL, Weusten B, Bergman J. Radiofrequency vapor ablation for Barrett’s esophagus: feasibility, safety and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. Nov
    2021;53(11):1162-1168. doi:10.1055/a-1319-5550

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FUNDAMENTALS OF ERCP, SERIES #4

ERCP Stone Extraction: Simple

March 2023 • Volume XLVII, Issue 3
Himmat S. Brar,Amaninder S. Dhaliwal

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Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) was initially developed as a diagnostic procedure for visualizing the pancreatic and biliary ducts. However, it has evolved over the years into a predominantly therapeutic tool. The most common indication for undergoing ERCP is biliary stone disease. Choledocholithiasis refers to the presence of gallstones in the common bile duct (CBD). (Figures 1-3) Stones in the CBD can cause stasis and obstruction leading to bacterial translocation and cholangitis. The clinical presentation varies from biliary colic, cholangitis, and can also include biliary pancreatitis. Therefore, ERCP plays a vital role in managing choledocholithiasis and preventing and treating complications. ERCP is used to identify the stones often seen as a filling defect. The modalities used to identify stones are the injection of undiluted contrast, diluted contrast, and regular and occlusion cholangiograms.1 Diagnostic ERCP is commonly performed with undiluted water-soluble contrast. The initial fluoroscopic images can reveal bile duct stones that manifest as a filling defect (an area where dye cannot go), often with a “meniscus sign,” or an arc of contrast at the level of the stone. Diluted contrast can be used if the bile duct is dilated, as the undiluted contrast can mask the small stones, although in practice the use of diluted or undiluted contrast during ERCP varies widely. An occlusion cholangiogram, whereby the bile duct is filled with contrast over an inflated occlusion balloon attached to an ERCP catheter, is performed in patients with suspected intrahepatic stones or stones proximal to a stricture or to prove duct clearance after stone removal. Bile duct stones will manifest as intraluminal filling defects, but other lesions can present as filling defects as well, including air bubbles, blood clots, parasites, mucus, tumors and neoplasms of the duct, and other etiologies. The patient’s clinical picture should be considered to make a definitive diagnosis.

Of utmost importance for stone extraction is for the operator to properly gauge the size of the exit passage. The size of the stone should be measured relative to the size of any intended or performed biliary sphincterotomy and the diameter of the bile duct. The sphincterotomy site should be adequate to allow for the stone to pass. Different methods can be used to measure the size of the ampullary orifice. One of the methods is by pulling a stone extraction balloon, inflated to the approximate size of the stone, through the sphincterotomy and the distal bile duct. The stone extraction should, in theory, be easily accomplished if the balloon passes easily and without resistance or deformation. However, stone extraction may prove to be difficult if there is resistance during the passage or the balloon becomes deformed during its transit through the distal CBD and the ampullary orifice-this suggests that the sphincterotomy itself may be inadequate and may need to be extended or completed. Another way of measuring sphincterotomy size is by pulling a fully bowed sphincterotome through the papilla. A bowed sphincterotome should be able to pass easily through the sphincterotomy, and with no resistance. If the sphincterotomy size is deemed inadequate even after what is felt to be a complete sphincterotomy has been performed, additional therapies such as balloon dilatation of the sphincterotomy and distal bile duct may be required for stone extraction.2

Balloon dilation of the bile duct itself is occasionally needed in patients harboring benign biliary strictures when the stone is proximal to the stricture or cases of intrahepatic stones. Biliary dilation balloons are used for dilation. These are low-profile balloons ranging from 4 to 10 mm in diameter and 2 to 4 cm in length that can be inflated to a single, fixed diameter (unlike esophageal dilation balloons, for example, which can often be inflated to several distinct sizes). Biliary dilation balloons can be placed over a guidewire across the biliary stricture in question and inflated using saline or dye to achieve effacement of the underlying stricture. A radio-opaque marker (or markers, depending on the vendor) placed at the end and/or in the middle of the balloon helps with proper positioning of the balloon across the stricture. The choice of balloon size is based upon the diameter of the bile duct. The balloon is visualized under fluoroscopy during inflation to provide an additional margin of safety. The disappearance of the waist (full effacement) during inflation would determine the effectiveness of the dilation and typically demonstrates if the dilation was successful. If there is distortion during inflation, it would suggest inadequate dilation or a recalcitrant stricture. Additional therapies, including stone fragmentation, may be warranted before attempting stone removal when the calculus itself is located above an incompletely dilated stricture. Alternatively, indwelling stents can be placed to allow biliary decompression, avoid cholangitis, and to prevent other complications until the stricture is adequately treated.3

Indications

(i) Common bile duct stones (ii) Intrahepatic duct stones

Contraindications

  • Medical conditions preventing the use of sedation in the patient
  • Anatomical – Gastric outlet obstruction that prevents the access to major papilla

Patient Preparation

Patients undergoing ERCP should be evaluated for their general fitness for the procedure itself as well as the sedation required to perform the procedure. In the United States, most ERCP procedures are performed under General Anesthesia or Monitored Anesthesia Care. Endotracheal intubation is preferred in patients with sepsis with unstable hemodynamics.4 Most patients can safely undergo ERCP, including young and old patients, cirrhotic and non-cirrhotic patients, children, and pregnant patients, depending on the circumstance.5

Positioning

There are several position options for patients undergoing ERCP: prone, supine, left lateral decubitus, or oblique. The positioning is determined by operator experience and preference as well as patient-related factors such as body habitus, neck mobility, or the presence of abdominal drains. The other factors that play a role in choice of patient position are anesthesia and airway considerations. The left lateral and oblique positions are sufficient for cases involving extrahepatic bile duct but can be less than ideal inadequate for patients requiring pancreatic duct or intrahepatic duct imaging.6 In these cases, either a prone or supine position is preferred. There have been studies that have compared prone and supine positioning during ERCP. A large randomized controlled trial at a tertiary center found no difference in cannulation rate or adverse events between the prone and supine groups, irrespective of operator skill.7 In addition, a retrospective study was performed with 649 patients undergoing ERCP: prone (n = 506) and supine (n = 143) with a mix of moderate and generalized anesthesia administered. The study found no difference between cannulation rate or adverse events between the prone and supine groups.8 In general, ERCP is usually performed in the prone position in the United States.

Antithrombotics

Many patients who need to undergo ERCP require antithrombotic or anticoagulant medications to treat other underlying illnesses, and practitioners of ERCP often must make decisions regarding if and when to stop and restart these medications so that the procedure can be performed. The decision to proceed with ERCP and whether to start or stop antithrombotic agents should be, in general, individualized and based on clinical urgency, the bleeding risk of the specific ERCP that needs to be completed, and the cardiovascular risk of holding the antithrombotics. For example, the active use of anticoagulants should not defer an ERCP procedure in cases of sepsis that require urgent ERCP i.e., a decompressive biliary stent can be quickly and safely placed in a patient on any anticoagulant and with any international normalized ratio (INR). This approach can save time in a critically ill patient but leaves for a later day the decision on how to manage anticoagulants so that the offending stone can be safely removed. One study has shown a threefold increase in organ failure in patients with cholangitis who waited for ERCP for > 48 hrs, further arguing for early intervention.9

Endoscopic sphincterotomy (ES), which is nearly universally practiced to facilitate the removal of bile duct stones in the United States, always carries a risk of causing acute or delayed bleeding, although the absolute risk of bleeding is low. Endoscopic papillary balloon dilatation (EPBD) without ES is a low-risk bleeding procedure, but carries an increased risk of causing pancreatitis, which can be severe. In non-urgent cases, antithrombotics and anticoagulants can be held prior to performing ES, whereas they can be continued in patients undergoing EPBD. In urgent cases, a plastic biliary stent can be placed for drainage without the need for ES to decrease the risk of bleeding. For patients with low cardiovascular risk who require ES, anticoagulation can frequently be held, whereas “bridging” with heparin can be considered in higher cardiovascular risk patients, although in practice bridging is rarely performed.

The 2016 ASGE guideline on the role of blood thinners in endoscopy provides a thorough review of this topic.10 The key concern generally involves weighing the risk of bleeding against the risk of a thromboembolic event. The primary risk factor for bleeding during ERCP is endoscopic sphincterotomy.11 Therefore, it is unnecessary to discontinue antithrombotics if ERCP without ES is planned.

Antibiotics

The guidelines recommend using preprocedural antibiotics for immunocompromised patients, liver transplant patients, cholangitis and patients with biliary obstruction in whom incomplete drainage is anticipated (multiple stones or complex strictures).12 The use of pre- and/or post-procedural antibiotics has shown lower rates of post-ERCP cholangitis in cases of biliary obstruction without cholangitis and anticipating complete drainage after ERCP.13 In many centers antibiotic prophylaxis is widely used for patients undergoing ERCP regardless of indication given the low cost and significant potential benefits.

Stone Extraction: Devices and Techniques

The choice of stone extraction device depends upon the number, size, and type of stones and the structure of the bile duct relative to the stone(s). The size of the stone and duct diameter can be estimated by comparing to the width of the duodenoscope, which is generally around 12mm.

ERCP Guidewires

Guidewires are the mainstay of ERCP. They are critical for duct cannulation, maintaining access to a desired duct, exchanging devices, guiding devices, dilating strictures, and placing stents; all of these maneuvers are employed during stone extraction cases. There are a variety of guidewires that are commercially available, and these differ widely in terms of materials, length, diameter, mechanical properties, and design.14

Broadly speaking, there are three general classes of guidewires available for ERCP: (1) Monofilament wires with stainless steel cores that are designed for rigidity. (2) Coiled wires are made of inner monofilament core and outer spiral core of stainless steel. The inner core provides stiffness, and the outer core provides flexibility. (3) Coated or sheathed wires made of stainless steel or nitinol monofilament cores with an outer sheath of Teflon, polyurethane, or other materials. Guidewires are advanced into the desired duct through a sphincterotome or a balloon catheter under endoscopic and fluoroscopic guidance. Most wires come with external markers of some type printed on their outer coatings to illustrate movement and measure depth of entry. Guidewire locking devices, that fit externally onto a duodenoscope, can be used to fix the proximal end of the guidewire (outside the patient) and reduce the risk of wire dislodgement.15 A summary of currently available guidewire types is listed in Table 1.

Sphincterotomy – Devices and Techniques

Biliary Sphincterotomy

Endoscopic sphincterotomy (ES) of the biliary sphincter is indicated for many biliary interventions and is critical for stone extraction. The sphincterotome itself helps in achieving deep bile duct cannulation and is then used to perform the sphincterotomy itself. Advantages of using sphincterotomes include the following: 1. When it is anticipated that a sphincterotomy will be needed, exchange to a sphincterotome from a straight biliary catheter is avoided. 2. A sphincterotome allows for the variable deflection of the catheter tip to facilitate biliary access during cannulation. Studies have shown a higher cannulation rate with sphincterotomes than with standard straight biliary catheters, with no difference in adverse effects.16,17 A recent meta-analysis showed an increased cannulation rate and decreased risk of post-ERCP pancreatitis for guidewire-assisted cannulation compared with contrast-assisted cannulation, both of which are generally performed with sphincterotomes in the modern era.18,19

Sphincterotomes (Figure 4) vary in the diameter and length of the tip, size, characteristics of the cutting wire, and shaft stiffness.20 Tapered devices can be easily inserted into the papilla but also come with a potentially higher incidence of tissue trauma when compared to blunt tip devices. Modern sphincterotomes are considered to be “triple lumen devices” with one channel for contrast injection, one for guidewire access, and the third lumen in the catheter being the one that contains the cutting wire itself. As such, most sphincterotomes have a lumen for the guidewire and an integrated hub for contrast injection, thus allowing contrast injection without guidewire removal (as was required in the past with so called “double lumen devices”).

Sphincterotomy Procedure for Biliary Stone Extraction

The papilla is approached with the sphincterotome from a distance so that the pre-curved distal part can be seen exiting the endoscope. The tip of the sphincterotome is inserted into the papillary opening, and the device is maintained by the short, straight position of the duodenoscope. The subsequent bowing of the tip allows the insertion into the common bile duct opening. The S-shaped distal part of the common bile duct is overcome by straightening the tip and gently withdrawing the endoscope. The guidewire is passed into the bile duct under endoscopy and fluoroscopy guidance without contrast injection. A soft hydrophilic guidewire is preferred to reduce the risk of ductal injury. The unbowed sphincterotome can then be advanced to attain deep cannulation. The guidewire is then moved into the proximal biliary system to secure ductal access for maneuvers and the exchange of accessories.

Precut Sphincterotomy for Biliary Cannulation

Selective biliary cannulation (SBC) is the mainstay of therapeutic ERCP.21 Despite significant advancements in imaging techniques and newer designs of guidewires and sphincterotomes, the success rate for biliary cannulation has been around 85% using standard cannulation techniques for average providers.22 Precut sphincterotomy, which refers to cutting into the ampulla before deep biliary access has been obtained, is performed when biliary cannulation is not attained using standard techniques. Difficult SBC has been defined variously but can be considered to apply when the cannulation requires ≥10 attempts and/or takes more than 10 minutes to achieve cannulation.23 Precut sphincterotomy increases the cannulation rate to approximately 98%.24 A ‘precut’ is defined as an incision made into the CBD or the ampulla of Vater before attaining SBC during ERCP.25

Endoscopic Papillary Balloon Dilatation

Endoscopic papillary balloon dilatation (Figure 5) is used to facilitate stone extraction with or without preceding endoscopic sphincterotomy. This technique is specifically helpful in achieving adequate opening (i.e., exit passage) to allow retrieval of stones, in cases of complicated anatomy (e.g., diverticulum), in cases of prior failed stone extraction, and in circumstances that prohibit sphincterotomy (e.g., coagulopathy) or extension of sphincterotomy. The dilation balloons (< 10 mm) include the Fusion dilation balloon (Cook Endoscopy, Winston Salem NC) and the Hurricane balloon (Boston Scientific, Natick MA). The balloon should not be dilated greater than the diameter of the proximal bile duct to avoid perforation. In addition, the dilation should be performed slowly and under fluoroscopy to evaluate for the disappearance of the “waist.” The balloon should be kept dilated for about 30 to 60 seconds after the disappearance of the waist according to some, but no hard and fast guidelines exist. However, a longer duration should be considered, as this may reduce the risk of pancreatitis (mainly when sphincterotomy is not performed). Balloon dilation with endoscopic sphincterotomy has comparable outcomes in terms of stone clearance. However, there is an advantage of overall lower risk of adverse events and pancreatitis than sphincterotomy alone.26

Balloon Extraction

Stone extraction balloons are available in multiple sizes. The size varies from 8 to 20 mm depending upon the amount of air in the balloon. The exit site is gauged by inflating the balloon to the maximum diameter of the bile duct below the stone and pulled out to check for resistance or change in the diameter or any significant deformity of the balloon under the fluoroscopy. The shape can be distorted and become “sausage-shaped” in cases of chronic pancreatitis due to inflammation. Triple lumen catheters allow the catheter to pass over the guidewire. This provides an advantage as it maintains access to the biliary system while allowing for the injection of the contrast. The disadvantage is that the triple-lumen balloon shafts are stiffer than the double-lumen shafts. Prior to introducing the balloon catheter into the endoscope, the tip of the catheter should be slightly bent or curved to allow for easier cannulation of the bile duct. (Figures 6-10) The catheter is passed into the bile duct, and the images are obtained under fluoroscopy. The catheter is passed proximal to the stone, and the balloon is inflated. It is gently pulled back until the stone reaches the level of the papilla. Once at the papilla, the axis of traction is adjusted by aligning the scope with the axis of the bile duct. This has a mechanical advantage and also reduces damage to the duct. The tip of the endoscope is angled upwards against the sphincterotomy. While continuing the slow pulling of the catheter, the scope is angled downward, leading to the expulsion of the stone from the ampulla. If the removal of the stone is unsuccessful at the first attempt, the scope should be angled upward, and gentle traction should be applied along with the repetition of a similar downward movement of the scope. It is necessary to maintain the traction as the stone is getting expelled from the bile duct. More traction can be applied if required by bending the scope downward and rotating it to the right to expel the stone.

Occasionally, the inflated balloon can also cause resistance, and it is essential to deflate the balloon to the size of the bile duct or the sphincterotomy. This can be done by adjusting the flow inside the balloon by the stopcock. In the case of multiple stones, the most distal stones are removed first and then the proximal ones. This will avoid the impaction of the stone or rupturing of the balloon. The balloon should be adjusted according to the size of the bile duct. The other thing to be careful about is not to dislodge the wire. The balloon goes over the wire, and excessive movement can dislodge the wire. The balloon should be pulled gently, and excessive movement should be avoided to prevent dislodgement of the wire. However, if the guidewire access is lost, the balloon should be withdrawn, and the bile duct should be recannulated with the guidewire. There are multiple advantages (Table 2) and disadvantages (Table 3) of using the stone extraction balloon. 

Basket Extraction

Wire baskets are commonly used for stone extraction. The baskets are available in different shapes and sizes and allow stone extraction for sizes ranging from 5 mm to 3 cm. A variety of baskets currently available (Table 4) are listed with their characteristics, advantages and disadvantages. However, stones that are larger than 2 cm require fragmentation before extraction. The most commonly used basket is the four-wire Dormia basket. It is made of braided steel and is hexagonal in shape. The stone is captured between the basket wires when it is closed. The stone is then removed by continuous gentle traction during basket withdrawal.27 Smaller stones are difficult to capture due to the large spacing between the wires. Newer baskets with a modified design help in capturing smaller stones. So called “flower baskets” are divided into eight wires, with narrow space between the wires, allowing for better engagement of smaller stones. The eight-wired basket allows for better engagement of small stones than the four-wired basket. There are spiral baskets that are used for relatively small stones. The wires wind closely around the stone when the basket is opened. These spiral baskets are not designed for mechanical lithotripsy. The baskets for lithotripsy have stronger wires and metal sheets that provide support to crush the stone. The tension can be applied manually or using a crank handle to crush the stones. Dilute contrast is injected during the procedure, and the images are obtained to outline the stones in the bile duct. Care should be taken to avoid injecting excessive contrast due to the risk of displacing the stones proximally into the intrahepatic ducts or interfering with proper visualization. The singlelumen basket allows for the free flow of dilute contrast when it is opened. A double-lumen basket has different channels for injection of contrast and passage of a guidewire. The basket can also be advanced over an already positioned guidewire. This is mainly useful for removing stones in the intrahepatic duct or those that could have migrated to the intrahepatic ducts. The traditional guidewires run through the entire length of the basket catheter. Modern baskets are typically designed for shortwire systems. These involve only a part of the basket going over the guidewire. The wire is locked in position, and then the manipulation is done. A newer modification is the “ropeway” basket. It is a single lumen system and has a catheter attached to the tip of the basket, which allows only the tip (instead of the shaft) of the basket to go over the wire. The contrast is injected, and images are obtained to specify the location of the stone. (Figure 11) The stone can also be visualized on the cholangiogram. The basket in a closed position is inserted into the bile duct and is advanced proximal to the stone. Once the basket is in the duct, it is opened slowly above the stone. An alternative is to go all the way to the intrahepatic duct and then open the basket and pull back gently to capture the stone. Caution should be taken to avoid opening the basket below the stone as this can push the stone proximally into the intrahepatic duct, thus making extraction difficult. The basket is pulled back and manipulated along the stone to engage it. Once the stone is captured, the basket is partially closed to avoid losing the stone. The endoscope is pushed further into the duodenum to help align the basket’s axis with the bile duct. Continuous gentle traction is applied to the basket catheter until it reaches the distal bile duct or the level of sphincterotomy. The endoscope tip is angled upward to the sphincterotomy, and the traction is applied. Once the stone is at the papilla, the tip of the scope is turned down, and traction is applied to remove the stone. If the stone is not extracted, the same motion can be repeated with the steady traction of the basket. Furthermore, the scope tip should be turned down and rotated to the right once it has reached the tip, helping to extract the stone out of the bile duct. The basket is closed gently during extraction instead of the fully open basket. The closed basket allows all the wires to come together, and the overall force is transmitted along with the wire basket and along the distal bile duct. However, if the basket is withdrawn in a fully opened position, the loose wires tend to cut across the sphincterotomy rather than the axis of the common bile duct. This leads to bruising and submucosal tissue damage. In addition, caution should be taken to avoid closing the basket tightly around the stone. This can lead to embedding the wires to the stone’s surface, resulting in the impaction of the stone, especially in cases of large stones. In some instances, the wires cannot be freed from the stone, thus leading to the impaction of the basket. Another technique that can be applied to capture stones in a dilated bile duct is an aspiration. The basket is opened above the bile duct, and the aspiration of the contrast or bile is done as the basket is withdrawn. This creates a negative suction force and helps trap the stones within the basket wires. The same technique can be applied to smaller stones that are difficult to capture. The basket can be placed at the level of the papilla to keep the open sphincter. Suction is applied from the duodenum that helps in the movement and capturing of the stones in the basket. This can also be used for small stones in the hepatic duct. The basket can be placed at the bifurcation of the duct, and the suction is applied. This leads the stones to descend in the hepatic duct and into the basket placed in the bile duct, from where the stones are eventually removed. There are numerous advantages of the extraction basket. These include more effective traction and help remove medium to large stones.

However, there are some disadvantages of extraction baskets. Smaller stones or fragments are difficult to engage in the wires. The stones in the intrahepatic ducts may be difficult to capture because of the narrow diameter and less flexibility of the capture baskets. There is also a constraint in opening the basket in the narrow intrahepatic ducts. Thus, in these scenarios, extraction balloons are perhaps a better choice. The recent trials comparing the extraction balloons to extraction baskets have favored balloons for smaller (10 to 11 mm) stones.28,29 However, the choice for smaller stone removal depends upon personal preference.

Comparing Balloon and Basket Extraction

Basket and balloon catheters are used for stone extraction. Nearly 85-90% of stones are easily retrieved by these methods following endoscopic sphincterotomy (EST), whereas difficulty is encountered in 10-15% of cases. The balloon catheter can capture small stones by obstructing the lumen. However, it cannot prevent small stones from slipping and impaction in the corner pocket at the distal third of the bile duct during stone extraction. Thus, the basket catheter has a better traction power than the balloon catheter.30

The European guidelines recommend using either technique as there is minimal difference between overall outcomes with basket or balloon catheters. However, the American guidelines recommend balloon catheters over baskets due to the risk of adverse effects related to basket impaction.31,32

Ishiwatari et al. performed a randomized control trial in Japan that primarily investigated the clearance rates between the basket or balloon catheters.33 The complete clearance rates were 92.3% (72/78) in the balloon group and 80.0% (64/80) in the basket group. The difference in the rates between the two groups was 12.3 percentage points, indicating noninferiority of the balloon method (noninferiority limit −10%; P< 0.001 for noninferiority).

Ozawa et al. conducted another randomized control trial in Japan.34 It was designed as a noninferiority study and compared basket extraction with balloon extraction. The study involved 184 patients over six institutions with bile duct stones < 11 mm in diameter. The primary aim of the study was the rate of complete stone extraction within 10 minutes. The rate of successful extraction within 10 minutes was 81.3% (74/91) in the basket group and 83.9% (78/93) in the balloon group (p = 0.7000). The complication rate was 6.6% in the basket group as compared to 11.8% in the balloon group (p = 0.3092). The complications included bleeding, pancreatitis, and cholangitis.

Ekmektzoglou et al. reported a randomized control trial from Greece.35 It was a noninferiority study with 180 patients randomized into balloon and basket groups. The study primarily looked at the complete bile duct clearance rate with each method. 69 out of 82 patients (84.1%) achieved complete clearance in the basket catheter group compared to 79 out of 84 patients (94%) in the balloon catheter group (p = 0.047). The time required for clearance was shorter in the balloon group than the basket group. The study concluded that the balloon extraction was noninferior to basket stone extraction (OR 3.35, 95% CI [1.12, 10.05], P = 0.031). Takeshita et al. conducted a retrospective cohort study that primarily investigated the rates of post-ERCP pancreatitis.36 244 cases were divided into the group that used a retrieval balloon as the first choice (n =107) and a group that used a basket catheter as the first choice (n = 137). The groups were further subdivided into one device group and a multiple-device group. 104 cases achieved complete stone removal by only using a balloon, and 88 cases had complete stone removal by only using a basket catheter. 5/104 had pancreatitis in the balloon only group compared with 3/88 in the basket only group (4.8% vs. 3.4%; P = 0.73). The sub-analysis revealed that the use of additional extraction balloon was significantly higher than that of a basket catheter, suggesting that the complete stone retrieval rate using a single device was higher with an extraction balloon than the basket catheters. The study concluded that the choice of the device did not affect PEP occurrence. Gbreel et al. conducted a meta-analysis comparing balloon extraction and basket extraction.37 The primary outcomes were divided into efficacy, including time to complete clearance, complete clearance, and clearance according to the number of stones. The secondary outcomes included pancreatitis, bleeding, perforation, and cholangitis. The analysis comprised 728 patients over four studies. The results revealed that the balloon catheter was better than the basket catheter in terms of incomplete bile duct clearance (RR = 0.91, 95% CI [0.85, 0.98], P = 0.01). It also found that the balloon catheter was better than basket for clearance of less than four stones (RR = 0.91, 95% CI [0.85, 0.99], P = 0.02) with no significant difference noted for more than four stones (RR = 0.77, 95% CI [0.48, 1.24], P = 0.29). The analysis concluded that a balloon catheter is better than a basket catheter for complete clearance with no significant difference in safety outcomes. A summary of all the included studies is shown in Table 5.

Adverse Effects

Extraction Balloons

Multiple adverse events can happen when using the extraction balloons. The most common is balloon rupture if pushed hard against the stone, although this is unlikely to cause actual patient injury. The other common complication is the impaction of the stone. The inflated balloon can get deformed alongside the stone and can slip out, leaving the stone impacted at the lower end of the common bile duct or the level of the papilla. The stone should be pushed proximally using accessories like forceps or the balloon itself to free the impacted stone. Alternatively, the sphincterotome can be used to extend the sphincterotomy, potentially liberating the stone. Another method is to use the needle knife to cut the bulging portion in the duodenum to free the stone from the bile duct. However, the balloon can be used if the stone is impacted at the distal bile duct but not the papilla. The inflated balloon is placed below the impacted stone, and the contrast is injected under pressure to push the stone proximally. Once the stone is freed, other therapies can be pursued to help in extraction. If the stone cannot be liberated, stenting should be done to provide adequate bile drainage to prevent cholangitis. The indwelling guidewire can be used to operate the balloon to maintain biliary access in case of failed extraction to ensure adequate drainage.

Extraction Basket

The most common adverse event while using the extraction basket is the migration of stones into the intrahepatic ducts. The stones in the bile duct can migrate proximally into the intrahepatic ducts. Therefore, capturing the stone from the intrahepatic duct can be challenging. Once this happens, balloon extraction should be used instead. A guidewire is used, and the required segment is cannulated. The wire is advanced into the intrahepatic duct, and the balloon is advanced over it. The balloon is then inflated proximal to the stone and pulled gently to bring the stone into the common hepatic duct or bile duct.

Further attempts can be made by balloon extraction or basket extraction to remove the stone. Although the basket can be used over the guidewire, the manipulation is difficult within the bile duct because of the basket’s stiffness and narrow diameter of the bile duct. In cases where it is difficult to extract the stone from the basket, care should be taken to avoid impaction. In this scenario, the basket is advanced proximally into the bifurcation zone of the duct and opened to free the stone as the wires open up. Once the stone is disengaged from the basket, the basket is closed gently and pulled back to avoid engaging the stone again. Once it is closed, it can be pulled out. However, the stone extraction would need further intervention with balloon extraction or lithotripsy.

The other complication of the basket extraction is the impaction of the stone in the bile duct or at the level of the papilla. This could occur due to large size of the stone, small exit passage (inadequate sphincterotomy), or inability to enlarge the sphincterotomy. In rare cases, the stone and basket impaction can happen at the level of the head of the pancreas. This occurs because of the narrow distal common duct. This would need emergent intervention involving lithotripsy to prevent complications. Emergent mechanical lithotripsy may be done using Soehendra lithotripter to either crush the stone or break the wires of the basket to allow its release.

Conclusion

Bile duct stones should be removed, even if asymptomatic, due to the high risk of obstruction, cholangitis, and pancreatitis. The biliary system is accessed via the sphincterotomy and sphincteroplasty. Basket and balloon catheters help remove most stones up to 1.5 cm in diameter. The use of guidance wire allows for proper access to the intrahepatic system, thus facilitating the removal of intrahepatic stones or migrated stones. Stones above a biliary stricture require balloon dilation of the stricture before successful removal. Mechanical lithotripsy is employed to break large stones and stones above a stricture to facilitate removal.

References

  1. ASGE Standards of Practice Committee, Chandrasekhara V, Khashab MA, et al. Adverse events associated with ERCP. GastrointestEndosc2017;85:32.
  2. Coelho-Prabhu N, Shah ND, Van Houten H, et al. Endoscopic retrograde cholangiopancreatography: utilisation and outcomes in a 10-year population-based cohort. BMJ Open 2013;3.
  3. ASGE Standards of Practice Committee, Early DS, BenMenachem T, et al. Appropriate use of GI endoscopy. GastrointestEndosc2012;75:1127.
  4. John C.T. Wong, James Y.W. Lau and Joseph J.Y. Sung. Choledocholithiasis. ERCP, 46, 441-448.e2
  5. Vandervoort J, Soetikno RM, Tham TC, et. al.: Risk factors for complications after performance of ERCP. GastrointestEndosc 2002; 56: pp. 652-656.
  6. Park TY, Choi SH, Yang YJ, et al. The efficacy and safety of the left lateral position for endoscopic retrograde cholangiopancreatography. Saudi J Gastroenterol 2017;23:296.
  7. Tringali A, Mutignani M, Milano A, et. al.: No difference between supine and prone position for ERCP in conscious sedated patients: a prospective randomized study. Endoscopy 2008; 40: pp. 93-97.
  8. Ferreira LE, Baron TH: Comparison of safety and efficacy of ERCP performed with the patient in supine and prone positions. GastrointestEndosc 2008; 67: pp. 1037-1043.
  9. Lee F, Ohanian E, Rheem J, et. al.: Delayed endoscopic retrograde cholangiopancreatography is associated with persistent organ failure in hospitalised patients with acute cholangitis. Aliment PharmacolTher 2015; 42: pp. 212-220.
  10. Acosta RD, Abraham NS, Chandrasekhara V, et. al.: The management of antithrombotic agents for patients undergoing GI endoscopy. GastrointestEndosc 2016; 83: pp. 3-16.
  11. Vandervoort J, Soetikno RM, Tham TC, et. al.: Risk factors for complications after performance of ERCP. GastrointestEndosc 2002; 56: pp. 652-656.
  12. Cotton PB, Connor P, Rawls E, et. al.: Infection after ERCP, and antibiotic prophylaxis: a sequential quality-improvement approach over 11 years. GastrointestEndosc 2008; 67: pp. 471-475.
  13. Niederau C, Pohlmann U, Lübke H, et. al.: Prophylactic antibiotic treatment in therapeutic or complicated diagnostic ERCP: results of a randomized controlled clinical study. GastrointestEndosc 1994; 40: pp. 533-537.
  14. American Society of Gastrointestinal Endoscopy (ASGE) : Guidewires for use in GI endoscopy. GastrointestEndosc 2007; 65:pp. 571-576.
  15. American Society of Gastrointestinal Endoscopy (ASGE) : Guidewires for use in GI endoscopy. GastrointestEndosc 2007; 65: pp. 571-576.
  16. Schwacha H, Allgaier HP, Deibert P, et. al.: A sphincterotome-based technique for selective transpapillary common bile duct cannulation. GastrointestEndosc 2000; 52: pp. 387-391.
  17. Cortas GA, Mehta SN, Abraham NS, et. al.: Selective cannulation of the common bile duct: a prospective randomized trial comparing standard catheters with sphincterotomes. GastrointestEndosc 1999; 50: pp. 775-779.
  18. Cheung J, Tsoi KK, Quan WL, et. al.: Guidewire versus conventional contrast cannulation of the common bile duct for the prevention of post-ERCP pancreatitis: a systematic review and metaanalysis. GastrointestEndosc 2009; 70: pp. 1211-1219.
  19. Tse F, Yuan Y, Moayyedi P, et. al.: Guide wire-assisted cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis. Endoscopy 2013; 45: pp. 605-618.
  20. ASGE Technology Committee, Kethu SR, Adler DG, et. al.: ERCP cannulation and sphincterotomy devices. GastrointestEndosc 2010; 71: pp. 435-445.
  21. Harewood GC, Baron TH. An assessment of the learning curve for precut biliary sphincterotomy. Am J Gastroenterol. 2002;97:1708– 1712.
  22. Freeman ML, Guda NM. ERCP cannulation: a review of reported techniques. GastrointestEndosc. 2005;61:112–125.
  23. Manes G, Di Giorgio P, Repici A, Macarri G, Ardizzone S, Porro GB. An analysis of the factors associated with the development of complications in patients undergoing precut sphincterotomy: a prospective, controlled, randomized, multicenter study. Am J Gastroenterol. 2009;104:2412–2417.
  24. Freeman ML, Guda NM. ERCP cannulation: a review of reported techniques. GastrointestEndosc. 2005;61:112–125.
  25. Siegel JH. Precut papillotomy: a method to improve success of ERCP and papillotomy. Endoscopy. 1980;12:130–133.
  26. Liao WC, Lee CT, Chang CY, et. al.: Randomized trial of 1-minute versus 5-minute endoscopic balloon dilation for extraction of bile duct stones. GastrointestEndosc 2010; 72: pp. 1154-1162.
  27. Andrew W. Yeng and Joseph W. Leung. Stone Extraction. ERCP,19,160-170.e1.
  28. Pan Y, Ngo C, Yen D, et. al.: A novel method of endoscopic removal of an impacted ampullary stone using a snare. J Interv Gastroenterol 2011; 1: pp. 177-178.
  29. Ishiwatari H, Kawakami H, Hisai H, et. al.: Hokkaido Interventional EUS/ERCP Study (HONEST) Group. Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. Endoscopy 2016; 48: pp. 350-357.
  30. Ishiwatari H et al (2016) Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. Endoscopy 48(4):350–357.
  31. Williams EJ, Green J, Beckingham I et al (2008) Guidelines on the management of common bile duct stones (CBDS). Gut 57:1004– 1021.
  32. Maple JT et al (Oct. 2011) The role of endoscopy in the management of choledocholithiasis. GastrointestEndosc 74(4):731–744.
  33. Ishiwatari H et al (2016) Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. Endoscopy 48(4):350–357.
  34. Ozawa N et al (2017) Prospective randomized study of endoscopic biliary stone extraction using either a basket or a balloon catheter: the BasketBall study. J Gastroenterol 52(5):623–630.
  35. Ekmektzoglou K et al (2020) Basket versus balloon extraction for choledocholithiasis: a single center prospective single-blind randomized study. Acta Gastro-EnterolBelg 83(4):577–584
  36. Takeshita K, Asai S, Fujimoto N, Ichinona T, Akamine E (2020) Comparison of the effects of retrieval balloons and basket catheters for bile duct stone removal on the rate of post-ERCP pancreatitis. Hepatobiliary Pancreat Dis Int.
  37. Elsnhory, A.B., Mandour, O.A., Montaser, A.G. et al. A Systematic Review and Meta-analysis of Basket or Balloon Catheter for the Retrieval of Choledocholithiasis. Indian J Surg (2022).

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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #2

Fact vs. Fiction : Fermented Foods and Gut Health

February 2023 • Volume XLVII, Issue 2
Andrea Hardy

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Despite their long history of use, there is a renewed interest in the consumption of fermented foods. The use of fermented foods is rapidly gaining popularity, garnering attention for purported digestive health benefits. While fermented foods have some evidence of benefit to human health, including improving digestive tolerance, enhancing nutrient bioavailability, and improving food safety and accessibility, many claims are overstated. Additional research is needed prior to making generalized health claims across all products of fermented foods. This review aims to explore the role of fermented foods in digestive health and wellness, and current available evidence for encouraging consumption in an individual’s diet.

Ancient Roots to Modern Science

While fermented foods have been consumed for thousands of years, recent advances in understanding the gut microbiome – the make-up of bacteria, viruses, and fungi in the gut – has renewed interest in their consumption. Traditionally, foods were fermented as a means of preservation to improve shelf life, food safety, and accessibility. Fermentation was also used to improve digestive tolerance, taste, and texture of foods. Their prominence in cultural dietary patterns and long history of use has led both consumers and researchers to wonder how fermented foods can fit into current dietary recommendations, how often an individual should consume them, and for what benefit.

Definition of Fermented Foods

To best understand their health benefits, it is important to first understand what constitutes a fermented food. The International Scientific Association for Probiotics and Prebiotics (ISAPP) expert consensus defines fermented foods and beverages as “foods made through desired microbial growth and enzymatic conversions of food components”.1

Microbes, although essential to the fermentation process, may or may not be present at time of consumption due to heating and processing (see Table 1). It is important to note that while some foods require fermentation to be identified by their common name (e.g., yogurt), others may not. Sauerkraut, for example, may be pickled or fermented, therefore not all sauerkraut can be considered a ferment (also referred to as a fermented food). Pickled foods are typically produced through submersion in vinegar, and do not require microbes or meet the definition of a fermented food.

It is important to also note that very few fermented foods meet the accepted definition of probiotics. Probiotics, as defined by the ISAPP expert consensus, are “live microbes, when consumed in adequate amounts; infer a benefit to the host”.1 Probiotics are strain-specific and have a demonstrated health benefit in a welldesigned research study to be classified as such. Most fermented foods do not meet the definition of a probiotic because their strains have not been defined, and adequate colony forming units (CFUs) are not guaranteed to sustain throughout shelflife. For example, while sauerkraut undergoes fermentation with lactic acid bacteria (LAB), the strains used here are not defined, nor are counts guaranteed throughout shelf life.

Production of Fermented Foods

Fermented foods are produced via spontaneous fermentation or a starter culture. Spontaneous fermentation utilizes microbes that happen to be present in the air or are on the ingredients to ferment upon, whereas a starter culture is used to initially inoculate the food to initiate fermentation.2 In using a starter culture, microbes may potentially go through a selection process for standardization of the product. While both a science and an art, when it comes to researching the health benefits of a fermented food, the variation in a food’s composition and microbes present due to methods of production leads to significant heterogeneity in the literature. A ferment can differ greatly from one to the next in numbers of strains, types of strains, and total CFUs, making it challenging to generalize results from studies. In addition, the foods each have their own nutritive benefits independent of production method, its microbes, and their metabolites.

Influence of Fermented Foods on Human Health

Health claims of fermented foods are often overstated. While fermented foods do have associated health benefits, other claims like the ability to treat ‘leaky gut’ or to replace antibiotic therapies is with minimal evidence. Current research suggests that microbes from ferments are transient.2 An individual’s microbiome is established and resistant to colonization; there is no niche to colonize and therefore exert their benefits transiently. Due to the transient nature of these microbes, it can be inferred that the benefits of fermented foods may only persist for the duration an individual consumes them.

The confirmed health benefits of fermented foods include food preservation, increased nutrient bioavailability, and enhanced digestive tolerance. Using fermentation as a means for food preservation can enhance food safety, accessibility, and retain nutrient values. Through the fermentation process, the transformation of food components can also increase the bioavailability of nutrients by reducing anti-nutritional factors (ANFs) such as phytates and tannins. In reducing these ANFs, micronutrients such as calcium, iron, and magnesium become more bioavailable for absorption.2,3 Many epidemiological studies have shown that the risk of chronic disease (e.g., diabetes and cardiovascular disease) often decline with increased consumption of fermented foods.1,2 Future research is needed to determine the mechanisms of action between ferments and chronic disease. Current theories propose that administration of live cultures may positively interact with our own gut microbiome and innate immune system to help outcompete potential growth of pathogenic bacteria and provide a substrate for fermentation-derived metabolites that infer a benefit to our health. While some benefits have been extensively researched; others are theoretical and require further studies. A recent study explored the role total fermented food intake had in modulating the human immune system. The randomized prospective study included 36 patients either to receive a diet high in dietary fiber, or to include fermented foods.4 Patients were monitored 3 weeks pre-intervention, and then had 4 weeks of a ‘ramp up’ phase where participants worked their way up to a high fiber or high fermented food diet, 6 weeks maintenance of the diet, and a 4 week ‘choice diet’ where participants maintained the diet to their desired extent. Researchers found that those individuals in the fermented foods arm who were consuming ~6 servings on average of fermented foods a day (up from a baseline of ~0.4 servings of fermented foods a day) had a reduction in pro-inflammatory cytokines. In addition, an increase in microbial diversity was seen with an increase in intake of fermented foods. This is the first study of its kind to assess total fermented food intake and its impact on immune function. While further research is needed, it begins to explore how dietary advice may shift to include a total fermented food target to positively influence human health.

Safety of Fermented Foods

The primary purpose of food fermentation is to increase the shelf-life and thereby enhance the safety of a food or beverage for consumption. Fermentation achieves the purpose in many ways, including reducing water activity and pH via the production of organic acids.2 The microbes used in fermentation are non-pathogenic and considered safe. While safe for most individuals, it should be noted that some by-products of fermentation may have a negative impact on health, most notably, alcohol and biogenic amines. The production of biogenic amines, like histamine and tyramine, can negatively influence patients diagnosed with mast cell disorders or placed on monoamine oxidase inhibitors (MAOIs).5,6,7 Through fermentation, amino acids are decarboxylated to release biogenic amines and are found in high quantities in fermented meat and fish products, cheese, wine, and beer. It may be prudent for those on MAOIs, and helpful for those that have histamine intolerance or a mast cell activation disorder to limit intake of biogenic amines and therefore fermented foods.5

The Health Benefits of Common Fermented Foods

Healthcare providers are more frequently being asked by their patients “should I consume fermented foods for my health?” or running into patients attempting to utilize fermented foods to treat their digestive symptoms (see Table 2). Being aware of the current evidence for fermented foods in gut health can ensure patients are receiving accurate information on the benefits of including fermented foods in their diet.

Yogurt

Yogurt is one of the most recognized ferments in North America. In epidemiological studies, yogurt consumption has been associated with a risk reduction for Type II diabetes mellitus, heart disease, and cancer. Additionally, it has been associated with improved bone health and weight management.2,8 It is well established that the fermentation of milk improves digestibility of lactose by reducing the lactose content both in the production of yogurt, and throughout digestion via the live microbes ability to express B-galactosidase.8 While some studies have shown benefit for yogurt consumption in reducing antibiotic associated diarrhea, results are inconsistent.9 While all yogurt is fermented, only some yogurts simultaneously meet the criteria of a fermented and a probiotic food – meaning their bacterial strains are adequately specific, has a therapeutic dose, and has been researched for a particular health benefit. Yogurts and other fermented milk products may include a specific probiotic strain to support specific therapeutic benefits, including improving constipation, reducing symptoms of irritable bowel syndrome (IBS), and reducing incidence of Clostridioides difficile (C. difficile) and antibiotic associated diarrhea.10 It is important to note these findings cannot be generalized to yogurt itself, but refer to the probiotic strain present. Beyond lactose maldigestion and strain-specific therapeutic effects of yogurts with added probiotics, the research supporting yogurt consumption to improve specific digestive disorders is yet to be elucidated.

Kefir

While kefir is often considered to be similar to yogurt, its starter cultures, termed ‘kefir grains’ include both bacteria and yeast. Kefir has extensive research exploring its impact on human health. Like yogurt, kefir improves the digestibility of the milk by reducing lactose content.8

In management of constipation, one uncontrolled pilot study of 20 patients (10 with slow transit constipation and 10 with normal transit constipation) were administered 500 mL of kefir daily for 4 weeks.11 In both groups of patients, improved stool frequency, stool consistency, and decreased laxative consumption was seen. In addition, a significant improvement was also seen in the group of patients with slow transit constipation. Kefir has shown promise as an adjunct in Helicobacter Pylori (H. Pylori) eradication.

A randomized double blind control study of 82 patients with H. Pylori were randomized to receive either 250 mL kefir twice daily, or 250 mL milk containing placebo twice daily as an adjunct to triple antibiotic therapy.12 In comparison to the patients in the milk group, the patients in the kefir group had a 78.2% eradication rate, whereas the patients in the milk group had a 50% eradication rate (p=0.26). The patients in the kefir group also experienced fewer antibiotic-related side effects including diarrhea, headache, nausea, and abdominal pain. Trials with probiotics as an adjunct to antibiotics also have shown similar results.10 The use of kefir alongside antibiotic therapy for the treatment of H. Pylori could be considered.

Kombucha

With roots dating back to Northeast China during the Qin Dynasty in 220 BC, kombucha, a fermented tea drink, is produced with a starter culture of LAB, acetic acid bacteria, and yeast.2

Acetic acid is produced through fermentation, and polyphenols and flavonoids from the tea increase. Despite its significant popularity in North America and purported benefits for digestive health, there are no human studies to date that explore these claims. While there are several in vitro animal studies that are promising for its antimicrobial and antioxidant effects, blood glucose control, and improving hypercholesterolemia, these cannot be generalized to humans.2

Sauerkraut

Produced from the spontaneous fermentation of cabbage via LAB, sauerkraut has been a cultural staple in food preservation for centuries. Very few studies have explored the health benefits of sauerkraut, however, one randomized doubleblind pilot study compared the administration of 75 gram/day pasteurized or unpasteurized sauerkraut in 58 patients with IBS over 6 weeks.13 Both groups showed a significant change in gut microbiota diversity and significant improvement of IBS Severity Scoring System (IBS-SSS). The researchers concluded that other properties of the sauerkraut, independent of pasteurization, including the prebiotic properties and the metabolic by-products of fermentation may have contributed to the favorable results.

However, without unfermented cabbage as an additional control, it is not possible to attribute the results to the fermentation process.

Kimchi

While the cabbage used in the production of kimchi is similar to sauerkraut, the fermentation of the cabbage differs. Kimchi is produced by brining a variety of vegetables, including cabbage, onion, garlic, chilies, and/or ginger, followed by seasoning and spontaneous fermentation. Interestingly, the variety of ingredients largely influences the microbial make-up of kimchi. In vitro and animal studies have found kimchi beneficial for weight control, improving hypercholesterolemia, and explored its anti-carcinogenic and antiinflammatory enhancing properties.2 Further studies in humans are indicated to learn of the potential benefits between kimchi and various chronic diseases, including its impact on digestive disorders as well as the gut microbiome.

Soy Products

Tempeh, miso, and nattō are staple fermented soybased foods often consumed in Asian cultures. While their consumption has been associated with a risk reduction in various chronic diseases, like hypercholesterolemia, cancer, obesity, and diabetes, there is limited research related to digestive health.2 Some observational studies have found association with miso intake and reduced occurrence of gastric cancer, albeit inconsistently. Nattō has been explored in a small, uncontrolled study of eight individuals for its impact on stool frequency, the gut microbiota, and its metabolites.14 Results showed an increase in stool frequency in those with infrequent bowel movements, and in fecal samples, an increase in Bacilli and Bifidobacteria in the stool microbiota, and an increase in production of short chain fatty acids. Although the study size was small and uncontrolled, this supports the need for additional human studies on fermented soy products.

Sourdough Bread

While sourdough bread does not contain live microbes upon consumption, it is produced through the fermentation of flour (usually wheat-based) and a sourdough starter, or mother dough. Sourdough starters can include both bacteria and yeast, with microbial make-up influencing enzymatic activity and altering nutrient composition of the fermented end-product. Yeast and LAB work synergistically, with the metabolic by-products from yeast fermentation going on to act as metabolites for the LAB fermentation. It is through these actions sourdough bread has taken a spotlight in improved digestive tolerance of wheat products in both healthy populations, and those with digestive disorders. It is important to note that some commercially available sourdough bread has not undergone extensive fermentation, rather is flavored with a sourdough flavoring agent – research on sourdough bread has been done with traditionally prepared, fermented sourdough. Through an intake reduction of fermentable carbohydrates (fructans, galactans, lactose, excess fructose, and sugar alcohols), the low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) diet has been shown to reduce digestive symptoms, particularly of abdominal pain and bloating, in patients with IBS.15 Fermentation of bread to make sourdough bread reduces fructan content, which renders certain sourdough breads to be suitable for intake on a low FODMAP diet in much larger quantities than non-fermented breads.16 A double-blinded crossover randomized control study confirmed the impact of sourdough bread consumption had on IBS symptoms in comparison with regular bread.17 Over two 4-week periods, 87 patients consumed either regular bread or sourdough rye bread, followed by a washout period prior to starting the next intervention group. Researchers assessed IBS symptoms using the validated IBS-SSS, and hydrogen breath excretion via breath test, with using the breads as the substrate. Results showed that during the intervention with the sourdough rye bread, patients showed a significant improvement in the total IBS-SSS as well as several symptoms including abdominal pain, flatulence, stomach rumbling, and intestinal cramping. In addition, during the sourdough rye bread intervention, a lower breath hydrogen excretion was seen via breath test, validating the reduced fermentation occurring in the gut compared to the unfermented bread product. In a small pilot study of 26 patients, who were randomized to receive wheat sourdough or wheat bread for 7 days, no changes were seen in digestive symptoms with wheat sourdough.18 However, with the sourdough consumption, the patients experienced significantly more tiredness, joint symptoms, and decreased alertness. This is difficult to interpret due to the small sample size and use of non-validated symptom assessment tools but does warrant further research.

Other Fermented Products

Independent of soy and wheat, research on the fermentation benefits of grains and legume products is limited. Fermented grain products like injera from Ethiopia, kvass from Europe, and dosa from India are staples in many cultures around the world. To the best of our knowledge, no specific research exists on fermented grain and legumes dishes and digestive health. However, it can be theorized that by way of enzymatic conversions, fermentation of grains and legumes may support digestive health. Additional research is indicated to explore these potential benefits.

Conclusion

While fermented foods do have evidence-based benefits for improving digestive tolerance, other claims are not supported in the literature. In addition to the long-realized benefits of food safety and accessibility, the fermentation process has also been shown to improve digestive tolerance and enhance nutrient profiles of some foods, benefiting certain patient populations like those with lactose intolerance or IBS. In addition, the cultural and nutritional relevance of fermented foods should not be overlooked. Further research is indicated to continue to explore the benefits of fermented foods on human health, especially as it pertains to our growing understanding of the gut microbiome. Although current research is inconclusive, many properties and known health benefits support the continued intake of fermented food and beverages.

References

  1. Marco ML, Sanders ME, Gänzle M, et al. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on fermented foods. Nature Reviews Gastroenterology & Hepatology. 2021;18(3):196-208.
  2. Dimidi E, Cox SR, Rossi M, Whelan K. Fermented foods: definitions and characteristics, impact on the gut microbiota and effects on gastrointestinal health and disease. Nutrients. 2019;11(8):1806.
  3. Rul F, Béra-Maillet C, Champomier-Vergès M, et al. Underlying evidence for the health benefits of fermented foods in humans. Food & Function. 2022;13(9):4804-4824.
  4. Wastyk HC, Fragiadakis GK, Perelman D, et al. Gutmicrobiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137-4153.
  5. Gardini F, Özogul Y, Suzzi G, Tabanelli G, Özogul F. Technological factors affecting biogenic amine content in foods: A review. Frontiers in microbiology. 2016;7:1218.
  6. Maintz L, Novak N. Histamine and histamine intolerance. The American journal of clinical nutrition. 2007;85(5):11851196.
  7. Weinstock LB, Pace LA, Rezaie A, Afrin LB, Molderings GJ. Mast cell activation syndrome: a primer for the gastroenterologist. Digestive Diseases and Sciences. 2021;66(4):965982.
  8. Savaiano DA, Hutkins RW. Yogurt, cultured fermented milk, and health: A systematic review. Nutrition reviews. 2021;79(5):599-614.
  9. Patro-Golab B, Shamir R, Szajewska H. Yogurt for treating antibiotic-associated diarrhea: systematic review and metaanalysis. Nutrition. 2015;31(6):796-800.
  10. Skokovic-Sunjic D. Clinical Guide to Probiotic Products Available in Canada. http://www.probioticchart.ca/. Accessed September 14, 2022.
  11. Turan İ, Dedeli O, Bor S, İlter T. Effects of a kefir supplement on symptoms, colonic transit, and bowel satisfaction score in patients with chronic constipation: a pilot study. Turk J Gastroenterol. 2014;25(6):650-656.
  12. Bekar O, Yilmaz Y, Gulten M. Kefir improves the efficacy and tolerability of triple therapy in eradicating Helicobacter pylori. Journal of medicinal food. 2011;14(4):344-347.
  13. Nielsen ES, Garnås E, Jensen KJ, et al. Lacto-fermented sauerkraut improves symptoms in IBS patients independent of product pasteurisation–a pilot study. Food & function. 2018;9(10):5323-5335.
  14. Fujisawa T, Shinohara K, Kishimoto Y, Terada A. Effect of miso soup containing Natto on the composition and metabolic activity of the human faecal flora. Microbial ecology in health and disease. 2006;18(2):79-84.
  15. Altobelli E, Del Negro V, Angeletti PM, Latella G. LowFODMAP diet improves irritable bowel syndrome symptoms: a meta-analysis. Nutrients. 2017;9(9):940.
  16. Loponen J, Gänzle MG. Use of sourdough in low FODMAP baking. Foods. 2018;7(7):96.
  17. Laatikainen R, Koskenpato J, Hongisto S, et al. Randomised clinical trial: low-FODMAP rye bread vs. regular rye bread to relieve the symptoms of irritable bowel syndrome. Alimentary Pharmacology & Therapeutics. 2016;44(5):460470.
  18. Laatikainen R, Koskenpato J, Hongisto SM, et al. Pilot study: Comparison of sourdough wheat bread and yeastfermented wheat bread in individuals with wheat sensitivity and irritable bowel syndrome. Nutrients. 2017;9(11):1215.

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BOOK REVIEWS

Pediatric Nutrition for Dietitians

March 2023 • Volume XLVII, Issue 3

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Praveen S. Goday and Cassandra Walia, eds.

ISBN-10: 0367705044

Pages: 464

Hardback: $220.00 Paperback: $99.95 eBook: $89.95 CRC Press

While registered dietitians (RD/RDN) have plenty of resources, we are often short on the “whys”. Pediatric Nutrition for Dietitians delivers not only a comprehensive look into pediatric nutrition but also answers the “whys” from a multidisciplinary approach in a straightforward and concise format.

Goday and Walia (2022) gathered some of the top physicians and RD/RDN experts in the field to provide everyday fundamentals of pediatric nutrition. The opening chapters offer a foundation including nutrition and growth assessments, specific nutrition-focused physical exam findings, and the Assessment, Diagnosis, Intervention, and Monitoring/Evaluation (ADIME) format from infancy to adolescence. Subsequent chapters give an in-depth review of the nutritional management for disease-specific sub specialities as well as evidence-based recommendations. An ADIME summary table concludes each of the disease specific chapters to provide a guide for providing proficient patient care. Pediatric Nutrition for Dietitians is a well organized and comprehensive book. It will equip dieticians, regardless of years of practice, setting, or situation with the guidance, support, tools, and references that are needed to deliver expert nutritional care. It is filled with common sense and real-life knowledge. It also includes graphics and tables that provide quick access to the information at your fingertips. Pediatric Nutrition for Dietitians can be used as a foundational tool for all nutrition staff and is available in hardcover, paperback, and eBook formats.

Pediatric Nutrition for Dietitians is a must have book.

Mimi Girten, RD, LDN, FAND

Clinical Nutrition Program,

Children’s Hospital of Philadelphia

Philadelphia, Pennsylvania

John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology

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SPECIAL ARTICLE

Peroral Endoscopic Myotomy (POEM) for Non-Achalasia Esophageal Disorders

February 2023 • Volume XLVII, Issue 2
Jessica M. Adler,David L. Diehl

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Peroral endoscopic myotomy (POEM) has emerged as an important treatment option for achalasia. While laparoscopic Heller myotomy and pneumatic dilation still have a role in achalasia management, the use of POEM has continued to increase since the first report of its use.1,2

The POEM procedure utilizes submucosal tunneling in the so-called “third-space” and has been one of the important factors for the expansion of “Third Space Endoscopy.” POEM is done by making a submucosal entry point that is several centimeters above where the myotomy will begin. Next is creation of the submucosal tunnel by careful dissection down to a point generally 2cm beyond the lower esophageal sphincter (LES). After completion of the tunnel, cutting of the circular muscle of the esophagus is done, typically 3-4cm below the mucosal entry point. Finally, closure of the mucosal entry point is done, typically with through-the-scope clips, to assure that contamination of the tunnel and mediastinal structures does not occur.

Early in the POEM experience for achalasia, the circular myotomy was approximately 8cm in length, with 6-7cm being on the esophageal side and 2cm down onto the gastric cardia. More recently, shorter myotomy lengths have been advocated for achalasia; for example, 3-4 centimeters on the esophagus for a total myotomy length of  5-6 cm.3 An advantage of POEM over laparoscopic myotomy is that the length of the myotomy can be varied depending on the clinical situation and provides the opportunity to perform long myotomies. Longer myotomies are preferred when POEM is used for spastic esophageal disorders.

Achalasia is classified into 3 types, according to the Chicago diagnostic criteria.4 In all there is inadequate relaxation of the lower esophageal sphincter. Type I achalasia is characterized by minimal contractility in the body of the esophagus. In type II achalasia, there are intermittent periods of panesophageal pressurization. Type III achalasia is characterized by spastic contractions in the esophageal body in addition to the tight LES. For type III achalasia, longer myotomies are done to relieve painful spasms of the esophageal body in addition to relieving outflow obstruction at the LES.

POEM is currently accepted as an effective treatment for achalasia. A review of 19 studies by Crespin et al. in 2016 included 1299 POEM procedures and found improvement in Eckhardt scores and LES pressure.5 Another meta-analysis by Barbieri et al. included 551 patients and also found POEM to be an effective, less invasive alternative to traditional laparoscopic Heller myotomy.6 Kumbhari et al. 2015 noted the success of POEM for type I and II achalasia and offered evidence that POEM can be considered safe and effective for type III patients. This study compared results of POEM and traditional laparoscopic Heller myotomy in type III disorders, finding POEM in this situation to have a smaller rate of adverse events than the Heller myotomy, as well as better results for type III cases than Heller myotomy patients.7

There is limited data concerning the effectiveness of POEM for non-achalasia esophageal disorders,8 but literature is emerging showing some success in these cases.9,10 This review will summarize several studies describing the outcomes of POEM for non-achalasia disorders. These non-achalasia disorders include spastic esophageal motility disorders including jackhammer esophagus, esophageal spasm, and esophagogastric junction outlet obstruction (EGJOO).

Jackhammer Esophagus (formerly referred to as “nutcracker esophagus”)

Jackhammer esophagus (JE) is a condition in which there are high amplitude contractions of the esophageal muscle, defined as at least one contraction with a distal contractile interval (DCI) of >8000 Hg.s.cm. The diagnosis is made with high resolution manometry (HRM).11 Kristensen et al. 2014 followed 3 patients with nutcracker esophagus and tracked their Eckhardt score, LES pressure, distal contractile integral, and amount of reflux pre- and post-POEM procedure.12 At one year followup, these patients had relief of symptoms, with one patient experiencing post-POEM reflux. In another study of 24 non-achalasia patients, including “nutcracker esophagus”, 70.8% experienced an improvement of dysphagia and 71.5% had resolution of chest pain.13 Using HRM after POEM, Kandulski et al. 2016 demonstrated that there are much fewer contractions post-procedurally.14 Bechara et al. 2016 treated 4 patients with JE and noted POEM as a suitable treatment for JE, with none of the patients experiencing intraoperative or postoperative complications. Three of the four patients received POEM that included LES, and they all experienced excellent clinical success. The remaining patient did not receive POEM including LES because the LES was believed to be uninvolved in the abnormal contractions. After the procedure, the patient developed symptoms of dysphagia and regurgitation. This patient received a second POEM procedure, which resulted in the resolution of his remaining symptoms.15 The length of the myotomy in this study was 12-23 cm (mean 19 cm). These investigators recommended LES myotomy in addition to a more proximal myotomy because the iatrogenic ineffective esophageal motility that can result can be made more symptomatic if no LES myotomy is done. The HRM tracing is helpful to help decide on the optimal length of the myotomy in JE.16 There is a distinct advantage to using POEM over surgery for JE because it allows performance of a long myotomy, which is not possible with the laparoscopic Heller myotomy procedure.17

Esophageal Spasm

Diffuse esophageal spasm (DES) is a dysmotility disorder characterized by abnormal contractions of the distal esophagus, with typical symptoms being dysphagia and chest pain.18 Minami et al. 2014 performed POEM on 2 patients with DES.19 The patients did not have dysphagia or gastroesophageal reflux at 5- and 6-months follow-up. Sugihara et al. 2018 also had a successful POEM in a 67-yearold man with a 4-year history of symptomatic DES.20 An extended myotomy is usually done for DES, much like JE. POEM for DES can be more technically difficult due to esophageal spasm during the procedure. Shiwaku 2013 reported a successful use of POEM for DES, in which their patient’s original Eckardt score of 7 was reduced to 0 after POEM.21 Sharata et al.13 used POEM with extended myotomy in 25 non-achalasia patients, including 5 with DES. Overall, dysphagia relief was better for achalasia patients (97.8%) compared to non-achalasia patients (70.8%).
Importantly, in patients with pre-POEM symptoms of chest pain, 91.5% reported complete relief.


Esophagogastric Junction Outlet Obstruction

Esophagogastric junction outlet obstruction (EGJOO) is characterized by an increase of the integrated relaxation pressure (IRP) of the LES, with maintenance of esophageal peristalsis. Jacobs et al. 2021 reported clinical success in 47 of 55 patients at a median of 117 days followup.22 There were several relatively minor adverse effects, including 2 mucosal perforations, 2 cases of pneumoperitoneum requiring decompression, and 1 mucosal perforation which was treated with an esophageal stent resulting in full recovery. Reflux esophagitis was observed in 10 of 25 patients who underwent post-procedural endoscopy. Ichkhanian et al. 2020 described POEM for 15 EGJOO patients, with a 93% success rate 6 months after the procedure. There was a significant decrease in the IRP, as well as improved quality of life scores.23 Data is incomplete on the long-term effectiveness of POEM for EGJOO. Some studies have a short follow-up period, and loss of effectiveness of the POEM in EGJOO over time has been noted in studies with longer clinical followup.24 For example, Modayil reported POEM in 15 EGJOO patients with initial success at 6-month follow-up. These cases had Eckhart scores of 1.9, which is higher than the usual score of 1.2 after POEM. At a 12-month follow-up, mean Eckhardt scores rose to 2.4 and success rates dropped to 87%, and at 24-month follow-up mean Eckhardt scores rose to 3.0 and success rates fell to 73%. Even in patients who were selected carefully due to their EGJOO conditions resembling achalasia disorder symptoms, POEM still appears to not be as effective as it is for the achalasia patients. Teitelbaum et al. 2018 reviewed clinical outcomes five years after POEM for several esophageal motility disorders, including EGJOO.25 Five of their patients had EGJOO and 2 required reintervention for symptom recurrence. One underwent a laparoscopic Heller myotomy 11 months after POEM. The other patient developed cervical dysphagia 2 years later, managed with endoscopic cricomyotomy. Both of the patients who had reintervention improved, with postoperative Eckhardt scores of ≤2. The authors concluded that POEM resulted in long term relief of symptoms in the majority of patients, for both achalasia and non-achalasia disorders.

Knowledge Gaps for Poem in Achalasia, NonAchalasia, and Esophageal Motility Diseases

Despite the large clinical experience with POEM, there are still relatively few being done for nonachalasia disorders. A knowledge gap in this field is defining the incidence of GERD after POEM in non-achalasia patients. Because of the lack of fundoplication with POEM, there is approximately a 30% likelihood of post-POEM patients GERD.26
However, it typically can be controlled with acid suppression. POEM is not typically followed by fundoplication, but there is data suggesting that the likelihood of GERD occurring post-POEM in nonachalasia esophageal motility disorders is not very different from the traditional Heller myotomy.27 Stavropoulos et al. 2021 noted decreases in postPOEM GERD over time after healing and scar contraction occur, which contrasts from the typical increase in GERD after the Heller myotomy procedure paired with fundoplication.

Modifications of the POEM Procedure

Procedural modifications may be necessary when doing a POEM for non-achalasia disorders. Wang et al. 2015 advocate for a shorter myotomy in achalasia, as well as a shorter submucosal tunnel.28 This modification may be ideal for some cases of EGJOO without esophageal spasm. This group performed a shorter myotomy (with a mean length of 4.9 cm plus 1 cm at the gastric side, compared to the traditional 8 cm) in the POEM procedure on 46 consecutive achalasia patients. At a 3-month follow-up, patients were experiencing lower Eckhardt scores, decreased lower esophageal sphincter pressure, integrated relaxation pressure, and a decrease in height of esophagus bariumcontrast column. Only 3 patients experienced GERD at 3-month follow-up. A short myotomy could be a solution to post-POEM reflux when long myotomy is not necessary. Longer myotomies are often required in nonachalasia disorder settings because the spasticity involves differing lengths of the esophageal body. The length of the myotomy can be determined by reviewing the high-resolution manometry and the proximal border of the high-pressure zone.29 Huang et al. 2020 compared the outcomes of 129 patients who received longer and shorter myotomies in otherwise equivalent POEM procedures.30 They determined that there was no significant difference in terms of efficacies of shorter and longer myotomies. Longer myotomies can prove to be needed in certain types of esophageal spasm disorders, such as for jackhammer esophagus.31

Ponds et al. 2018 describes the challenges of POEM as a treatment method for DES.32

Intraprocedural esophageal spasm and problematic contractions can occur, which can make the procedure more difficult. Administration of nitroglycerin during the procedure was found to be of benefit. Myotomy should start more proximally than in non-spastic achalasia patients, otherwise some of the contractions may persist postoperatively. HRM can be used as a method to guide this process. Ponds et al. concluded that POEM has much promise for treating therapyrefractory DES.

Conclusion

POEM can be effectively used for both achalasia and non-achalasia esophageal disorders. For spastic motility disorders of the esophagus, including jackhammer esophagus, esophageal spasm, and esophagogastric junction outlet obstruction, POEM has been shown to be effective in reported cases, although there are a relatively small number of reports for these types of cases. Modifications of the POEM procedure for non-achalasia disorders is typically necessary, with longer myotomies required for adequate treatment of spastic disorders, and potentially shorter myotomies for EGJOO. As POEM continues to be used by an expanding number of advanced endoscopists, more data should become available on the effectiveness of this treatment for non-achalasia esophageal disorders.

References

  1. Pasricha P, Hawari R, Ahmed I, et al. Submucosal endoscopic esophageal myotomy: a novel experimental approach for the treatment of achalasia. Endoscopy. 2007;39(09):761-764. doi:10.1055/s-2007-966764
  2. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy. 2010;42(04):265-271. doi:10.1055/s-0029-1244080
  3. Hasan A, Low EE, Fehmi SA, Yadlapati R. Evolution and evidence-based adaptations in techniques for peroral endoscopic myotomy for achalasia. Gastrointestinal Endoscopy. 2022;96(2):189-196. doi:10.1016/j.gie.2022.03.004
  4. Khan A, Yadlapati R, Gonlachanvit S, et al. Chicago Classification update (version 4.0): Technical review on diagnostic criteria for achalasia. Neurogastroenterology & Motility. 2021;33(7). doi:10.1111/nmo.14182
  5. Crespin OM, Liu LWC, Parmar A, et al. Safety and efficacy of POEM for treatment of achalasia: a systematic review of the literature. Surgical Endoscopy. 2016;31(5):2187-doi:10.1007/s00464-016-5217-y
  6. Barbieri LA, Hassan C, Rosati R, Romario UF, Correale L, Repici A. Systematic review and meta-analysis: Efficacy and safety of POEM for achalasia. United European Gastroenterology Journal. 2015;3(4):325-334. doi:10.1177/2050640615581732
  7. Kumbhari V, Tieu A, Onimaru M, et al. Peroral endoscopic myotomy (POEM) vs laparoscopic Heller myotomy (LHM) for the treatment of Type III achalasia in 75 patients: a multicenter comparative study. Endoscopy International Open. 2015;3(03):E195-E201. doi:10.1055/s-0034-1391668
  8. Filicori F, Dunst CM, Sharata A, et al. Long-term outcomes following POEM for non-achalasia motility disorders of the esophagus. Surgical Endoscopy. 2018;33(5):1632-doi:10.1007/s00464-018-6438-z
  9. Bernardot L, Roman S, Barret M, et al. Efficacy of per-oral endoscopic myotomy for the treatment of nonachalasia esophageal motor disorders. Surgical Endoscopy. 2020;34(12):5508-5515. doi:10.1007/s00464-019-07348-y
  10. Morley TJ, Mikulski MF, Rade M, Chalhoub J, Desilets DJ, Romanelli JR. Per-oral endoscopic myotomy for the treatment of non-achalasia esophageal dysmotility disorders: experience from a single high-volume center. Surgical Endoscopy. Published online September 12, 2022. doi:10.1007/s00464-022-09596-x
  11. Bredenoord AJ, Hebbard GS. Technical aspects of clinical high-resolution manometry studies. Neurogastroenterology
    & Motility. 2012;24:5-10. doi:10.1111/j.1365-
    2982.2011.01830.x
  12. Kristensen HØ, Bjerregaard NC, Rask P, Mortensen FV, Kunda R. Peroral endoscopic myotomy (POEM) for nutcracker esophagus. Three cases with 12 months follow-up. Scandinavian Journal of Gastroenterology. 2014;49(11):1285-1289. doi:10.3109/00365521.2014.958096
  13. Sharata AM, Dunst CM, Pescarus R, et al. Peroral Endoscopic Myotomy (POEM) for Esophageal Primary Motility Disorders: Analysis of 100 Consecutive Patients. Journal of Gastrointestinal Surgery. 2014;19(1):161-170.doi:10.1007/s11605-014-2610-5
  14. Kandulski A, Fuchs KH ., Weigt J, Malfertheiner P. Jackhammer esophagus: high-resolution manometry and therapeutic approach using peroral endoscopic myotomy (POEM). Diseases of the Esophagus. 2014;29(6):695-696. doi:10.1111/dote.12182
  15. Bechara R, Ikeda H, Inoue H. Peroral endoscopic myotomy for Jackhammer esophagus: to cut or not to cut the lower esophageal sphincter. Endoscopy International Open. 2016;04(05):E585-E588. doi:10.1055/s-0042-105204
  16. Ko WJ, Lee BM, Park WY, et al. Jackhammer esophagus treated by a peroral endoscopic myotomy. The Korean Journal of Gastroenterology. 2014;64(6):370. doi:10.4166/ kjg.2014.64.6.370
  17. Chandan S, Mohan BP, Chandan OC, et al. Clinical efficacy of per-oral endoscopic myotomy (POEM) for spastic esophageal disorders: a systematic review and meta-analysis. Surgical Endoscopy. 2019;34(2):707-718. doi:10.1007/s00464-019-06819-6
  18. Khalaf M, Chowdhary S, Elias PS, Castell D. Distal Esophageal Spasm: A Review. The American Journal of Medicine. 2018;131(9):1034-1040. doi:10.1016/j. amjmed.2018.02.031
  19. Minami H, Isomoto H, Yamaguchi N, et al. Peroral endoscopic myotomy (POEM) for diffuse esophageal spasm. Endoscopy. 2014;46(S 01):E79-E81. doi:10.1055/s-0032-1309922
  20. Sugihara Y, Harada K, Kato R, et al. A Case of Diffuse Esophageal Spasm Treated with Peroral Endoscopic Myotomy. Acta Medica Okayama. 2018;72(6):595-600. doi:10.18926/AMO/56378
  21. Shiwaku H, Inoue H, Beppu R, et al. Successful treatment of diffuse esophageal spasm by peroral endoscopic myotomy. Gastrointestinal Endoscopy. 2013;77(1):149-doi:10.1016/j.gie.2012.02.008
  22. Jacobs CC, Perbtani Y, Yang D, et al. Per-Oral Endoscopic Myotomy for Esophagogastric Junction Outflow Obstruction: A Multicenter Pilot Study. Clinical Gastroenterology and Hepatology. 2021;19(8):1717-1719. e1. doi:10.1016/j.cgh.2020.08.048
  23. Ichkhanian Y, Sanaei O, Canakis A, et al. Esophageal peroral endoscopic myotomy (poem) for treatment of esophagogastric junction outflow obstruction: Results from the first prospective trial. Endoscopy International Open. 2020;08(09). doi:10.1055/a-1198-4643
  24. Modayil R, Stavropoulos SN. POEM for Achalasia and Esophageal Motility Diseases: What Are the Knowledge Gaps? Current Treatment Options in Gastroenterology. Published online March 15, 2022. doi:10.1007/s11938-
    022-00374-1
  25. Teitelbaum EN, Dunst CM, Reavis KM, et al. Clinical outcomes five years after POEM for treatment of primary esophageal motility disorders. Surgical Endoscopy. 2017;32(1):421-427. doi:10.1007/s00464-017-5699-2
  26. Ward MA, Ujiki MB. Peroral endoscopic myotomy.
    Achalasia. 2016:45-50. doi:10.1007/978-3-319-13569-4_7
  27. Stavropoulos SN, Parsa N, Omrani L, et al. Unlike heller myotomy (HM), per oral endoscopic myotomy (POEM) is associated with improvement in objective gastroesophageal reflux disease metrics on long term follow-up. Gastrointestinal Endoscopy. 2021;93(6):AB307. doi:10.1016/j.gie.2021.03.630
  28. Wang J, Tan N, Xiao Y, et al. Safety and efficacy of the modified peroral endoscopic myotomy with shorter myotomy for achalasia patients: a prospective study. Diseases of the Esophagus. 2014;28(8):720-727. doi:10.1111/ dote.12280
  29. Nabi Z, Reddy DN. Non-achalasia esophageal motility disorders: Role of per-oral endoscopic myotomy. International Journal of Gastrointestinal Intervention. 2020;9(2):67-71. doi:10.18528/ijgii200003
  30. Huang S, Ren Y, Peng W, et al. Peroral endoscopic shorter versus longer myotomy for the treatment of Achalasia: A Comparative Retrospective Study. Esophagus. 2020;17(4):477-483. doi:10.1007/s10388-020-00739-4
  31. Kim JY, Min YW. Peroral Endoscopic Myotomy for Esophageal Motility Disorders. Clinical Endoscopy. 2020;53(6):638-645. doi:10.5946/ce.2020.223 32. Ponds FAM, Smout AJPM, Fockens P, Bredenoord AJ. Challenges of peroral endoscopic myotomy in the treatment of distal esophageal spasm. Scandinavian Journal of
    Gastroenterology. 2018;53(3):252-255. doi:10.1080/0036
    5521.2018.1424933

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #49

A Practical Approach to Integration of Diet and Nutrition in the Management of Patients with IBD

February 2023 • Volume XLVII, Issue 2
Ashwin N. Ananthakrishnan

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Inflammatory bowel diseases (IBD; Crohn’s was anecdotal, there is a growing burden of disease (CD), ulcerative colitis (UC)) are rigorous epidemiologic studies supported by global diseases with a rising prevalence across mechanistic experiments that highlight various several regions of this world.1,2

While changes in several external environmental factors likely contribute to this increase in incidence over the past decade, one such factor that likely plays a central role is the change in diet. Most patients with IBD believe that diet plays an important role in either their disease onset or relapse.3 While previously evidence in support for this was anecdotal, there is a growing burden of rigorous epidemiologic studies supported by mechanistic experiments that highlight various mechanisms through which diet contributes to intestinal inflammation.4-6 Patients also seek to actively incorporate dietary changes in the management of their IBD. It is important for physicians and treating providers to recognize the role diet plays in IBD, familiarize themselves with the various dietary therapies, and develop a practical algorithm to guide patients through this decision process. In this review article, we will summarize the evidence for the role of diet in IBD and present practical tips for integration of dietary therapy in the management of IBD.

Epidemiologic Studies of Diet and Incidence of IBD

Several levels of evidence support a role for dietary changes as being important in the global emergence of IBD. Worldwide, diets have seen a decline in consumption of fiber along with an increase in fatty and sugar-rich diets that derive a significant fraction of their energy from ultraprocessed foods.7 This temporal evolution in dietary practices parallels the rising incidence of IBD, particularly in regions of the world such as Asia and South America that have been more recent venues of such westernization in diet.8 Over the past decade, several rigorously conducted prospective cohort studies from North America, Europe, and low/ middle income countries have provided important signals about the association between diet and the development of IBD.9 In a prospective analysis of 170,776 women enrolled in the Nurses’ Health Study cohorts, women in the highest quartile of intake of dietary fiber had a lower risk of incident Crohn’s disease (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.39 – 0.90).10 Strikingly, this association was strongest for fiber derived from fruits and vegetables and weaker for insoluble fiber from whole grains and cereals. Dietary fat intake has also been demonstrated to be associated with development of IBD. In both European and North American cohorts, a diet high in n-6 polyunsaturated fatty acids (PUFA) was associated with an elevated risk of ulcerative colitis (odds ratio (OR) 6.09, 95% CI 1.05 – 35.23) while a high n-3/n-6 PUFA ratio was inversely associated with UC risk (HR 0.69, 95% CI 0.49 – 0.98).11,12 There is less consistent data on the impact of a protein rich diet with mixed evidence suggesting an association between animal protein intake or a red-meat rich diet and risk of ulcerative colitis.13 In addition to dietary macronutrients, intake of micronutrients such as vitamin D and zinc, or other food components such as polyphenols, have been hypothesized to modify risk of IBD.14,15 Cohort studies examined the association between dietary patterns and risk of IBD. In the Swedish cohorts, adherence to a Mediterranean diet was associated with a lower risk of older onset Crohn’s disease but not ulcerative colitis (OR 0.42, 95% CI 0.22 – 0.80).16 Western-style diets rich in sugar-rich foods have been associated with increased risk of IBD.17 Hypothesis-driven identification of dietary factors associated with elevated levels of circulation serum inflammatory markers contributing to an Empiric Dietary Inflammatory Potential (EDIP) score was associated with risk of IBD.18 Importantly, the latter study showed diet as a modifiable risk factor in adulthood, demonstrating that a change from a low inflammatory potential to a high inflammatory potential diet was associated with an increase in risk of Crohn’s disease (HR 2.05, 95% CI 1.10 – 3.79). In addition to food constituents themselves, processing of food modified nutritional consult removes certain beneficial components and incorporates additives, emulsifiers, and preservatives to boost taste and preserve shelf-life. A diet rich in ultraprocessed foods was associated with risk of Crohn’s disease both in North America19 as well as in emerging low/middle income countries. In the Nurses’ Health Study cohorts, participants in the highest quartile of energy intake from ultraprocessed foods20 had a two-fold increase in risk of incident CD (HR 1.70, 95% CI 1.23 – 2.35).19

Evidence for Dietary Therapies for the Management of IBD

In contrast to the robust epidemiologic evidence regarding dietary risk factors for IBD, until recently, high-quality evidence for modulation of IBD activity through dietary changes has been sparser.21 The dietary therapy with the strongest evidence behind its efficacy is exclusive enteral nutrition (EEN).22-24 This dietary strategy incorporates exclusion of all table foods while meeting caloric requirements through consumption of either elemental or polymeric formulas. Both types of enteral preparations are similarly effective with the latter being more palatable. In randomized controlled trials, EEN induces clinical remission, normalization of fecal calprotectin and endoscopic healing in Crohn’s disease without evidence supporting its efficacy in UC.25-27 Its efficacy is comparable or only modestly inferior to oral systemic corticosteroids or anti-TNF therapy.25,28 A challenge precluding wider use of this strategy is the difficulty to maintain compliance over the long-term. Partial enteral nutrition (PEN) along with consumption of an unrestricted diet is less effective in achieving resolution of inflammation in CD. However, a strategy of combining PEN with modified exclusion diets that encourage incorporation of dietary fiber and n-3 PUFA while reducing sugar-rich and ultraprocessed foods in the Crohn’s disease exclusion diet (CDED) demonstrated the ability to achieve clinical remission (75% vs. 59%) that was comparable to EEN at 6 weeks and superior to expanding to an unrestricted diet for the subsequent 6 weeks of treatment (75.6% vs. 45.1%, p=0.01).29 A modified version of the CDED that eliminated the use of PEN, relying just on dietary changes was also effective in improving symptoms and resolving inflammation in adult patients with Crohn’s disease.30 Analysis of the initial clinical trial of CDED data showed that response by 3 weeks was a strong predictor of both compliance and clinical improvement. Lack of improvement by 3 weeks in patients who were compliant with the diet was predictive of poor efficacy at the end of treatment. The specific carbohydrate diet (SCD) has gained popularity among patients but supporting evidence of this diet is primarily through case series demonstrating symptom resolution or improvement of calprotectin in some patients.31 The DINE-CD study compared the SCD to a Mediterranean diet in 191 patients with mild to moderately symptomatic Crohn’s disease.32 At 6 weeks, 46.5% of patients in the SCD group and 43.5% in the Mediterranean diet group achieved symptomatic remission (p=0.77). However, only a small fraction of patients in both groups achieved normalization of fecal calprotectin (34.8% vs. 30.8%), highlighting the discrepancy between symptom improvement and objective resolution of inflammation.

Other dietary strategies that have been examined including the autoimmune protocol diet, IBD-anti-inflammatory diet, the IBD-treat diet, an allergy-based diet, a low emulsifier diet, all of which have mixed evidence supporting efficacy primarily from case series without rigorous data on improvement in inflammation.21 In an intriguing strategy incorporating dietary changes along with microbiome-directed therapy, Kedia et al. conducted an RCT of 66 patients with mild-to-moderate ulcerative colitis who received either standard medical therapy or seven weekly colonoscopic infusions of fresh multi-donor FMT and subsequently initiated an anti-inflammatory diet.33 At the end of the clinical trial, the combination of FMT-AID was superior to standard medical therapy in achieving clinical remission (60% vs. 32%) at 8 weeks. The AID was superior to standard medical therapy in maintaining deep remission until 48 weeks (25% vs. 0%).

Practical Tips for Incorporation of Dietary Modification in Management of Patients with IBD

Most gastroenterologists and other treating providers will be asked the question “what can I eat?” by their patient with IBD at some point in the clinical course. The first step in answering that question is to understand the intent of dietary changes (Figure 1). The intent could be to use dietary modification to treat underlying inflammation in IBD, changes to address residual functional symptoms after resolution of inflammation, or to incorporate healthy lifestyle behavior for overall good health. These three aims of the dietary changes merit different answers. For the patient who has residual functional symptoms of diarrhea, abdominal pain, or bloating, despite achieving endoscopic remission of their underlying IBD, dietary strategies can focus on identifying specific dietary triggers of these symptoms and eliminating them from diet. A low FODMAP diet is effective in improving symptoms of abdominal pain and bloating in randomized controlled trials. Trials of lactose-free or gluten-free diets may help identify patients who have lactose intolerance of gluten sensitivity. It is important to ensure that non-culprit food items are re-introduced back in the diet.

For patients who are seeing general good health and reduction in risk of subsequent IBD relapses, a Mediterranean style diet may confer overall health benefits and reduce risk of cardiovascular disease and improve longevity. In addition, mechanistically such diets may be beneficial in preventing IBD relapses though high-quality data on this is lacking. In the absence of stricturing disease, incorporation of sufficient amount of dietary fiber, particularly soluble fiber from fruits and vegetables is important and may be associated with reduced risk of IBD relapses. In addition, minimizing consumption of emulsifier and processed foods is also likely to be beneficial in reducing risk of inflammatory activity. If dietary strategies are being used to achieve remission in symptomatic patients with objective inflammation, it is important to first ensure the patient is appropriate for dietary treatment. Most studies of dietary treatment have focused on those with mild disease activity with paucity of data demonstrating the efficacy of diet for moderate-tosevere disease or those with high-risk phenotypes. Consequently, patients with milder disease can be prioritized for a strategy of dietary modulation. While most studies have focused on diet as the sole treatment, it is reasonable and indeed more acceptable to consider using dietary treatment along with pharmacologic therapy, particularly in those with disease at the more moderate end of the spectrum. The second step is to identify the best dietary intervention based on quality of evidence at that time. Since this is a rapidly evolving field, it is best to identify strategies most supported by high quality data at the time such interventions are being suggested. As for pharmacologic therapy, dietary therapies are effective only if one is able to be adherent to them. Thus, it is important to assess patient motivation, lifestyle, and ability to adhere to diet in deciding the right therapeutic diet for the patient. The third step is to define the right duration of intervention before assessment of outcome. For most dietary studies, the initial phase has been 6-8 weeks long. This is an appropriate duration for a dietary trial with close monitoring for disease worsening. Finally, as for other medical therapies, it is important to ensure objective remission through either biomarkers and/or endoscopic evaluation to ensure that symptom improvement parallels resolution of inflammation. 

In parallel with incorporation of diet, it is important to monitor patient for development of nutritional deficiency either as a consequence of their disease or exclusion diets. It is also important to monitor for the development of avoidant eating disorders in patients relying on diet for treatment of their underlying disease or owing to their symptoms. Multidisciplinary care with a trained dietician is a critically important component for ensuring success of dietary treatment strategies in patients with IBD.

References

  1. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 2015;12:20517.
  2. Ananthakrishnan AN, Kaplan GG, Ng SC. Changing Global Epidemiology of Inflammatory Bowel Diseases: Sustaining Health Care Delivery Into the 21st Century. Clin Gastroenterol Hepatol 2020;18:1252-1260.
  3. Crooks B, McLaughlin J, Limdi J. Dietary beliefs and recommendations in inflammatory bowel disease: a national survey of healthcare professionals in the UK. Frontline Gastroenterol 2022;13:25-31.
  4. Lee D, Albenberg L, Compher C, et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 2015;148:1087-106.
  5. Levine A, Rhodes JM, Lindsay JO, et al. Dietary Guidance From the International Organization for the Study of Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020;18:1381-1392.
  6. Lewis JD, Abreu MT. Diet as a Trigger or Therapy for Inflammatory Bowel Diseases. Gastroenterology 2016.
  7. Popkin BM. Global changes in diet and activity patterns as drivers of the nutrition transition. Nestle Nutr Workshop Ser Pediatr Program 2009;63:1-10; discussion 10-4, 259-68.
  8. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2018;390:2769-2778.
  9. Khalili H, Chan SSM, Lochhead P, et al. The role of diet in the aetiopathogenesis of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2018;15:525535.
  10. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 2013;145:970-7.
  11. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut 2014;63:776-84.
  12. de Silva PS, Olsen A, Christensen J, et al. An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis. Gastroenterology 2010;139:1912-7.
  13. Jantchou P, Morois S, Clavel-Chapelon F, et al. Animal protein intake and risk of inflammatory bowel disease: The E3N prospective study. Am J Gastroenterol
  14. Ananthakrishnan AN, Khalili H, Higuchi LM, et al. Higher predicted vitamin d status is associated with reduced risk of Crohn’s disease. Gastroenterology 2012;142:482-9.
  15. Ananthakrishnan AN, Khalili H, Song M, et al. Zinc intake and risk of Crohn’s disease and ulcerative colitis: a prospective cohort study. Int J Epidemiol 2015;44:1995-2005.
  16. Khalili H, Hakansson N, Chan SS, et al. Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn’s disease: results from two large prospective cohort studies. Gut 2020.
  17. Racine A, Carbonnel F, Chan SS, et al. Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study. Inflamm Bowel Dis 2016;22:345-54.
  18. Lo CH, Lochhead P, Khalili H, et al. Dietary
    Inflammatory Potential and Risk of Crohn’s Disease and Ulcerative Colitis. Gastroenterology 2020;159:873883 e1.
  19. Lo CH, Khandpur N, Rossato SL, et al. Ultraprocessed Foods and Risk of Crohn’s Disease and Ulcerative Colitis: A Prospective Cohort Study. Clin Gastroenterol Hepatol 2022;20:e1323-e1337.
  20. Narula N, Wong ECL, Dehghan M, et al. Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study. BMJ 2021;374:n1554.
  21. Sasson AN, Ananthakrishnan AN, Raman M. Diet in Treatment of Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2019.
  22. Critch J, Day AS, Otley A, et al. Use of enteral nutrition for the control of intestinal inflammation in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2012;54:298-305.
  23. Day AS, Burgess L. Exclusive enteral nutrition and induction of remission of active Crohn’s disease in children. Expert Rev Clin Immunol 2013;9:375-83; quiz 384.
  24. Kansal S, Wagner J, Kirkwood CD, et al. Enteral Nutrition in Crohn’s Disease: An Underused Therapy. Gastroenterol Res Pract 2013;2013:482108.
  25. Soo J, Malik BA, Turner JM, et al. Use of exclusive enteral nutrition is just as effective as corticosteroids in newly diagnosed pediatric Crohn’s disease. Dig Dis Sci 2013;58:3584-91.
  26. Wall CL, Day AS, Gearry RB. Use of exclusive enteral nutrition in adults with Crohn’s disease: a review. World J Gastroenterol 2013;19:7652-60.
  27. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2007:CD000542.
  28. Lee D, Baldassano RN, Otley AR, et al. Comparative Effectiveness of Nutritional and Biological Therapy in North American Children with Active Crohn’s Disease. Inflamm Bowel Dis 2015;21:1786-93.
  29. Levine A, Wine E, Assa A, et al. Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial. Gastroenterology 2019;157:440-450 e8.
  30. Yanai H, Levine A, Hirsch A, et al. The Crohn’s disease exclusion diet for induction and maintenance of remission in adults with mild-to-moderate Crohn’s disease (CDED-AD): an open-label, pilot, randomised trial. Lancet Gastroenterol Hepatol 2022;7:49-59.
  31. Suskind DL, Wahbeh G, Gregory N, et al. Nutritional therapy in pediatric Crohn disease: the specific carbohydrate diet. J Pediatr Gastroenterol Nutr 2014;58:87-91.
  32. Lewis JD, Sandler RS, Brotherton C, et al. A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn’s Disease. Gastroenterology 2021;161:837-852 e9.
  33. Kedia S, Virmani S, S KV, et al. Faecal microbiota transplantation with anti-inflammatory diet (FMTAID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial. Gut 2022.

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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #1

Exclusive Enteral Nutrition in Inflammatory Bowel Disease: An Under-Appreciated Therapeutic Gem

January 2023 • Volume XLVII, Issue 1
Kelly Issokson,Eric Vasiliauskas

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Patients with inflammatory bowel disease (IBD) experience periods of disease flares and remission throughout their lives. Despite advances in medical therapy that provide increasing treatment options to help patients achieve and maintain remission, complementary diet strategies can work synergistically to improve the clinical course in IBD. Exclusive enteral nutrition (EEN) is a nutritional therapy that has shown promise as a low-risk therapeutic approach to improve symptoms and reduce inflammation, with the potential to heal gut mucosa, heal fistulas, and decrease perioperative complications, all while providing nourishment to the individual. Current underutilization of EEN in the clinical setting may be related to a myriad of factors, including lack of provider awareness and experience, insufficient support staff, or assumed high rate of non-adherence. The aim of this review is to discuss the evidence supporting EEN in adults with IBD and provide practical suggestions for the implementation of this nutritional therapy.

INTRODUCTION

Inflammatory bowel diseases (IBD) are chronic diseases for which there are no known cure. The two main subtypes of IBD include Crohn’s disease (CD) and ulcerative colitis (UC). Individuals with IBD experience periods of disease flares and remission throughout their lives and are commonly managed with medications, which have become increasingly effective for inducing and maintaining remission.

A significant subset of patients does not adequately respond to medical therapies, and it is not uncommon for patients to experience a loss of therapeutic response over time. Further, medications that are traditionally used to induce rapid reduction in symptoms or remission, such as corticosteroids, come with significant potential side effects that increase with long-term use. The European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines for IBD recommend the use of Exclusive Enteral Nutrition (EEN) as primary therapy for inducing remission in pediatric Crohn’s disease, and in adults when steroids are not tolerated or are contraindicated.1

When used as adjunctive therapy, nutritional therapeutics can work synergistically to improve the clinical course in IBD by nourishing the patient, while also reducing symptoms, decreasing inflammation, and synergistically augmenting response to medical therapy. An increasing number of studies in adults with IBD suggest that EEN shows promise as a low-risk therapeutic agent with the potential to not only improve symptoms, but to also reduce inflammation, and even to heal both gut mucosa and fistulas, as well as to decrease perioperative complications. Despite the evidence supporting EEN’s potential benefits, current underutilization in both the inpatient and outpatient clinical settings may be related to a myriad of factors, including lack of clinician awareness and experience, insufficient support staff, or assumed high rate of non-adherence.

What is EEN?

EEN is a nutritional therapy that involves consuming a complete nutrition liquid formula as a sole source of nutrition for 1-12 weeks. Formula is usually taken by mouth but can also be infused via enteric tube. The type of formula and duration of therapy depends on the indication for use, patient history, allergies, budget, tolerance, taste and ingredient preference, and availability. See Table 1 for a list of complete nutrition formula options that are commercially available.

The wider variety of formula flavors and compositions, including more organic and vegan options has improved patient acceptance and preference. Formula types that are available include: polymeric (whole, intact proteins), semielemental (hydrolyzed proteins) and elemental (free amino acids). The more palatable polymeric formulas are effective for induction of remission, but patients with allergies, impaired absorption, or prior resections may require a semi-elemental or elemental formula.

Shorter durations of EEN can be used to reduce clinical symptoms or for nutritional optimization in preparation for planned surgery; longer durations are needed to induce endoscopic and histologic remission and healing gut mucosa. EEN has historically been used in children and adolescents with Crohn’s disease, and although its efficacy has been demonstrated in adults, EEN is underutilized as an adjunctive therapy. While the experience with EEN in UC is emerging, to date there remains a paucity of literature for its potential roles in UC management.

EEN for Induction of Remission

Corticosteroid therapy has traditionally been used to induce remission in active IBD. While often effective, the short- and long-term side effects, including hyperglycemia, fluid retention, changes in mood, insomnia, hypertension, glaucoma, cataracts, osteoporosis, avascular necrosis, and effects on wound healing and body distortion such as rapid weight gain, moon facies and stretch marks remain a concern to patients and providers, so reducing exposure to corticosteroids is

imperative. EEN provides an opportunity to limit steroid exposure, and has the added benefits of nourishing the individual, correcting dysbiosis seen in active disease, decreasing inflammatory cytokine production, and promoting mucosal healing.2 EEN can be particularly beneficial for those desiring to avoid steroids, those who are intolerant to steroids, and those who are pregnant.

EEN has been predominantly studied in pediatric Crohn’s disease, where durations of therapy of 6-12 weeks have demonstrated remission (clinical and potentially biochemical, endoscopic, radiologic) in up to 80% of cases.3 While the mechanics of EEN are thought to be the same in adults, a recent Cochrane meta-analysis found EEN was slightly less effective than steroids for remission induction in adults with Crohn’s disease.4 It is important to consider the studies used for this meta-analysis were of low quality and had a high rate of non-adherence to EEN.5 Low adherence and underutilization are likely multifactorial and may be due to palatability of formula, lack of insurance coverage, lack of knowledgeable support staff, and lack of training, experience, and conviction of efficacy among providers. A recent prospective study of children and adults on EEN, mucosal healing was reported in 79% of patients on EEN for an average of 123 days (range 50-212 days).6 Thus, emerging evidence supports the role of EEN as a very safe, effective option for primary induction therapy for adult Crohn’s disease patients who are flaring.

While the literature surrounding the effectiveness of EEN in pregnancy is limited, a recent retrospective study demonstrated the potential to achieve clinical remission in patients with Crohn’s disease who were pregnant and consumed a peptide-based EEN formula for 12 weeks.7 A recent randomized controlled trial of 62 adults hospitalized for acute severe ulcerative colitis flares found that 7 days of EEN using a semielemental formula augmented response to steroids, reduced hospital length of stay, and resulted in reduced colectomy and re-hospitalization at 6 months compared to those who received standard of care.8 That being said, there remains a paucity of published evidence for the potential roles of EEN in UC.

It should be acknowledged that replacing food with formula exclusively can be too challenging for some patients to implement in real life. Thus, it is important to recognized that evidence suggests that even partial enteral nutrition (PEN) strategies (formula combined with foods) may be effective as a combination therapy along with biologics for inducing and maintaining remission in patients with Crohn’s disease. A meta-analysis of four studies in adults with Crohn’s disease (n=342) found the PEN approach as combination therapy with a biologic (infliximab) resulted in 69% of patients achieving clinical remission versus 45% on a biologic as monotherapy. The study authors pointed out that that amounts to over a 2-fold increase in the odds of achieving clinical remission amongst patients on combination therapy with PEN added to infliximab compared with those on infliximab monotherapy alone. Further, 74% on infliximab/ PEN combination therapy remained in clinical remission at one year, compared to 49% of those on infliximab monotherapy and the probability of maintaining clinical remission on combination therapy appeared to extend beyond 1 year.9

EEN and Fistulizing Disease

A severe complication of Crohn’s disease includes fistula formation. A fistula is an abnormal connection between the gut and another organ (e.g., bladder, vagina, skin, or other part of the intestinal tract). In IBD, fistulas can form as a result of inadequately treated inflammation. Medical therapy traditionally involves starting or adjusting immunosuppressive/ biologic medications, surgery, and/or local control with the placement of setons (flexible tubing or material inserted within the fistula tract that keeps the fistula open to allow it to drain). Studies investigating EEN in patients with Crohn’s disease demonstrate high rates of remission and fistula closure after 4-12 weeks of EEN therapy. A single-center prospective study (n=41) of patients with entero-cutaneous fistulas (ECF) found 80% achieved full clinical remission and 75% had fistula closure after 12 weeks on EEN.10 Another study (n=48) found similar rates of ECF closure at 62% after 3 months on EEN using a semi-elemental formula, with an average fistula closure time around 32 days. Additionally, they found improvements in nutrition with increases in weight, BMI, and hemoglobin, and identified lower baseline CRP and higher baseline BMI as predictors of response to EEN.11

EEN in Elective Surgery

A recent meta-analysis of contemporary studies found a 5-year cumulative risk of surgery of 7% in UC and 18% in Crohn’s disease.12 Importantly, in patients heading towards surgery malnutrition is frequently identified and increases the risk for post-op complications and mortality. Therefore, clinical guidelines recommend nutrition support for optimization perioperatively in those with weight loss >10% in 6 months, BMI <18.5 kg/m2, or an albumin of <3 g/dL, and delaying surgery for 7-14 days if feasible to allow for nutrition optimization.1 Administration of EEN 4-6 weeks perioperatively may serve as a tool to improve nutrition status pre-operatively, decrease inflammation, improve post-operative outcomes, and a small, but significant subset of patients may even be able to avoid surgery when treated with perioperative EEN. The latter was highlighted by a retrospective study (n=51) of adult patients with complicated Crohn’s disease in which 25% of patients who received EEN as part of their preoperative management for an average of 6 weeks were able to avoid surgery. In those who proceeded with surgery, there was a significant decrease in length of time in the operating room, anastomotic leak, and abscess formation.13 The positive findings from this study are limited by the design (retrospective, single center, small study population). Another single center study (n=87) found 4 weeks of EEN taken via naso-gastric tube decreased risk for surgery over a 2-year follow-up period in adult patients with Crohn’s disease and intra-abdominal abscess compared to those who received standard care (26% vs. 56%, p=0.01).14 Furthermore, a meta-analysis found pre-op EEN significantly reduced post-operative complications compared to those who did not receive EEN (21% vs. 73%, p<0.001), with a number needed to treat of 2.15 While larger, prospective trials are needed to confirm these results, these studies do highlight the use of EEN as a promising potentially effective tool to improve surgical outcomes.

PRACTICAL APPLICATIONS
Commencement of EEN

The primary reason EEN is not used as widely in adults is the lack of multidisciplinary support. Many, if not most, gastroenterologists and surgeons who care for adult patients with IBD are not well-educated on the potential benefits of enteral nutrition, nor are convinced of its potential efficacy, and few have the experience to effectively initiate, guide, and monitor patients on EEN. Optimizing success with EEN therapy involves much more that writing a prescription for EEN. A registered dietitian (RD) who is experienced in IBD and experienced with EEN is a vital member on the care team who can provide a comprehensive nutrition assessment and guide patients who are appropriate for and desire EEN as therapy (see Figure 1 for an EEN algorithm). Small studies suggest that adult patients with IBD do not have increased energy requirements above the general population, therefore standard predictive equations (e.g., Mifflin St. Jeor) can be used when estimating nutrition needs.1 Importantly, additional calories may very well be needed to assist with wound healing, perioperative needs, or weight gain. Similarly, while protein needs are comparable to the general population in quiescent disease (1 gm/kg), they are increased during active disease (1.2-1.5 grams/kg) due to increased proteolysis, enteric losses, or effects of disease treatments such as corticosteroids.1

Ideal candidates for EEN include not only those who are malnourished, but also those motivated patients with active disease, disease complications (e.g., fistulas, strictures), those who are planning for potential surgery, and those desiring to limit corticosteroid exposure (e.g., those intolerant or non-responsive to corticosteroids, or those who are pregnant). It is also important to consider psycho-social factors, as EEN can be cognitively and emotionally demanding. Researchers found that those with greater levels of conscientiousness were more adherent to therapy.16 Access to a social worker,psychologist and/or psychiatrist – ideally as part of the multidisciplinary IBD team, or at least familiar with IBD – is important for supporting patients during disease flares and may help with successful completion of EEN therapy. Once a nutrition prescription has been developed, the next step in initiating EEN is to choose a formula. Consider nutrition content, cost, availability, allergies/intolerances, medical/ surgical history (length of functional intestine remaining), palatability, and patient preference when selecting a formula. It may be beneficial for patients to try multiple formula options before deciding on which to use for their EEN treatment, as palatability, tolerance, and cost are important

factors for adherence. Some patients desire organic formulas or formulas with less sugar, and some desire concentrated formulas to allow nutrient needs to be met in a smaller volume. Formulas for EEN are not often covered by insurance companies but writing a prescription along with a letter of medical necessity can increase the odds of formula coverage. This is important for the patient to know upfront so they can determine if EEN is an affordable therapy in the event they must pay out of pocket. The cost of formulas vary; with standard 1 kcal/mL formulas being the most cost-effective and concentrated or semi-elemental or elemental being the most expensive (see Table 1 for commercially available formulas). When discussing the cost of EEN or PEN therapy, it can be helpful to point out that the formula will be replacing what they would normally spend on meals, snacks, and beverages consumed at home or when eating out. During the initial consultation, the patient should receive instruction on the anticipated duration of EEN, which will be determined by the indication for use. The route of administration can be oral or via a small diameter flexible enteric feeding tube (self-inserted or inserted by staff). Monitoring patients on EEN may include weekly update on weight and symptoms, and periodic labs or stool tests to monitor disease activity and nutrition status (e.g., chemistry panel, c-reactive protein, sedimentation rate, fecal calprotectin, iron studies and complete blood count, zinc, vitamin D (25-OH), vitamin B6).

After selecting a formula, the patient should be provided with instruction on how to start EEN. If the patient regularly consumes caffeine, he or she may want to wean off caffeine in the days before starting EEN to avoid caffeine-withdrawal symptoms. While there is no consensus on how to start EEN, a gradual transition onto EEN over a few days may help with tolerance (e.g., replace one meal each day with 2-3 formula shakes until completely on EEN and off solid foods). This approach would also be recommended if the patient is severely malnourished or at high risk for refeeding syndrome.

Encourage strict adherence to EEN (no other food or beverage except water), as efficacy decreases with exposure of other foods and beverages. Patients should be advised to stop all other nutrition supplements (e.g., multivitamin, calcium) as the nutrition formulas are considered “complete” and fortified, usually providing 100% of the recommended dietary allowance in about 1 liter.

Clinical symptoms, such as bloating, pain, diarrhea, urgency, constipation, may occur during the transition period off food and onto EEN, thus patients should be reassured that such symptoms should subside and improve within 1-2 weeks. Drinking the formula slowly (over 30-60 minutes) and spacing the formula out throughout the day can help with tolerance. If symptoms persist at two weeks, consider alternate formula or alternate route of administration (e.g., small bore nasogastric feeding tube) or alternate therapy. Hydration is important to emphasize. To optimize tolerance and success, patients who struggle with any aspect of EEN should be encouraged to contact their RD for support and guidance as issues arise. At our center, patients are given instructions to provide weekly updates to the RD through a secure patient portal to ensure the patient is tolerating EEN, weight goals are met, symptoms are improving, and that EEN remains an appropriate treatment. The weekly patient updates allow the RD to intervene early if changes to the treatment plan are needed, such as increases in formula volume goal to support weight gain, or to provide support if patients are having difficulty implementing EEN at home or in social settings.

Navigating Life on EEN

Relying on a liquid diet as a sole source of nutrition for weeks at a time can be emotionally and cognitively challenging. Eating food is how we nourish our bodies, both physically and emotionally. The ritual of eating plays a large part in how we experience cultures, celebrate with friends, socialize with colleagues, connect with family, and grieve. Acknowledge the impact EEN will have on patients. For some, EEN may feel isolating. For others, EEN may be liberating by allowing them to be more active and social because the symptoms they had been experiencing prior to EEN are improved by EEN.

With the reduction in inflammatory cytokines, mucosal healing, and the full nourishment of the patient, an increase in quality of life is to be expected. Patients should be encouraged to engage in activities that bring them joy (e.g., hiking, biking, swimming, going to the beach, seeing family or friends). If activities involve food, it may be best to arrive full (drink shakes beforehand) or bring shakes to the event to allow nourishment at the same time others are eating and drinking.

The formulas can become monotonous in both flavor and texture. Encourage patients to choose different flavors of formula to help decrease monotony. Mixing flavors (chocolate, vanilla) can also provide a little extra variety. Some find freezing formula in ice cube trays to blend with formula from the can is a fun way to add different texture. Other creative options include freezing formula in popsicle molds to serve as a cool treat on a hot day, or warming chocolate formula in a mug can provide some soothing comfort on a cold night. Some formulas can be difficult to purchase from the store and transport home. Writing a prescription for EEN and connecting the patient with a home health company may help increase the odds that the formula will be covered, all or in part, by their insurance. Additionally, patients will receive supplies of formula shipped directly to their home, ensuring they have enough formula for their EEN. In our center, we also provide travel letters to patients who will be going through security checkpoints. This allows them to carry their formula with them during their travels instead of having to go without.

Transitioning from EEN

EEN is not a sustainable long-term therapy for most individuals. There is a lack of evidence to recommend an evidence-based specific strategy for food reintroduction after EEN. Discussions about how to transition off EEN can happen at any point during the patient’s journey but should commence prior to the end date for EEN.

A single center study in pediatric patients with Crohn’s disease found no difference in rates of clinical remission at 12 months with a gradual food reintroduction over 5 weeks versus rapid reintroduction of food over 3 days.17 While this study was done in children and not adults, it provides some reassurance that a rapid food reintroduction doesn’t worsen disease outcomes and may be the best approach, as long and drawnout food reintroductions may result in inadequate intake, weight loss, or nutrient imbalances. It may be prudent to advise patients to start with small portions of low fat and well-cooked foods (see Table 2 for examples) to assist with tolerance when initially re-introducing foods.

Research suggests specific diet therapies may assist with maintenance of remission; these include adoption of longer-term PEN, a semi-vegetarian diet, or a diet that follows guidelines from the International Organization of the Study for IBD (IOIBD); it is beyond the scope of this article to review these diets. Thus, transitioning from EEN to such an adjunctive nutritional strategy should be considered beyond just maintenance medicinal strategies alone. Regardless of the strategy, a follow-up visit with the RD a few weeks before stopping EEN or after starting foods is recommended to ensure diet balance and tolerance.

Conclusion

EEN is a safe and effective therapy for IBD with the potential to induce clinical, endoscopic, and histologic remission, heal fistulas, and when used perioperatively, to improve nutrition status and surgical outcomes, while avoiding steroid side effects. While most studies have shown the benefit of EEN in pediatric IBD, an increasing number of small studies and meta-analyses show benefits in the adult population as well. EEN is currently underutilized and should be considered in patients as an adjunctive therapeutic tool in the expanding treatment armamentarium. Thoughtful implementation of EEN guided by and supported by the multidisciplinary IBD team is likely to maximize adherence and therapeutic success.

References

  1. Bischoff SC, Escher J, Hebuterne X, et al: ESPEN practical guideline: Clinical Nutrition in inflammatory bowel disease. Clin Nutr 2020;39(3):632-653.
  2. Mitrev N, Huang H, Hannah B, et al: Review of exclusive enteral therapy in adult Crohn’s disease. BMJ Open Gastroenterol 2021;8(1):e000745.
  3. Ashton J, Gavin J, Beattie M: Exclusive enteral nutrition in Crohn’s disease: Evidence and practicalities. Clin Nutr 2019;38(1):80-89.
  4. Zachos M, Tondeur M, Griffiths A. Enteral nutritional therapy for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev 2007;24(1):CD000542.
  5. Wall CL, Day AS, Gearry RB: Use of exclusive enteral nutrition in adults with Crohn’s disease: a review. World J Gastroenterol 2013;19(43):7652-7660.
  6. Chen JM, He LW, Yan T, et al: Oral exclusive enteral nutrition induces mucosal and transmural healing in patients with Crohn’s disease. Gastroenterol Rep (Oxf) 2019;7(3):176-184.
  7. Yang Q, Tang J, Ding N, et al: Twelve-week peptidebased formula therapy may be effective in inducing remission of active Crohn disease among women who are pregnant or preparing for pregnancy. Nutr Clin Pract 2022;37(2):366-376.
  8. Sahu P, Kedia S, Vuyyuru SK, et al: Randomized clinical trial: exclusive enteral nutrition versus standard of care for acute severe ulcerative colitis. Aliment Pharmacol Ther 2021;53(5):568-576.
  9. Nguyan DL, Palmer LB, Nguyen ET, et al: Specialized enteral nutrition therapy in Crohn’s disease patients on maintenance infliximab therapy: a meta-analysis. Therap Adv Gastroenterol 2015;8(4):168-175.
  10. Yang Q, Gao X, Chen H, et al: Efficacy of exclusive enteral nutrition in complicated Crohn’s disease. Scand J Gastroenterol 2017;52(9):995-1001.
  11. Yan D, Ren J, Wang G, et al: Predictors of response to enteral nutrition in abdominal enterocutaneous fistula patients with Crohn’s disease. Eur J Clin Nutr 2014;68:959–63.
  12. Tsai L, Ma C, Dulai PS, et al: Contemporary Risk of Surgery in Patients with Ulcerative Colitis and Crohn’s Disease: A Meta-Analysis of Population-Based Cohorts. Clin Gastroenterol Hepatol 2021;19(10):2031-2045.
  13. Heerasing N, Thompson B, Hendy P, et al. Exclusive enteral nutrition provides an effective bridge to safer interval elective surgery for adults with Crohn’s disease. Aliment Pharmacol Ther 2017;45:660–9.
  14. Zheng X-B, Peng X, Xie X-Y, et al: Enteral nutrition is associated with a decreased risk of surgical intervention in Crohn’s disease patients with spontaneous intra-abdominal abscess. Rev Esp Enferm Dig 2017;109:834–42.
  15. Brennan GT, Ha I, Hogan C, et al: Does preoperative enteral or parenteral nutrition reduce postoperative complications in Crohn’s disease patients: a metaanalysis. Eur J Gastroenterol Hepatol 2018;30:997– 1002.
  16. Wall CL, McCombie A, Mulder R, et al: Adherence to exclusive enteral nutrition by adults with active Crohn’s disease is associated with conscientiousness personality trait: a sub-study. J Hum Nutr Diet 2020;33(6):752-757.
  17. Faiman A, Mutalib M, Moylan A, et al: Standard versus rapid food reintroduction after exclusive enteral nutritional therapy in paediatric Crohn’s Disease. Eur J gastroenterol Hepatol 2014;26(3):276-281.

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INTRODUCTION: NUTRITION REVIEWS IN GASTROENTEROLOGY

Nutrition Reviews in Gastroenterology The Series: An Homage and a Transition

January 2023 • Volume XLVII, Issue 1
Neha D. Shah,Elizabeth Wall

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Over the years, the series, Nutrition Issues in Gastroenterology, has been a valuable resource for reviews of current evidencebased research in gastrointestinal (GI) nutrition. The series has elevated the status of, and attention to, medical nutrition therapies for GI disorders. One might argue that it has fostered the growth of GI/Nutrition as a discipline for physicians and dietitians alike. The series has solidified that nutrition has an essential place in the literature to advance nutrition research, education, and practice in gastroenterology.

The founding editor, Carol Rees Parrish, MS, RD, has built a library from the series. Since 2003, over 200 articles have been published in the Journal of Practical Gastroenterology. We are thankful for her passion, dedication, and diligence towards the series that has served to counteract misinformation and give practical applications to integrate into clinical practice. Through the years, Carol Rees Parrish, MS, RD has recruited countless interdisciplinary authors to contribute their knowledge and nutrition expertise on a variety of topics. It takes a village!

Starting January 2023, the baton will pass and so begins a new era of the Practical Gastroenterology Nutrition Series. As the new editors for the series, now called Nutrition Reviews in Gastroenterology, we will continue to strive to publish evidencebased nutrition reviews to provide updates for clinical practice. We look forward to our new role.

We welcome your ideas. If there are GI-related nutrition topics of interest to the readers of Practical Gastroenterology, please contact the series editors, Neha D. Shah MPH, RD, CNSC, CHES at neha@nehashahnutrition.com and Elizabeth Wall, MS, RDN-AP, CNSC at Elizabeth.Wall@uchicagomedicine.org.

Thank you for your ongoing support for the series.

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