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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MEDICAL BULLETIN BOARD

Liver Health Initiative Working Toward Eliminating Hepatitis

Promoting Liver Health Education. Our Passion is Prevention. Health programs and efforts to inform the public about the importance of sharing liver education can play a major role in prevention as well as patient care.

January 3, 2023 – Health programs and efforts to inform the public about the importance of sharing liver education can play a major role in prevention as well as patient care.

Despite major advances and extensive awareness campaigns being promoted to encourage testing for hepatitis, we’re very far from reaching elimination targets. Many barriers exist including poor access to prompt testing, persistently high costs of treatment, and ultimately, lack of awareness about the need for testing and treatment.

One study out of Kentucky is attempting to make headway by utilizing diagnostic methods for on-the-spot testing with rapid results in approximately one hour after a finger prick. This can significantly improve testing opportunities, and if coupled with immediate treatment, we have greater odds of reaching difficult to reach vulnerable populations.

However, this new effort to fortify testing does not negate the power of public education and awareness.

A vitally important component that has been glaringly absent in current efforts to eliminate hepatitis B and hepatitis C has been education about the liver itself. Most people have little to no knowledge of how important their noncomplaining liver is, how it is damaged by hepatitis viruses or how to protect it from harm. Tragically, they are unknowingly participating in liver damaging activities including those that expose them to hepatitis viruses that infect their liver and its miraculous life supporting liver cells.

Awareness campaigns have tried for several years to encourage people to be tested for silent or undiagnosed hepatitis that affects an organ they know little or nothing about. This issue is deterring screening and testing, as well as treatment initiation and compliance.

Addressing this issue, hepatitis, and other liver related diseases including obesity and cancer, the Liver Health Initiative (LHI) has made information about complex liver functions understandable, personal and even entertaining using memorable analogies and story-telling techniques. These communication techniques empower individuals to act on information provided.

Prominent institutions including Virginia Commonwealth University Medical School, Johns Hopkins University Medical School and Bloomberg School of Public Health, University of Illinois, The Carle Illinois Medical School, and University of North Texas Health Sciences Center among others have adopted LHI’s approach and Foundation for Decision Making teaching tools to enhance their health education programs and efforts to inform their audiences about the importance of communicating liver health information to patients and the public as well.

Currently, information about the liver is absent in schools and most hepatitis agencies and programs. Although two research studies confirm the effectiveness of liver health education in motivating individuals to avoid liver damaging behaviors, children and adults are being denied information about the liver. The National Academy of Sciences requires additional studies to be conducted to provide a stronger foundation for integrating this approach broadly in interventions to address hepatitis and other liver diseases.

While working hard to develop a long-awaited vaccine against hepatitis C, Sir Michael Houghton,

PhD, Nobel Laureate and member of LHI Board of Directors said, “These understandable and memorable liver related communication techniques enhance efforts to empower patients to seek testing for hepatitis and other liver diseases. An initiative that is long overdue.”

For further information, visit us at:

Thelma King Thiel, Chair Liver Health Initiative

Email: livrlady@gmail.com

Twitter: @the_liver_lady

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #48

The Overlooked Symptoms of Cirrhosis

January 2023 • Volume XLVII, Issue 1
Elliot B. Tapper

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Cirrhosis is increasingly common and morbid. While contemporary care often focuses on the classic complications of cirrhosis, the overlooked symptoms of cirrhosis pose a great toll on patient well-being. These symptoms include muscle cramps, itching, sleep disorder, falls, sexual dysfunction, itching, and chronic pain. This review aims to provide a practical way of addressing the symptoms of cirrhosis with the aim of enriching quality of life for those living with cirrhosis.

Cirrhosis is common and morbid. Its prevalence addressing the symptoms of cirrhosis with the aim exceeds >1 million persons in the United of enriching quality of life for those living with States (US) alone,5 rising by 50% in the past cirrhosis. Recommendations are summarized in 20 years.6 There has been substantial progress in the early detection and supportive care for cirrhosis. While contemporary care often focuses on screening for and managing the complications of cirrhosis such as hepatocellular carcinoma, varices, ascites, and hepatic encephalopathy (HE), the overlooked symptoms of cirrhosis take a great toll on patient well-being.7 These symptoms include muscle cramps, sleep disorder, falls, sexual dysfunction, itching, and chronic pain. It is recognized that the identification and management of these symptoms is part of high-quality care.1-4 This review aims to provide a practical way of addressing the symptoms of cirrhosis with the aim of enriching quality of life for those living with cirrhosis. Recommendations are summarized in Figure 1.

Pruritus

Patients with cholestatic liver disease can experience profound itching.8 Patients with noncholestatic liver disease also experience bothersome itching, however the evidence supporting specific interventions is often lacking for these patients. Pruritus can be screened with the question “How much of the time have you been troubled by itching during the last two weeks?”, after which its severity can be assessed using a visual analog scale. The mechanisms of itch in cirrhosis are varied and involve dry skin, increased pruritogens (known, like bile salts, or unknown), and increased itch perception or catastrophizing. For this reason, treatments address each step in this conceptual model of pruritis.8 Pharmacotherapeutic options for cholestatic pruritus that have been tested in clinical trials include bile acid binders cholestyramine (48g BID-QID),9 colesevelam (2-8g BID),10 rifampin (150-300mg BID),11,12 naltrexone (50mg daily),13-15 sertraline (25-100mg daily),16 and bezafibrate (can be replaced with fenofibrate, 100-145mg daily).17,18 These therapies are often ineffective in noncholestatic cirrhosis. A prudent clinical strategy is to identify bothersome itch, counsel on the importance of frequent whole-body moisturizing, and cautiously utilize therapies for patients with persistent unmet needs.

Muscle Cramps

Muscle cramps are common in cirrhosis, impacting 1 in 3 patients and causing poor health-related quality of life.19-21 Muscle cramps can be identified by asking “During the past month, how many painful muscle spasms, cramps, or charley horses have you had? Do they bother you?” Thereafter, the severity of muscle cramps should be assessed using a visual analog scale. Pharmacological treatments for muscle cramps in patients with cirrhosis include taurine (1g TID),22 quinidine,23,24 and sips of pickle juice at cramp onset.25 The largest trial enrolling patients with cirrhosis in the US is the PICCLes trial. Upon contact with the oropharynx, the ascetic acid triggers a nerve reflex that aborts the muscle cramp. Though pickle brine has sodium, only 1 tablespoon (~25mg sodium) is required. Compared to a tap water control, sips of kosher or dill pickle brine at cramp onset were more likely to abort the muscle cramp and reduce cramp severity. This intervention did not reduce the frequency of muscle cramps. For this reason, if short-duration, high frequency cramps are the patient’s problem, a trial of taurine may be reasonable.

Sexual Dysfunction

Sexual dysfunction impacts 53%-93% of patients with cirrhosis.19 Sexual satisfaction can be assessed with the questions: Have you had any sexual activity in the past few weeks? How satisfied were you with your sexual function during the past few weeks? Patients who report dissatisfaction who are smoking should be counselled that smoking interferes with sexual function and cessation therapy should be considered. Comorbid depression should be assessed, and care initiated if present. Finally, if the patient is consuming alcohol, abstinence should be recommended with assistance from psychotherapy or pharmacotherapy. Sexual function improves with freedom from alcohol and this expectation can be used when counseling patients.26 A randomized controlled trial of tadalafil safely enhanced erectile function along with improved depression, anxiety, and quality of life compared to placebo.27 Similar results may be seen from sildenafil but this has not been trialed. Testosterone has been trialed and is a promising therapy for men with low testosterone without HCC or prostate cancer who have been counselled regarding cardiovascular risks.28 It may also improve frailty and sarcopenia. There have been no clinical studies of pharmacological treatments for female sexual dysfunction in patients with cirrhosis.29 Vaginal dryness can be queried and addressed with personal lubricants. For postmenopausal women, a trial of topical vaginal estrogen can be helpful. In patients who experience recurrent urinary tract infection, vaginal estrogen can significantly reduce recurrence rates.30

Sleep Disturbances

Sleep disturbances, which include sleepwake inversion, excessive daytime sleepiness, and insomnia, affect 50-80% of patients with cirrhosis.19,31-33 Sleep quality can be assessed with the following question “During the past month, how would you rate your sleep quality overall?” (graded with a 5-point Likert scale from Very Good to Very Bad). Sleep quality can be poor if sleep hygiene is poor, or the patient has sleep apnea. These things can be addressed in parallel with considering the influence of cirrhosis with factors including muscle cramps and HE. Treatment of HE may help to improve sleep disturbances in patients with cirrhosis.34,35 Minimal HE can be identified with using the EncephalApp.com or the animal naming test. Short courses of melatonin (1-3mg), zolpidem, and hydroxyzine (25-50mg) have also been shown to improve sleep quality in randomized trials of patients with Child Pugh A and B cirrhosis.36-38 However, zolpidem should be avoided as it increases the risk of falls and fractures.39,40

Falls

Falls are common. The probability of falls among patients without prior HE was 28.8% and 50.2% at 1 and 3 years.4 HE is likely an even stronger risk factor. The CDC recommends screening for falls among those older than 65 by asking about falls within the past 6 months. However, cirrhosis is a risk factor for falls and falls occur at younger ages in cirrhosis. As such, screening may be beneficial. Interventions should be focused on eliminating as many risk factors as possible in each individual patient. Evidence-interventions include HE-directed therapy for those with cognitive dysfunction, tai chi, exercise programs, and reduction of polypharmacy, particularly hypnotics like zolpidem.41

Pain

Chronic pain is a challenging comorbidity in the management of cirrhosis. Pain is common – cramps, symptomatic ascites, injurious falls with fractures – and its management is complicated by a narrow therapeutic index related to cirrhosis physiology. For example, nonsteroidal antiinflammatory medications can cause renal injury and worsened ascites and opioids can cause constipation, precipitating HE. The management of chronic pain benefits first from an accurate classification of pain: nociceptive (bodily injury), neuropathic, and nociplastic. Nociplastic pain is typically widespread and features no evidence of tissue or nerve damage such as fibromyalgia or irritable bowel syndrome. Nociceptive pain should be managed with low dose (maximum 2000mg daily) acetaminophen, topical therapy (e.g., topical diclofenac), or low dose opioids for acute pain such as fractures, provided that constipation is proactively avoided. Neuropathic pain can be treated with topical therapy (e.g., capsaicin, lidocaine), local injections if amenable, or tricyclic antidepressants. Nociplastic pain benefits from a holistic approach including addressing sleep disorder and mood disorder and promoting physical and mindfulness activities prior or in addition to any pharmacologic interventions.42

Conclusion

The overlooked symptoms of cirrhosis are common, morbid, and matter to patients. There are simple, quick ways to screen for these symptoms. Each symptom, furthermore, can be improved with evidence-based therapies and approaches. In many cases, first-line therapies may not prove effective. However, patients will appreciate the attention to a distressing problem after which stepwise, multidisciplinary care can deliberately trial supportive therapies. The expectation is not that these recommendations will solve all symptoms – though in some cases they will – but rather that patient’s well-being becomes of focus of their clinical care.

References

  1. Kanwal F, Tapper EB, Ho C, et al. Development of quality measures in cirrhosis by the Practice Metrics Committee of the American Association for the Study of Liver Diseases. Hepatology 2019;69:17871797.
  2. Tapper E, Kanwal F, Asrani S, et al. Patient Reported Outcomes in Cirrhosis: A Scoping Review of the Literature. Hepatology (Baltimore, Md.) 2017.
  3. Asrani SK, Ghabril MS, Kuo A, et al. Quality measures in HCC care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases. Hepatology 2022;75:12891299.
  4. Serper M, Parikh ND, Thiele G, et al. Patientreported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases. Hepatology 2022.
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INTRODUCTION: DISPATCHES FROM THE GUILD CONFERENCE

Dispatches from the GUILD Conference 2023

January 2023 • Volume XLVII, Issue 1
Uma Mahadevan

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Welcome to the seventh annual Dispatches from GUILD Conference series. The Gastrointestinal Updates-Inflammatory Bowel-Liver Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February (GUILD 2023: February 19-22). We are delighted to offer a hybrid meeting with over 250 health care providers attending live. GUILD again provides cutting edge updates in gastroenterology by world class speakers. Our topics this year include 2 days of IBD updates, a day of hepatology and a day devoted to esophageal disorders. We understand that trainees are our future. Ten Gastroenterology fellows were selected to attend the meeting and receive daily mentoring and networking from our star faculty. GUILD also recognizes the role played by nurse practitioners and physician assistants in the care of IBD and Liver patients and introduced a boot camp in 2019, awarding 10 scholarships to APPs to attend the meeting.

To share our learning with the gastroenterology community at large, we are happy to continue our series beginning with the following article, “The Overlooked Symptoms of Cirrhosis”.

We look forward to providing informative and educational articles covering IBD, Hepatology and special topics in GI in Practical Gastroenterology over the following months. We hope to see you all in person for GUILD 2023 in Maui February 19-22.

For more information on the GUILD Conference, visit: guildconference.com

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From the Pediatric Literature

From the Pediatric Literature

January 2023 • Volume XLVII, Issue 1

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More Diagnostic Use for MMP-7?

The finding of direct hyperbilirubinemia in a neonatal infant is a significant concern as cholestatic disorders, especially biliary atresia, need diagnostic and therapeutic interventions quickly. However, other causes of cholestasis can occur in neonates, especially in those infants receiving total parenteral nutrition (TPN) with resultant cholestasis. Serum matrix metalloproteinase-7 (MMP-7) has shown tremendous promise in helping to diagnose biliary atresia in neonates. Thus, the authors looked at the ability of MMP-7 to differentiate cholestasis caused by biliary atresia versus cholestasis caused by TPN in neonates. 

The authors of the retrospective study evaluated MMP-7 levels in infants less than 6 months of age with conjugated hyperbilirubinemia (defined as a direct hyperbilirubinemia ≥ 1 mg/dL). Infants were defined as having TPN-associated cholestasis if they received TPN in the first 30 days of life, had no other identified cause of cholestasis, had an improvement in cholestasis after stopping TPN, or were found to have normal biliary anatomy upon death and subsequent autopsy. MMP-7 levels were obtained while patients had active cholestasis. A total of 15 patients with TPN-associated cholestasis then were compared to 4 patients with biliary atresia status post hepatoportoenterostomy surgery. Of note, none of the patients with biliary atresia had exposure to TPN.  There was no significant difference in age at which time MMP-7 levels were obtained. The median time of TPN exposure was 50 days (interquartile range: 40-67 days). Infants with TPNassociated cholestasis had a significantly lower gestational age compared to patients with biliary atresia, likely due to their history of prematurity. The authors found that total serum bilirubin levels, direct serum bilirubin, and gamma-glutamyl transferase levels were not significantly different between infants with biliary atresia and infants with TPN-associated cholestasis. However, infants with biliary atresia had a significantly higher MMP-7 level compared to patient with TPN-associated cholestasis (112.3 versus 37.8 ng/mL, P = 0.03). Only one patient with TPN-associated cholestasis had an MMP-7 level in a range similar to patients with biliary atresia. Overall, a serum MMP-7 cutoff level of 52.8 ng/mL in this patient cohort had a sensitivity of 100%, specificity of 93.3% (95% confidence interval 68.1% – 99.8%), positive predictive value of 80% (95% confidence interval 28.4% – 99.5%) and negative predictive value of 100% in identifying cholestasis from biliary atresia versus cholestasis from TPN. No association between time duration of TPN and MMP-7 levels was noted.

Thus, it appears that MMP-7 testing is becoming an important tool in determining the presence of biliary atresia in infants. An elevated MMP-7 level would warrant a quicker intervention (i.e., potential hepatoportoenterostomy) to prevent complications from a delay in a biliary atresia diagnosis. The ability to obtain MMP-7 levels in children’s hospitals and newborn intensive care units is warranted.

Pooja S, Fawaz R, Cowles R. Comparing serum matrix metalloproteinase-7 in parenteral nutrition-associated liver disease and biliary atresia. Journal of Pediatrics 2022; 249: 97-100.

Changes in Outcomes of Pediatric Crohn’s Disease Over Time

Crohn’s disease (CD) in children is increasing in incidence worldwide for reasons that are not clear. Immunosuppressant (azathioprine, 6-mercaptopurie, methotrexate) and anti-tumor necrosis factor alpha (anti-TNF-α) medications (infliximab, adalimumab, etc.) are being used much more frequently in pediatric patients with CD, and the authors evaluated changes in outcomes in pediatric patients with CD over time via a population study using a pediatric cohort of patients with CD. Patients for this study came from EPIMAD, which is a longitudinal and prospective study of patients with inflammatory bowel disease (IBD) in northern France. All patients diagnosed with CD between 1988 and 2011 that were younger than 17 years of age were evaluated in this database to see if immunosuppressant and anti-TNF-α therapy reduced pediatric CD complications. Patients were evaluated from 1988 to 1993 (the period before immunosuppressant use), 1994 to 2000 (the period before anti-TNF-α use), and 2001 to 2011 (the period when anti-TNF-α therapy was used). Outcomes, including CD disease behavior, intestinal resection, and hospitalization due to CD flares were compared during these three time periods. 

A total of 1007 pediatric patients with CD were evaluated using the EPIMAD registry. Females comprised 44.8% of the study with the median age at diagnosis being 14.5 years (IQR (interquartile range), 12.0–16.1 years) and the median duration of patient follow-up being 8.8 years (IQR, 4.6–14.2 years). Ileocolonic disease was present in 54.9% of patients. There were 167 pediatric patients (16.7%) enrolled during the time period before immunosuppressant use, 260 patients (25.8%) enrolled during the time period before anti-TNF-α use, and 580 patients (57.5%) enrolled during the time period when anti-TNF-α therapy was used. The authors noted that a 5-year cumulative exposure rate to exclusive enteral nutrition increased significantly throughout the three time periods while the 5-year cumulative exposure rate to any type of corticosteroid did not significantly change. The 5-year cumulative exposure rate to immunosuppressant therapy and anti-TNF-α significantly increased throughout the study while age in years at first exposure to immunosuppressant therapy and anti-TNF-α decreased significantly throughout the study. The exposure rate to a combination of these two types of CD therapies increased significantly throughout the study. Progression to CD-associated stricturing complications decreased significantly over time while progression to CD-associated penetrating disease did not significantly change over time. The authors also noted that the cumulative 5-year intestinal resection rate decreased significantly throughout the study while the 5-year cumulative hospitalization rate for CD-related flares did not significantly change.

This study appears to show that new therapies for pediatric CD may be affecting disease outcomes with the encouraging effects of less stricturing disease and less requirement for intestinal resection. Since children with CD appear to have a higher rate of identifiable genetic causes for immune dysfunction in the setting of CD compared to adults, the long-term use of immunosuppressant therapy and anti-TNF-α in this scenario is still unknown. However, the results of this study suggest that the introduction of new therapies for CD in children appear to be clinically effective.

Ley D, Leroyer A, Dupont C, Sarter H, Bertrand V, Spyckerelle C, Guillon N, Wils P, Savoye G, Turck D, Gower-Rousseau C, Fumery M, on behalf of the Epimad Group. New therapeutic strategies have changed the natural history of pediatric Crohn’s disease: a two-decade population-based study. Clinical Gastroenterology and Hepatology 2022; 20: 2588-2597.

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