NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #222

The Clinician’s Toolkit for the Adult Short Bowel Patient Part I: Nutrition and Hydration Therapy

June 2022 • Volume XLVI, Issue 6
Carol Rees Parrish,Elizabeth Wall

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The care of patients with short bowel syndrome (SBS) varies nationwide. How do we know? Because we receive emails and phone calls from patients and clinicians all over the country (and even outside the country) desperate for help. SBS patients also present to clinic suffering with SBS (or undiagnosed SBS) with very little to no education provided to them. Patients just want a reasonable life back, and to take the best care of their health going forward; clinicians want to help their patients achieve just that. This article aims to address the most common diet and hydration issues that SBS patients struggle with and to provide clinicians with the tools to successfully improve both nutrition and hydration status as well as the overall health and well-being of the adult SBS patient.

Introduction

The gastrointestinal (GI) tract is an intricate and carefully orchestrated food-processing organ designed to digest and absorb the foods and beverages that enter it. Significant loss of the primary absorptive surface area resulting in short bowel syndrome (SBS) will require modifications to the oral diet for the remaining GI tract to compensate for this loss. SBS is defined as < 200cm or >75% of working small bowel (SB—not to be confused with SBS) lost.1 It is also described as an inability to nourish and hydrate an individual while consuming a normal diet and fluid intake. Luminal nutrients from food intake (or enteral infusion in some) are paramount to the GI tract adaptation process for those with SBS; these nutrients initiate the signaling in the GI tract through the secretion of enterohormones that control intestinal motility, absorption, and adaptation.2,3 The most common etiologies that can result in SBS in adults are found in Table 1.4,5

SBS is not just about the loss of SB absorptive surface area causing malabsorption, but encompasses all the regulatory processes that the diseased or resected SB segment controls such as: gastric emptying, motility and transit time, and gastric secretions.6,7 The loss of this “gut intelligence” results in:

  • Intestinal hurry making it difficult for nutrients to have enough time to be absorbed before being excreted
    Poor mixing of pancreatic and biliary secretions with ingested nutrients making digestion of fat particularly challenging
  • Too much acid entering the upper gut from gastric hypersecretion can denature pancreatic enzymes and destabilize bile salts rendering micelle formation ineffective
  • A diminished bile salt pool if too much ileum is resected as the bile salts will be lost in the stool instead of reabsorbed through enterohepatic circulation, and
  • Small intestinal bacterial overgrowth due to loss of the ileocecal valve, or areas of stricture, narrowing, or slowed motility. 

The SB primarily absorbs the vast majority of nutrients ingested. However, in addition to avid absorption of sodium and water, the colon can also absorb up to 500 calories per day through the generation of short chain fatty acids from fiber fermentation.8 Therefore, the presence of a colon can significantly improve the outcome of an individual with SBS and substantially improve survival. In most settings, recruitment of any remaining colon should be performed.
Given the complex malabsorptive disorder associated with SBS, it is difficult for patients to nourish and hydrate themselves without the help of diet modification and attention to oral hydration, selective use of medications, and when necessary, parenteral nutrition or intravenous fluids. Negotiating all aspects of care required of individuals with SBS challenges even the fittest of our patients and exhausts the rest. Patient and caregivers buy into a near fulltime job with honorary degrees in medicine, nursing, physical therapy, pharmacy, dietetics and more. Clinicians on the other hand (many without formal training or experience with SBS), suddenly find themselves in the role of air traffic control at Chicago O’Hare on a Friday night with serious weather approaching when dealing with the complexity that is SBS. Part I of this two-part series will address the most common diet and hydration issues seen in clinic that SBS patients struggle with and will provide clinicians with the tools to successfully improve both nutrition and hydration status, and in turn, overall health and well-being of the adult short bowel patient.

A Word about Anti-motility Medications

While diet and hydration therapy are critical for the success of the SBS patient, most will also require antimotility medications to slow intestinal transit and optimize digestion and absorption of nutrients and fluids in the SB. Often, providers simply prescribe these medications with a flexible dosing schedule of two, three or four times daily. However, taking antimotility medications consistently in a scheduled fashion 30-60 minutes prior to meals will slow gastric emptying, improve digestion, and allow increased nutrient and fluid contact time with intestinal mucosa for increased absorption and reduced stool output.9 There are some patients who will benefit from liquid antimotility agents or crushing the tablet to increase efficacy of the medication. The clinician should discuss proper timing of antimotility medications with meals when talking to SBS patients about diet and hydration. It is imperative for SBS patients to understand why providers might order these medications and how to administer the drugs to optimize absorption. Part II of this series will provide more in-depth information about medication use and abuse in the SBS patient.10

Diet and Nutrition Therapy

Because different sections of the GI tract have different responsibilities, understanding normal anatomy and physiology, with knowledge of the patient’s remaining GI anatomy, will help the clinician tailor the diet to the individual SBS patient. A crucial role of the dietitian is to translate alterations in digestion and nutrient absorption after a bowel resection into a meal plan that not only meets the individual’s preferences and lifestyle but is also presented in a manner that the patient can understand. The patient must be informed of not only what they need to avoid, but more importantly, what they can eat, and the amount and frequency of meals and snacks. Clinicians should ideally start with a good 2 to 3-day diet record of what is normally consumed and then tailor the meal plan—it may feel less like taking things away when readjusting the diet that the patient is familiar with. Expertise in the SBS diet highlights the role of the dietitian as an invaluable team member to these patients. 

The SBS diet is quite similar for those with and without a colon, however, there are some important differences. Table 2 lists the general SBS diet guidelines and Table 3 provides recommendations specific to remnant anatomy. 

About Dietary Oxalate Restriction in SBS

Oxalate kidney stones are of concern for individuals with SBS and some colon in continuity. In the normal GI tract, dietary calcium and oxalate bind to form an insoluble complex that passes unabsorbed in the stool.12 However, when dietary fat is malabsorbed, the fat will preferentially bind to calcium leaving oxalate free in the gut lumen. Free, unbound oxalate passes into the colon where it is readily absorbed across the mucosa into the bloodstream, is then filtered by the kidney, and can bind to blood calcium forming insoluble calcium-oxalate kidney stones.13 As oxalate is not absorbed by the SB, calcium oxalate stones are only expected to occur in the setting of a colon in continuity (although patients without a colon are at higher risk for dehydration and therefore stone formation).14

Kidney stones are not only extremely painful to pass, but if left in the kidney can lead to end stage kidney disease. The last thing someone with SBS needs is reliance on hemodialysis or a kidney transplant. Prevention of calcium-oxalate kidney stones is the best approach. Limit dietary fat in those with a colon. Be mindful that treating bile acid malabsorption with bile acid binders can worsen fat malabsorption, further enhancing oxalate absorption in the colon. Work to balance bile salt sequestration and dietary fat restriction. Of note, for those with > 100 cm of terminal ileum lost (or dysfunctional due to disease), the normal compensatory increase in bile acid synthesis cannot keep up to maintain the intraluminal bile acid pool. As a result, these patients should not be put on bile acid sequestrants or steatorrhea will worsen.15

The best defense against kidney stone formation is to flush the oxalate through the urinary tract by maintaining a urine output > 1500 mL/day.16 A calcium citrate supplement taken with meals will correct metabolic acidosis, if present, and in addition, the calcium will bind free oxalate in the intestinal lumen to prevent absorption. Avoid using calcium carbonate in the setting of acid suppression (proton pump inhibitor or H2-receptor antagonist); the calcium will not solubilize at the higher pH, making it unavailable to bind oxalate.6 A low oxalate diet on top of the SBS diet becomes very restrictive and should only be necessary once a patient has “earned it” by developing a kidney stone or hyperoxaluria. A 24-hour urine collection for volume and urine oxalate can help decipher need for dietary oxalate restriction and increased daily urine volume is warranted when there is concern for calcium oxalate kidney stone formation.

Essential Fatty Acids

Essential fatty acids (EFA) are required for health and development. Good sources of EFAs are plantbased oils such as sunflower, soybean, and walnut. Those with SBS who are dependent on parenteral nutrition and receiving less than 1 g soy-based lipid emulsion/kg/week are at risk of developing EFA deficiency.1 Clinical signs of EFA are dry, scaly, or red patches of skin. Assessment for EFA deficiency (triene-tetraene ratio on a fatty acid panel) is suggested as part of the routine monitoring of micronutrient levels.

Hydrating the SBS Patient

Attaining adequate hydration can be very difficult for patients with end ileostomies;17 it is even more difficult for those with SBS with SB stomas (without a colon in continuity). Renal impairment in the short bowel patient has been well documented.18,19 Most clinicians are aware that individuals with SBS will have difficulty meeting nutritional requirements without diet modification, selected medications, and possibly parenteral nutrition. What is not so apparent is how well they can achieve hydration goals or what hydration goals are for an individual patient. Although serum laboratory values provide clues, they are not the most reliable criteria to assess hydration status; some are only abnormal when significant volume contraction occurs, or worse, acute kidney injury. It is therefore incumbent upon the clinician to ensure both nutrition and hydration adequacy (see Table 4 for signs and symptoms). Clinicians should always ask:

  1. Can the patient nourish themselves?
  2. Can the patient hydrate themselves?
  3. How will each of the above be monitored to ensure success?

to have patients periodically measure their 24hour urine volume to ensure they can make a minimum of 1000-1200 mL/day. Keep in mind, there is nothing wrong with making more urine (ask any nephrologist), but there is a lot wrong with not making enough. Another promising measure of adequate hydration status is a morning spot urine sodium.20 For those with kidney stones, collaboration with the managing nephrologist or urologist may help to determine the appropriate 24-hour urine volume for a particular patient. Remember, the goal for hydration is to protect kidney function and prevent end stage renal disease and future dialysis-dependence.

Hydration Management

Unfortunately, more than one SBS patient has been advised to “just drink more” when they have presented to clinic or the emergency room with dehydration as healthcare providers have presumed the patient was just not drinking enough. However, the true problem in SBS is the lack of absorptive surface area for both salt and water; that their remaining bowel just cannot absorb enough of the fluid consumed. In fact, a vicious cycle of drinking (often hypotonic or hypertonic fluids) can develop in SBS patients who experience an uncontrollable desire to constantly drink fluids. This is caused by chronic, severe, dehydration. In the same way that the patient malabsorbs food and feels constantly hungry (as they are starving); the same is true for the patient who cannot sufficiently absorb enough fluid; they feel constantly and insatiably thirsty. When a patient feels thirsty, they are already dehydrated. Hence, the cycle is perpetuated by drinking more fluids, aggravating diarrheal losses, leading to more thirst, and more drinking yet. Furthermore, there are patients who, no matter what they drink (including oral rehydration solutions [ORS]), only add to their stool or ostomy losses and worsen dehydration. Some patients just need IV fluids, at least until enough adaptation occurs. It is very important for clinicians to identify these patients before deterioration of their renal function occurs. See Table 5 for common scenarios patients report or experience.

Table 6 illustrates the experience of one such patient who thought she was supposed to drink a lot because she had a high output stoma (she was drinking primarily oral rehydration therapy, some water, and 6 ounces of coffee). Her oral fluid intake was reduced every 2 weeks with no other changes to demonstrate to her how much her drinking was driving her unwanted high ostomy output. This underscores how important it is to not only have patients record what they are eating, but what, and how much they are drinking.

Maintaining euvolemia and sodium balance while ingesting common oral liquids can be dependent on the presence or absence of a colon. With a colon segment in continuity, many SBS patients can tolerate hypotonic fluids without excessive fluid losses.21 However, without a colon in continuity, high ostomy outputs are commonly encountered when excess fluid losses result from consuming either hypertonic or hypotonic fluids. Table 7 lists common types of beverages based on their tonicity. It is not enough to suggest to a SBS patient what to drink, but equally as important to teach how to drink, especially how much to drink. It is recommended that in SBS, patients drink small amounts of fluids with meals to ease passage of the food bolus. However, the majority of fluid intake should come from sipping all day long between meals as fluids are more efficiently absorbed when consumed in small amounts, frequently, and between meals.22 Some patients need to be educated on this behavior. A smaller volume of liquid prevents a surge of fluid in the small intestine. This surge can reduce fluid absorption rates through the SB as opposed to absorption.23 In particular, for those with a SB ostomy, excessive fluid intake or drinking too fast (regardless of the fluid type), will lead to a significant loss of fluid, further worsening dehydration. Therefore, good practice is to advise patients of their daily fluid volume goal (which is patient dependent) and encourage sipping these fluids over the course of a day. Until urine output is adequate and stable, 24-hour urine volume should be measured and monitored to optimize volume status and protect kidney function. It may be necessary to demonstrate to patients how the oral fluids they are consuming drive stool output. This can be accomplished by asking the patient to decrease oral fluid intake to only 500mL over 24 hours and have them measure both urine and stool/ostomy output to illustrate the effect of the limited oral fluid intake. However, do not try this without a mechanism to ensure hydration of the patient. Oral Rehydration Solutions (ORS)

In those SBS patients without a colon, additional sodium is often required since every liter of stool output contains 90-110mEq of sodium (2 g sodium or 1 teaspoon table salt).24 However, this amount of salt is usually unpalatable, so consumption of salty foods and ORS is necessary to effectively replace sodium losses. Water absorption in the SB is dependent on the sodium-glucose co-transport system which draws glucose and sodium across the epithelial membrane in equimolar fashion, while allowing for water absorption via paracellular passage.25 Commercial and homemade ORS recipes are based on this premise, and therefore, need similar concentrations of sodium and glucose to allow for water absorption and ultimately hydration of the individual. See Table 8 for examples of commercial ORS (and ORS recipes that can be made at home).

ORS, while lifesaving in many, is not a panacea for all patients with SBS. When starting ORS, it is advisable to have the patient sip 1-2 cups throughout the day while tracking 24-hour urine output. If urine output increases without significant increase in stoma or diarrheal output, then it is ok to slowly increase the daily ORS volume to somewhere between 1-2 liters/day. However, if slowly sipping ORS throughout the day leads to significantly increased stoma output (without a concomitant increase in urine output, or worse, a decrease in urine production), then the ORS trial has failed, and the patient should reduce the consumption of ORS. Before declaring an ORS trial a failure, make sure the patient is slowly sipping the ORS throughout the day and not rapidly consuming the solution just to finish it.

Vitamins and Minerals

Many SBS patients will require vitamin and mineral supplementation throughout their lifetime. The sites of remaining bowel, health of the bowel, intestinal transit time, and nutrient quality of the habitual diet will influence the need for supplementation. Micronutrients of concern, specific to SBS, include fat soluble vitamins (A, D, E, and K), vitamin B12, folate, calcium, magnesium, zinc, iron, copper, and selenium.26 Rapid intestinal transit, chronic vomiting, and parenteral multivitamins less than five days a week (if parenteral support dependent), may necessitate water-soluble vitamin supplementation. The exception to this rule is for vitamin B12; all SBS patients will need routine monitoring for vitamin B12 deficiency by checking both serum B12 and methylmalonic acid on a periodic basis. This is an area ripe for study.27

Table 9 lists examples of oral vitamin and mineral supplements that might be needed by those with SBS. Remember, micronutrient absorption can improve with bowel adaptation and therefore, lifelong monitoring of serum vitamin and mineral levels, as well as a periodic nutrition focused physical exam are essential for the SBS patient. Clinicians monitoring micronutrient levels must recognize that inflammation, acute illness, and hypoproteinemia, can alter transport protein concentrations leading to factitious serum and plasma levels making results difficult to interpret.29,30 It is critical that clinicians do not rely solely on biochemical interpretations to develop micronutrient treatment strategies when a deficiency is suspected. 

Bone health is an excellent example of the need for comprehensive assessment to determine the need for supplementation. Since calcium, vitamin D, and magnesium absorption are often suboptimal in those with SBS, periodic DEXA scans are recommended to evaluate bone density to guide therapy and prevent metabolic bone disease (Table 10).1

Conclusion

Maintaining both nutrition and hydration status are central components to the care of patients with SBS. Failure to attend to these key issues puts the SBS patient at risk for malnutrition, weight loss, nutrient deficiencies, dehydration (with or without electrolyte disarray), nephrolithiasis, and, worse-case scenario, for acute kidney injury, and over time, loss of renal function. With careful education regarding principles of nutrition and hydration, this will set the SBS patient on a path to ensure good health and protection of their renal function. Lifelong monitoring and support from a healthcare team are necessary in all SBS patients as management goals can change over time. Table 11 provides a summary of common clinical blunders and the suitable solution in the care of SBS patients. See Table 12 for SBS-related resources for the clinician.

References

  1. Cuerda C, Pironi L, Arends J, et al. ESPEN practical guideline: Clinical nutrition in chronic intestinal failure. Clin Nutr. 2021;40:5196-5220.
  2. Ziegler TR, Fernandez-Estivanz C, Gu LH, et. al. Distribution of the H+/peptide transporter PepT1 in human intestine: upregulation expression in the colonic mucosa of patients with short-bowel syndrome. Am J Clin Nutr. 2002;75:922-930.
  3. Matarese LE, O’Keefe SJ, Kandil HM, et al. Short bowel syndrome: Clinical guidelines for nutrition management. Nutr Clin Pract. 2005;20(5):493-502.
  4. Dabney A, Thompson J, DiBaise J, et al. Short bowel syndrome after trauma. Am J Surg. 2004;188:792-795.
  5. Dumronggittigule W, Marcus EA, DuBray BJ, et al. Intestinal failure after bariatric surgery: Treatment and outcome at a single-intestinal rehabilitation and transplant center. Surg Obes Relat Dis. 2019 Jan;15(1):98-108.
  6. Massironi S, Cavalcoli F, Rausa E, et al. Understanding short bowel syndrome: Current status and future perspectives. Dig Liver Dis. 2020 Mar;52(3):253-261.
  7. Parrish CR, DiBaise JK. Managing the Adult Patient with Short Bowel Syndrome. Gastroenterol Hepatol (N Y). 2017 Oct;13(10):600-608.
  8. Mortensen PB, M R Clausen MR. Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scand J Gastroenterol Suppl. 1996;216:132-48.
  9. Chan L-N, DiBaise JK, Parrish CR. Short bowel syndrome in adults, Part 4B A guide to front line drugs used in the treatment of short bowel syndrome. Pract Gastroenterol. 2015;4:32-38.
  10. Kumpf V, Parrish. The Clinician’s Toolkit for the Adult Short Bowel Patient: Part II – Pharmacologic Intervention. Pract Gastroenterol. 2022;July(7): in press.
  11. Marteau P, Messing B, Arrigoni E, et al. Do patients with short-bowel syndrome need a lactose-free diet? Nutrition, 1997;13(1):13-16.
  12. Mitchell T, Kumar P, Reddy T, et al. Dietary oxalate and kidney stone formation. Am J Physiol Renal Physiol. 2019 Mar 1;316(3):F409-F413.
  13. Nightingale JMD. The management of intestinal failure: methods to reduce the severity. Pro Nutr Soc. 2003;62:703710.
  14. Rudzinski M, Lawinski M, Gradowski L, et. al. Kidney stones are common in patients with short-bowel syndrome receiving long-term parenteral nutrition: A predictive model of urolithiasis. JPEN J Parent Enteral Nutr. 2022;46(3):671-677.
  15. Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008 Aug;65(16):2461-83.
  16. Borghi L, Meschi T, Amato F, et al. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol. 1996;155(3):839-843.
  17. Squeo GC, Parrish CR. High output ileostomies: preventing acute kidney injury. Pract Gastroenterol. 2022;2:28-39.
  18. Agostini F, Sasdelli AS, Guidetti M, et al. Outcome of kidney function in adults on long-term home parenteral nutrition for chronic intestinal failure. Nutrition. 2019 Apr;60:212-216.
  19. Wang P, Yang J, Zhang Y, et al. Risk Factors for Renal Impairment in Adult Patients withShort Bowel Syndrome. Front Nutr. 2021 Jan 18;7:618758.
  20. Pedersen AKN, Rud C, Wilkens TL, et al. A single urine sodium measurement may validly estimate 24-hour urine sodium excretion in patients with an ileostomy. J Parent Enteral Nutr. 2020;44(2):246-255.
  21. Kelly DG, Nadeau J. Oral rehydration solution: a “low-tech” oft neglected therapy. Nutr Issues Gastroenterol 2004;28:5162.
  22. Sentongo TA. The use of oral rehydration solutions in children and adults. Curr Gastroenterol Rep 2004;6:307-313.
  23. Modigliani R, Bernier JJ. Absorption of glucose, sodium, and water by the human jejunum studied by intestinal perfusion with a proximal occluding balloon and at variable flow rates. Gut 1971;12:184-193.
  24. Nightingale JMD, Lennard-Jones JE, Walker ER, et al. Oral salt supplements to compensate for jejunostomy losses: comparison of sodium chloride capsules, glucose electrolyte solution, and glucose polymer electrolyte solution. Gut 1992;33:759-761.
  25. Ofei SY, Fuchs GJ 3rd. Principles and Practice of Oral Rehydration. Curr Gastroenterol Rep. 2019 Dec 7;21(12):67.
  26. Pironi L, Arends U, Bozzetti F, et al. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr. 2016;35:247-307.
  27. Wall EA. Vitamins: Supplementation and monitoring. In; Short Bowel Syndrome: Practical Approach to Management. Eds, DiBaise JK, Parrish CR, Thompson JS. Boca Raton, FL: CRC Press, 2016, pp. 155-170.
  28. Wall B. Micronutrient Supplementation and Monitoring in Short Bowel Syndrome. under Resources, then educational resources for Clinicians at: SBSCurbside.org; accessed 5/20/22.
  29. Krenitsky J. Management of trace elements in short bowel syndrome. In; Short Bowel Syndrome: Practical Approach to Management. Eds, DiBaise JK, Parrish CR, Thompson JS. Boca Raton, FL: CRC Press, 2016, pp. 171-182.
  30. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guidelines. Clin Nutr. 2022; in press.
  31. Faisal S, Mirza FS. Sublingual vitamin D3 effective in a patient resistant to conventional vitamin D supplementation. AACE Clin Case Rep. 2020 Sep 24;6(6):e342-e345.
  32. Holick MF. Biological Effects of Sunlight, Ultraviolet Radiation, Visible Light, Infrared Radiation and Vitamin D for Health. Anticancer Res. 2016;36(3):1345-56.

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #46

Safety of IBD Medication During Pregnancy and Conception for Men and Women with Inflammatory Bowel Disease

June 2022 • Volume XLVI, Issue 6
Rishika Chugh,Uma Mahadevan

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Inflammatory bowel disease (IBD) has an increasing prevalence worldwide, including young adults. Fertility and pregnancy safety are common topics of concern in this patient population. Maintaining fertility and achieving healthy maternal and fetal outcomes are dependent on disease severity. Steroid free remission for at least three months prior to conception increases the likelihood of sustained remission throughout pregnancy and decreases the risk of pregnancy related complications for both the mother and child. Data from large registries, including PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes), has demonstrated that biologics and thiopurines are low risk during pre-conception, pregnancy, delivery, and lactation. Children with in utero or breastmilk exposure to these medications are not at increased risk of infection during their first year of life and achieve developmental milestones at a rate consistent with that of the general population. Methotrexate must be avoided due to the risk of teratogenicity. Data to support use of small molecule therapies during pregnancy and breastfeeding is lacking at this time.

INTRODUCTION

Inflammatory bowel disease (IBD) is commonly diagnosed between the ages of 18 and 35 years of IBD today. This number is anticipated to go up old, a period when many patients are considering further. The increasing prevalence of IBD in young having children of their own.1 The prevalence of IBD
is continuing to rise, and there are approximately 3.1 million people in the U.S. who carry a diagnosis
of IBD today. This number is anticipated to go up further. The increasing prevalence of IBD in young
adults makes conception and pregnancy in IBD a topic of high importance for gastroenterology providers.2

Fertility

Infertility is defined as the inability to conceive after 12 months of regular, unprotected sexual intercourse.3 In the IBD population, however, a referral to a fertility specialist is suggested after 6 months.4 There are multiple factors that play a role in fertility including psychological factors, history of bowel surgery, zinc deficiency, certain medications, and alcohol and tobacco use.

IBD medications that may contribute to male infertility include methotrexate and sulfasalazine.5 5-aminosalicyclic acid (5-ASA) typically does not impact fertility,6 but sulfasalazine is associated with reversible oligospermia and should be discontinued three to four months prior to attempted conception.7,8

Methotrexate can also result in oligospermia which is reversible with discontinuation of the drug. Biologics and thiopurines do not have any documented impact on fertility.9,10 Data on the fertility risk of approved small molecule drugs, tofacitinib and ozanimod, are lacking at this time.11,12

Other medications used to manage conditions associated with IBD must also be considered. Anxiety and depression have a high prevalence in the IBD population, and the use of psychotropic drugs is common.13 Selective serotonin reuptake inhibitors can cause ejaculatory dysfunction, increased ejaculation latency, and alteration in circulating hormones.14,15 Furthermore, opioid analgesics significantly increase the risk of erectile dysfunction.16,17,18 Zinc deficiency may also be a contributing factor to infertility and levels should be checked when this is a concern.19

Fertility in women is not impacted by most IBD medications. However, methotrexate should be discontinued in women three months prior to conception due to the risk of teratogenicity.

Most surgical management for IBD does not impact fertility in men or women, including limited bowel resection or surgical management of perianal disease. However, total colectomy with ileal pouch anal anastomosis is associated with a 3-fold higher rate of infertility among women and attributed to fallopian tube scarring from pelvic dissection.20,21,22

Pre-Conception Disease Activity

Patients should achieve at least three months of steroid free remission, both clinical and endoscopic, prior to conception. The importance of remission should be emphasized with all women of childbearing age to ensure that they are in optimal health for conception if and when the time comes.4,23 Women with IBD who conceive while in remission will remain in remission 80% of the time whereas those with active disease will either continue to have active or worsening disease in over 60% of cases.24,25 Active disease during pregnancy portends a poor outcome for the mother and fetus and will increase the likelihood of eclampsia, preterm birth, low birth weight, small for gestational age, and poor maternal weight gain leading to intrauterine growth restriction.26-28 On the other hand, pregnancy outcomes in IBD patients with quiescent disease are similar to the general population.29,30

IBD Heritability

Misconceptions regarding heritability have led to voluntary childlessness among men and women with IBD. While genetic inheritance plays a strong role in IBD, other modifiable factors influence heritability including environmental exposures such as tobacco smoke, diet, and air pollution.31 It is suspected that the interaction of genetics under environmental conditions is what leads to the increased incidence of IBD among family members.32

Healthcare Maintenance

Optimizing maternal health prior to conception is critical. Alcohol, tobacco, recreational drugs, and cannabis should all be discontinued. Continued opioid use during pregnancy can lead to neonatal opioid withdrawal syndrome and long-term neurodevelopmental consequences.33,34 Furthermore, women should aim for a healthy body mass index (BMI); increased pre-pregnancy BMI can lead to gestational diabetes, hypertensive disorder, and Caesarean delivery.35

All patients should be up to date with ageappropriate cancer screening including colon cancer screening in those with more than 8 years of colitis, regular pap smears in women, and annual total body skin exams for all patients on thiopurines and biologic therapies.36

Nutrition

Women planning pregnancy should supplement with folic acid 400 micrograms (μg) daily. A minimum of 2 grams of folate daily is suggested for those with a prior small bowel resection or active small bowel disease. Vitamin D supplementation is recommended for all patients, and its administration may decrease the risk of flares in those with ulcerative colitis.37 Vitamin D, zinc, folate, vitamin B12 and other nutritional markers should be evaluated pre-pregnancy and thereafter as needed.4,38-40

Pregnancy Coordinated Care

Coordinated care among multiple specialties and teams is needed to ensure good maternal and fetal outcomes.41,42 A gastroenterologist, ideally one who specializes in IBD, should follow the patient throughout pregnancy, seeing the patient at least once during the first or second trimester and as needed thereafter.4 A maternal fetal medicine specialist should be involved early in pregnancy, regardless of disease activity. A nutritionist, mental health provider, and lactation specialist knowledgeable about IBD drugs may be of assistance as well.4

Disease Flare

Disease activity can increase during pregnancy leading to adverse outcomes. Controlling disease activity prior to conception and during pregnancy with the appropriate medical therapy can mitigate the risk of spontaneous abortion, preterm birth, and labor complications (Figure 1).43

As in non-pregnant IBD patients, when disease activity flares, infection must be ruled out first with evaluation of stool studies. In pregnancy, diagnostic evaluation to obtain objective evidence of inflammation with non-invasive markers is preferred. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may not be as reliable in the pregnant patient, although monitoring overall trends can be helpful.44 Fecal calprotectin (FCP) does rise in correlation with disease activity as well.45,46 Imaging studies can be pursued to obtain further objective information, and MRI without gadolinium or intestinal ultrasound (where available) is preferred.

A flexible sigmoidoscopy can be safely performed during any trimester without sedation and limited preparation with enemas and is preferred over pan-colonoscopy.47 However, when necessary, a complete colonoscopy can be performed in the pregnant patient as well.48 The American Society for Gastrointestinal Endoscopy (ASGE) guidelines suggest placing the patient in the left lateral tilt position to avoid decreased maternal and placental perfusion.49

Treating a disease flare may consist of using a short course of steroids, increasing medication dose, and changing therapy. When medical therapies prove ineffective, surgery can be pursued, preferably during the second trimester. The threshold for surgery in pregnancy is higher but the indications are the same as those in the non-pregnant population – obstruction, perforation, abscess, severe hemorrhage, or acute refractory disease.

Medication Use and Safety

Medication safety is a significant concern among patients who are considering conception or pregnancy.50 Data from the PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes) registry as well as European registries has shown that most IBD drugs do not result in adverse outcomes including congenital malformations, spontaneous abortion, preterm birth, low birth weight, increased infections during the child’s first year of life, or inability to achieve developmental milestones.27,51

Here we will discuss the various medication categories in depth.

5-aminosalycylic acid

5-aminosalicylic acid (5-ASA) agents are low risk during pregnancy and should be continued.52,53 Sulfasalazine does interfere with folate metabolism and carries a theoretical risk of interfering with DNA and RNA synthesis in the fetus, increasing the risk of neural tube defects. However, sulfasalazine can be continued throughout pregnancy along with folic acid supplementation at an increased dose of 2 mg per day.54

Corticosteroids

Corticosteroids may be necessary for disease flare management during pregnancy, but this is not without risk. Children born to mothers who had intrapartum exposure to corticosteroids or in the three months prior to conception were found

to be at increased risk for preterm birth, small for gestational age, low birth weight, intrauterine growth restriction and neonatal intensive care unit admission.55 Steroids should be used at the lowest dose and shortest duration possible. Due to its high first-pass metabolism, budesonide is considered lower risk in pregnancy.

Methotrexate

Methotrexate use during pregnancy is associated with spontaneous abortion and embryotoxicity and must be discontinued at least three months prior to conception.56 This is the only IBD medication to date that is absolutely contraindicated in pregnancy due to its greater than acceptable risk.

Thiopurines: 6-mercaptopurine and azathioprine

Patients who are taking thiopurines pre-conception to maintain remission can continue on their regimen through pregnancy. Data on thiopurines from the PIANO registry has shown no increase in spontaneous abortions, congenital malformations, low birth weight, preterm birth, rates of infection in the child, or developmental delays.57-61 Notably, there may be an increased incidence of intrahepatic cholestasis of pregnancy with thiopurine use.62 Thiopurines should not be started in pregnancy given small but unpredictable risk of leukopenia and pancreatitis as well as slow onset.

Biologic Therapies

Intrapartum use of biologic therapies does not worsen pregnancy or neonatal outcomes, including the risk for intensive care unit admission, infections, and developmental milestones.51,57 These medications can be continued throughout pregnancy. Pre-pregnancy weight should be used for dosing. Changes in drug levels during pregnancy are negligible and do not warrant closer monitoring during this time.63,64

Anti-tumor necrosis factor (anti-TNF) agents used in IBD, including infliximab, adalimumab, certolizumab, and golimumab, are low risk for pregnant patients and their offspring. Dosing can continue throughout pregnancy.65,66

Natalizumab and vedolizumab are integrin receptor antagonists and are also low risk in pregnancy.67,68-70,51 While vedolizumab does carry a more favorable side effect profile compared to anti-TNF agents, a study comparing outcomes in anti-TNF and vedolizumab exposed pregnancies found that there was no difference in rates of prematurity, live births, congenital anomalies, or miscarriages.71

Ustekinumab, an interleukin-12/23 antagonist, can also be continued during pregnancy; health outcomes in the exposed mother and child are comparable to those of the general population.51,72,73

Small Molecule Drugs

Unlike monoclonal antibodies which began active transfer across the placenta in the second trimester, small molecules can cross the placenta during the first trimester.

Tofacitinib, a janus kinase (JAK) inhibitor, and ozanimod, a sphingosine-1-phosphate receptor agonist, are both approved for use in ulcerative colitis.74,75 At this time, there is inadequate data to make conclusions on their safety in pregnancy.

Delivery

Mode of Delivery

The obstetrician should determine the mode of delivery. The two scenarios where the patient’s gastroenterologist suggests method of delivery is if the patient has active perianal disease or a history of ileal pouch anal anastomosis (IPAA). In these situations, a C-section may be recommended due to the risk of fourth-degree laceration and anal sphincter dysfunction with vaginal delivery.76,77,78,79 Anorectal motility may be impacted by IPAA construction and vaginal delivery independently of each other. It is therefore suggested that vaginal delivery be avoided in patients with a history of IPAA to avoid compounding the risk.

Anticoagulation

The incidence of venous thromboembolism (VTE) is elevated in the pregnant IBD patient during pregnancy, and up to 6-12 weeks postpartum, compared to pregnant non-IBD patients.80,81 VTE prophylaxis is indicated during hospitalization and potentially thereafter depending on the patient’s individual risk factors. Unfractionated heparin, low molecular weight heparin, and warfarin are safe for breastfeeding women.4,82

Postpartum Care of Mother

In the first six months postpartum, one third of patients will experience a postpartum flare.83,84 De-escalating IBD therapy during or immediately postpartum is a predictor of a postpartum flare.84 As long as there are no signs of infection, biologic therapies can be resumed as scheduled 24 hours after a vaginal delivery and 48 hours following a C-section.4,85 Non-steroidal anti-inflammatory drugs (NSAIDs) can be used for pain relief but for the shortest duration possible to avoid disease flares. Opioids should be utilized for the shortest duration possible as well, particularly in the breastfeeding woman, to avoid infant sedation.86

Contraception

Contraception should be addressed postpartum. Non-estrogen containing, long-acting reversible contraception (LARC) is preferred due to the increased risk of VTE associated with exogenous estrogen use87,88 and the reduced efficacy of oral contraceptives in those with active small bowel inflammation and prior small bowel resection.4,89

Post-Delivery Care of Baby

Breastfeeding

All biologics and thiopurines used for IBD management are present in low to undetectable levels in breastmilk and can be continued without interruption.90,91 There is no data to support a “pump and dump” method after an injection or infusion of a biologic.

On the other hand, the active metabolite of methotrexate is detectable in breastmilk and most sources recommend not breastfeeding on methotrexate.

5-ASA therapies can be continued in breastfeeding as well. Alternatives to sulfasalazine are preferred since the sulfapyridine metabolite transfers to breastmilk and may cause hemolysis in infants born with a glucose-6-phosphate dehydrogenase (G6PD) deficiency.91

There is not enough data on small molecule therapies in IBD at this time to support breastfeeding safety.

The transfer of steroids to the child via breastmilk does occur but at subtherapeutic levels.4 Budesonide has high first pass metabolism and is low risk during breastfeeding.92,93

Vaccines and Infection Risk

If a child’s mother was exposed to any biologic agents (excluding certolizumab) during the third trimester, any live vaccines should be withheld in the first six months of life. In the United States, this currently only applies to the vaccine against rotavirus, administered at 2 months of age.4,94 All other vaccines can proceed on schedule as indicated by the Center for Disease Control and Prevention guidelines. Children are demonstrated to achieve immunity even when exposed to IBD therapies through breastmilk.95

A child with in utero exposure to biologic therapies does not have an increased risk of infection in the first year of life when compared to the general population. This further applies to biologic exposed children attending day care, a setting that is known to increase incidence of infection in children.96

Developmental Milestones

Infant exposure to biologics and thiopurines either in utero and/or through breastmilk has not been shown to result in any developmental delays. The PIANO study measured developmental milestones at 48 months from birth and found no differences when compared to validated population norms.51 This again holds true when looking at childhood development up to 7 years of age in patients born to IBD-affected mothers.97

CONCLUSION

Pregnancy and fertility should be addressed in all IBD patients considering conception. Fertility, pregnancy outcomes for the mother, and the health of the offspring are all impacted by disease activity. Maternal and fetal outcomes are largely dependent on appropriate IBD care pre-conception and achieving steroid-free remission. Data from the PIANO registry has demonstrated that IBD medications, with the exception of methotrexate, can be used without interruption during pregnancy and breastfeeding. There is inadequate data on small molecule therapies at this time to recommend their use. Fertility in men and women is also negatively impacted by disease activity. While certain medications may be implicated in oligospermia or sperm dysfunction in men, these effects are reversible with discontinuation of the drug.

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FRONTIERS IN ENDOSCOPY, SERIES #82

ERCP During Pregnancy: A Review of Safe Practices

June 2022 • Volume XLVI, Issue 6
Apaar Dadlani,John J. Brandabur,Christopher J. Carlson,Rajnish Mishra,Amarnath V. Ramakrishnan,Mohit Girotra

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Introduction

Hormonal changes during pregnancy contribute to elevated cholesterol levels and a delay in gallbladder emptying, both of which can increase the risk of gallstone formation, the incidence of which is between 3-12% during pregnancy.1 The majority of pregnant patients with cholelithiasis are asymptomatic and do not require therapy. However, 1.2% of pregnant women with cholelithiasis may exhibit symptoms, including right upper quadrant discomfort, nausea, or symptoms of cholecystitis.2 Symptomatic gallstone disease is in fact the second most common abdominal emergency during pregnancy, after acute appendicitis, and may require surgical intervention.

On occasion, a stone or sludge may escape the gallbladder and lodge in the common bile duct (CBD) causing biliary colic, gallstone pancreatitis and/or obstructive jaundice. Although uncommon, choledocholithiasis during pregnancy is a challenging dilemma for treating gastroenterologists, given its complications including pancreatitis and cholangitis, which can be life threatening for both the mother and the fetus, and often necessitate immediate intervention.3,4 Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and stone extraction is the standard of care for management of choledocholithiasis. Aside from the inherent risks of the ERCP procedure, pregnant patients face additional concerns due to the potential harm that ionizing radiation could have on the fetus.5 There have been strategies implemented to relegate the radiation risk to the fetus, such as reducing fluoroscopy time or adopting non-radiation ERCP (NR-ERCP) techniques whenever possible.

Overall, ERCP is now considered relatively safe and effective during pregnancy, and this article intends to discuss the various nuances of this clinical scenario.

Indications

Advances in imaging modalities, including abdominal ultrasound (USG), magnetic resonance imaging/cholangiopancreatography (MRI/MRCP), and endoscopic ultrasound (EUS), have generally obviated diagnostic ERCP in non-pregnant and pregnant patients. Prior to undertaking an ERCP, a strong suspicion of the presence of a CBD stone, as well as radiological assessment is essential.

ERCP should be avoided for weak indications such as preoperative cholangiography in patients with a low probability of having choledocholithiasis. Intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (CCY) should be done in patients thought to have an intermediate probability of a retained CBD stone, and if definite filling defect/s seen, a postoperative ERCP can be performed, thereby avoiding unnecessary preoperative ERCP.

The most common indications for performing therapeutic ERCP during pregnancy are symptomatic choledocholithiasis, obstructive jaundice, biliary pancreatitis, cholangitis or less commonly biliary or pancreatic ductal injury.

ERCP has also been utilized in pregnant patients for management of choledochal cysts, pancreatic adenocarcinoma, and parasitic infestation of the biliary tree according to a few reports.6,7 ERCPs are considered therapeutic when one or more of the following procedures are performed: endoscopic sphincterotomy, stone removal, stent placement, and/or stricture dilation.8 Pancreatic endotherapy generally requires relatively lengthy fluoroscopy time, can be technically challenging, and may be associated with increased risk, and hence, it should preferentially be avoided unless absolutely indicated.

Contradictions

In serious obstetric complications such as placental abruption, imminent delivery, ruptured membranes, or eclampsia, endoscopy is generally contraindicated.

Concerns and Risks Associated with ERCP in Pregnancy

Radiation Risk to the Fetus

Exposure to ionizing radiation prenatally can have an impact on embryonic and fetal development, depending on the dose and gestational age at which the exposure occurs. Potential radiation exposure risks to the fetus can be divided into four categories: intrauterine fetal death; malformations and disturbances of growth and development; mutagenic; and carcinogenic effects. Radiation-induced damage can result in fetal growth restriction and congenital malformations, often associated with intellectual disability, as well as the possibility for increased cancer risk. Although the risk of developing cancer from radiation is low, it is a stochastic effect with no clear radiation threshold level defined.9-12 Fetal radiation exposure is not routinely assessed, and hence total fluoroscopy time is the most suitable alternative surrogate, although they do not directly correlate well. A thermoluminescent dosimeter (TLD) placed on the upper back in the line of primary radiation beam has been shown to best correlate with fetal radiation exposure.

Maternal Outcomes

Pancreatitis, post-sphincterotomy bleeding, perforation, and cholecystitis are among the maternal non-pregnancy related post-ERCP adverse events. The data on patients being more susceptible to post-ERCP pancreatitis (PEP) during pregnancy versus the general population are conflicting. The literature, however, is limited by a small sample size and its retrospective nature. A national cohort study compared data from pregnant women (n=907) to non-pregnant women (controls, n=2721) who underwent ERCP and found that PEP occurred in 12% of pregnant women and in 5% of controls (P<0.001). This higher rate was attributed to the avoidance of fluoroscopy to verify wire and catheter position, as well as time constraints to perform ERCP as soon as possible during pregnancy.13-15 In another retrospective case series involving 68 ERCPs on 65 pregnant women by Tang et al., PEP occurred in 16% of patients. However, all cases of PEP in this study were mild with no systemic or local complications.16

Fetal Outcomes

ERCP is also associated with a higher risk of preterm labor, especially when performed during the first trimester. Tang et al., observed in the same study that following ERCP, 53 patients (90%) had a full–term pregnancy, but patients who underwent ERCP during the first trimester had only 73% of deliveries at term, but a higher risk of preterm delivery (20%), and an increased risk of lowbirth-weight infants (21%).16 However, in 2019, a systematic review and meta-analysis by Azab et al. (27 studies, 1307 pregnant patients who underwent ERCP) noted that, despite the increased risk of preterm labor and low birth weight, ERCP was deemed relatively safe on the fetus without any reported cases of fetal congenital malformation or stillbirth.14 Another systematic review in 2018 showed that therapeutic ERCP has a very high rate of technical success in clearing the bile duct of gallstones, and has a relatively low and acceptable rate of maternal and fetal complications.15

Special Considerations and Modifications of ERCP During Pregnancy

A general principle in the care of women with an acute biliary tract disorder during pregnancy is to provide the most conservative management possible with the hope of delaying intervention only when

absolutely indicated, until after pregnancy or until the second trimester, when surgical intervention is relatively safest.

As previously stated, ERCP should not be used as a diagnostic procedure and instead noninvasive imaging modalities (USG, MRI/MRCP) are relied upon to achieve a diagnosis. MRCP does not require the use of paramagnetic contrast agents like gadolinium, which has been shown to cross the placenta, and is hence safe. Because of the risk of radiation exposure and low sensitivity for choledocholithiasis, computed tomography (CT) scans are generally avoided in pregnant patients,6,8,17-19 but may become necessary in rare malignancy related circumstances, or to assess severe pancreatitis.

If ERCP is planned for a pregnant patient, there are some special considerations and strategies that need to be deliberated. The primary goal of these approaches is to improve overall safety of ERCP for pregnant patient and fetus, and reducing the amount of radiation exposure to the fetus. It may be reasonable to manage asymptomatic and mildly symptomatic choledocholithiasis patients expectantly, with the understanding that there is still a risk of cholangitis and gallstone pancreatitis if stones are left untreated.6,9

Timing of ERCP

When possible, ERCP should be postponed to until after delivery or at least until the second trimester, which is regarded a relatively safer trimester to perform surgical interventions, although ERCP has been performed safely throughout all trimesters of pregnancy. To avoid fetal exposure to ionizing radiation during the period of organogenesis and the risk of spontaneous abortion, ERCP during the first trimester should be avoided, recognizing that this may not always be the case. Similarly, during the late third trimester, elective ERCP should be deferred to after delivery, if possible, to minimize fetal loss and birth related complications.6-7,17

Informed Consent, Position, Radiation Shielding, Medications and Sedation

Informed Consent: The patient and family should be extensively counseled about the indication and steps of the ERCP procedure, along with detailed discussion of expected benefits, and risks for the mother and the fetus, as well as alternatives, and obtain written informed consent from the patient.15 Involving patient’s spouse/significant other and additional family members (of patient’s choice) is essential to build trust as well as to relieve their anxiety. Although the perceived risk of radiation exposure is much greater than the actual risk, the importance of full explanation of these risks to the woman and her family prior to the exposure cannot be overemphasized.

Patient Position: During the ERCP, the patient should be placed in a left pelvic tilt or left lateral position to avoid vena cava or aortic compression. Supine position is also equally acceptable. The patient may be placed in the standard prone position if the procedure is performed early in the pregnancy or second trimester, but should be avoided in the later part of pregnancy.

Radiation Shielding: Lead shields ought to be employed to reduce radiation exposure to the fetus. They should be placed underneath the patient’s abdomen, keeping in mind that the x-ray beam originates from beneath the patient.6,20 The value of placing a second lead shield over the patient’s abdomen is unproven, and is practiced per endoscopist’s discretion.

Maternal-Fetal Monitoring: An astute monitoring is recommended during the ERCP procedure, with documentation of fetal heart tones prior to sedation and immediately upon completion of the procedure. In the first and second trimester, the procedure can be performed in GI endosuite, but in the third trimester, it is generally better to perform the procedure in Operating Room (OR) with presence of Obstetrics support, in an event of labor or other complications necessitating delivering of the baby.

Medications: Glucagon (category B) is used to reduce intestinal contraction during ERCP and has been shown to have no significant teratogenicity or other adverse effects on the mother or the fetus, so it can be used safely. Diatrizoate (category D) is a contrast agent used during ERCP to visualize the biliary tree. Because the contrast is iodine-based, transient fetal hypothyroidism is a theoretical risk; however, no convincing evidence prevents its use, especially when the risk of maternal cholangitis and its consequences on the fetus are weighed against the theoretical risk of fetal hypothyroidism. The use with no fluoroscopy requirement of a low concentration formulation of the contrast agent and a limited number of intraductal injections help further reduce this theoretical potential risk.20

Sedation: ERCP in pregnant patients should preferably be performed with anesthesia professionals, so that the patient is adequately sedated, and hemodynamics and airway are appropriately managed, while the endoscopist is able to concentrate solely on the procedure steps.9,15 Decision regarding monitored anesthesia care using Propofol versus general anesthesia with intubation should be per anesthesia professional’s prerogative, depending on patient comorbidities, clinical situation and procedural indication. Sedative medications for ERCP, such as meperidine

(Category B), propofol (Category B), fentanyl (Category C), and midazolam (Category D), are thought to be generally safe during pregnancy. Meperidine alone can be used for procedural sedation during pregnancy (preferred over category C agents such as fentanyl and morphine), followed by small doses of midazolam as needed. Propofol can cause respiratory depression rapidly and should only be used in pregnant patients with the consultation of an anesthesiologist.9,21,22 In our anecdotal clinical experience at our centers, the majority of pregnant patients underwent safe and successful ERCP with use of propofol, administered by anesthesia professionals.

Rectal Indomethacin: Rectal indomethacin is considered standard of care for prevention of postERCP pancreatitis,36 however, there is lack of data for its use in pregnant women for us to comment on its routine use. In pregnant women presenting with preterm labor or shortened cervix, which places them at risk for preterm labor and delivery, oral or vaginal or rectal indomethacin is often used as a tocolytic to prolong pregnancy by decreasing uterine contractions. However, increased neonatal complications including oligohydramnios, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, and closure of the patent ductus arteriosus have been reported with the use of indomethacin. Since the physiological effects of single dose of rectally administered indomethacin during ERCP (especially if done during second trimester) is unclear, and given these concerns, the authors endorse this decision to be made on a case-bycase basis considering the degree of difficulty of biliary cannulation, inadvertent pancreatic duct cannulation/injection and other procedural factors.

Multidisciplinary Approach

Obstetric support should be available in the event of any pregnancy-related complications. As stated before, anesthesia professionals should be preferably involved.

Modified ERCP Techniques in Pregnant Patients

A few modifications to ERCP technique could be considered in a pregnant patient, with an overall goal of minimizing procedure time and fluoroscopy time, in order to achieve best outcomes for both the mother and the fetus.

A)Techniques to Reduce Fluoroscopy Time and Exposure

The majority of our understanding of radiation effects on fetal outcomes is derived from epidemiological and observational studies from atomic radiation survivors or from animal studies. According to the American College of Obstetrics and Gynecology (ACOG), fetal growth restriction, fetal risk of anomalies, or abortion have not been reported with a dose of radiation less than 50 mGy (or 5 rad), which is much higher than the typical ERCP exposure range, which maybe as low as 0.1 – 3 mGy per procedure.14,23 Such complications may occur at radiation doses higher than 100-200 mGy, but such doses are not usual in general diagnostic radiology, especially with ERCP, where the fetus lies outside the primary beam.

During the fluoroscopy phase in an ERCP, radiation is used to visualize the anatomy of the biliary tract. It is also used to verify that the bile duct cannulation, stone extraction, and sphincterotomy are all done safely and successfully.14 Certain modifications in fluoroscopy should be employed, carefully communicated to the fluoroscopy technician assisting on the case, to reduce radiation exposure, as below:

  • Minimizing the overall fluoroscopy time by using short taps of fluoroscopy and avoiding hard copy images, which emit between 25 to 2000 mrem of radiation per procedure17
  • Utilizing the last-image hold feature to review images
  • Avoiding the use of magnification
  • Using low-dose-rate pulsed fluoroscopy and collimating the x-ray beam to the smallest field possible.6 (Figures 3A and 3B) Collimation prevents unnecessary exposure of anatomy outside the area of interest, and it also improves image quality by producing less scatter radiation from these areas.

For confirmed choledocholithiasis, sphincterotomy and stone extraction need be performed (Figure-1). Biliary strictures and leaks are generally treated with stenting.20,24 To further minimize radiation use in a pregnant patient, a two-stage approach can also be employed in complicated pancreatobiliary pathologies, wherein the initial ERCP is done as a temporary measure using minimal or no fluoroscopy, and typically includes biliary sphincterotomy and stent placement, and the subsequent ERCP is definitive in the post-partum period, with required detailed interventions.25

B) Techniques to Avoid Radiation

Radiation-free ERCP for biliary stone removal in pregnant patients has been shown to be successful in various case reports and series.

Radiation-Free ERCP Techniques

  • In a pregnant patient with previous sphincterotomy, successful biliary cannulation can be performed without use of fluoroscopy, using a choledochoscope (SpyglassTM), as reported by Girotra et al., with accurate localization of biliary calculi and successful removal.26 Complete clearance of the bile duct can also be confirmed using choledochoscopy (Figures 3C and 3D). Placement of a biliary stent is optional; to prevent recurrent biliary events during pregnancy, especially if the gallbladder is still in-situ with more confirmed stones/sludge. This stent can later be removed post partum, once CCY is accomplished.
  • For pregnant patients with native papilla, an empirical bile aspirate guided technique is used, which includes biliary cannulation using a sphincterotome, followed by bile aspiration to confirm biliary access, and then sphincterotomy, and stone extraction with a balloon catheter. This technique may miss additional stones due to the lack of a clear definition of the ductal system. However, most residual stones, if present, should pass without difficulty with an adequate sphincterotomy.17,24,27-31 Alternately, a biliary stent can be placed temporarily until postpartum period, as discussed above.

Imaging-Guided Techniques

Transabdominal ultrasound, EUS or choledochoscopy/cholangioscopy can be used to provide imaging guidance.

The use of trans-abdominal ultrasound during ERCP procedure has the benefit of allowing realtime visualization, wire placement confirmation, and observation of stone clearance.32

EUS is now widely available and can be used to determine common bile duct diameter, as well as the number, morphology, and size of bile duct stones (Figure 2), and can sometimes eliminate the need for an ERCP, in cases where stones spontaneously pass.15,33-34 Choledochoscopy is a helpful tool, not only for visualizing calculi and confirming ductal clearance as previously discussed, but also for disrupting choledocholithiasis with laser therapy or electrohydraulic lithotripsy.15 Therefore, to confirm clearance of the common bile duct, one could consider using EUS or choledochoscopy, in order to minimize radiation use.35

The potential disadvantages of not using radiation may include the possibility of a lengthier procedure time, difficulty with visually confirming bile duct cannulation, inadvertent cystic duct cannulation, remnant biliary stones and difficulty recognizing bile leak or stricture.31 As per the systematic review by Azab et al., radiation-free techniques do not appear to decrease the fetal and pregnancy related complications, but they seem to reduce the rates of non-pregnancy complications.14

CONCLUSION

Therapeutic ERCP during pregnancy can be safely and effectively performed, when definitively indicated. A multidisciplinary approach should be adopted, wherein an experienced endoscopist performs the procedure, with assistance of anesthesia professionals, with a parallel active involvement of obstetricians and surgeons, to manage any potential peri-procedural pregnancy related issues. The procedure should be scheduled during the second trimester, which is generally deemed safest for any surgical intervention. First trimester (early organogenesis period) and late third trimester (higher chances of obstetric complications) are generally avoided, if possible. The general principle while performing ERCP during pregnancy should be to minimize the amount of radiation that the fetus is exposed to, and as a result, radiation-avoidance strategies have been suggested and proven to be effective in smaller series.

References

  1. Ko CW, Beresford SA, Schulte SJ, Matsumoto AM, Lee SP. Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology. 2005;41(2):359-365.
  2. Schwulst SJ, Son M. Management of Gallstone Disease During Pregnancy. JAMA Surg. 2020;155(12):1162-1163.
  3. Wu W, Faigel DO, Sun G, Yang Y. Non-radiation endoscopic retro grade cholangiopancreatography in the management of choledocholithiasis during pregnancy. Dig Endosc. 2014;26(6):691-700.
  4. Celaj S, Kourkoumpetis T. Gallstones in Pregnancy. JAMA. 2021;325(23):2410.
  5. Arce-Liévano E, Del Río-Suárez I, Valenzuela-Salazar C, et al. Endoscopic retrograde cholangiopancreatography results for the treatment of symptomatic choledocholithiasis in pregnant patients: A recent experience at a secondary care hospital in Mexico City. Rev Gastroenterol Mex (Engl Ed). 2021;86(1):21-27.
  6. Muniraj T, Jamidar PA. ERCP in Pregnancy. In: Baron TH, ed. ERCP. Third edition. Elsevier;2019:282-287.e2.
  7. Daas AY, Agha A, Pinkas H, Mamel J, Brady PG. ERCP in pregnancy: is it safe?. Gastroenterol Hepatol (N Y). 2009;5(12):851-855.
  8. Smith I, Gaidhane M, Goode A, Kahaleh M. Safety of endoscopic retrograde cholangiopancreatography in pregnancy: Fluoroscopy time and fetal exposure, does it matter? World J Gastrointest Endosc. 2013;5(4):148-53.
  9. ASGE Standard of Practice Committee, Shergill AK, Ben-Menachem T, et al. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc. 2012;76(1):18-24.
  10. De Santis M, Cesari E, Nobili E, Straface G, Cavaliere AF, Caruso A. Radiation effects on development. Birth Defects Res C Embryo Today. 2007;81(3):177-182.
  11. Wagner LK, Lester RG, Saldana LR. Exposure of the pregnant patient to diagnostic radiations: a guide to medical management. Philadelphia: Lippincott;1985.
  12. Baron TH, Schueler BA. Pregnancy and radiation exposure during therapeutic ERCP: time to put the baby to bed? Gastrointest Endosc. 2009;69(4):832-834.
  13. Inamdar S, Berzin TM, Sejpal DV, et al. Pregnancy is a Risk Factor for Pancreatitis After Endoscopic Retrograde Cholangiopancreatography in a National Cohort Study. Clin Gastroenterol Hepatol. 2016;14(1):107-114.
  14. Azab M, Bharadwaj S, Jayaraj M, et al. Safety of endoscopic retrograde cholangiopancreatography (ERCP) in pregnancy: A systematic review and meta-analysis. Saudi J Gastroenterol. 2019;25(6):341-354.
  15. Cappell MS, Stavropoulos SN, Friedel D. Systematic review of safety and efficacy of therapeutic endoscopic-retrograde-cholangiopancreatography during pregnancy including studies of radiation-free therapeutic endoscopic-retrograde-cholangiopancreatography. World J Gastrointest Endosc. 2018;10(10):308-321.
  16. Tang SJ, Mayo MJ, Rodriguez-Frias E, et al. Safety and utility of ERCP during pregnancy. Gastrointest Endosc. 2009;69(3 Pt 1):453461.
  17. Al-Hashem H, Muralidharan V, Cohen H, Jamidar PA. Biliary disease in pregnancy with an emphasis on the role of ERCP. J Clin Gastroenterol. 2009;43(1):58-62.
  18. Anderson SW, Rho E, Soto JA. Detection of biliary duct narrowing and choledocholithiasis: accuracy of portal venous phase multidetector CT. Radiology. 2008;247(2):418-427.
  19. Moon JH, Cho YD, Cha SW, et al. The detection of bile duct stones in suspected biliary pancreatitis: comparison of MRCP, ERCP, and intraductal US. Am J Gastroenterol. 2005;100(5):1051-1057.
  20. Hass DJ. Risks of Endoscopy in Special Populations: The Pregnant and the Elderly. Tech Gastrointest Endosc. 2007;9(4):236-241.
  21. Cappell MS. The fetal safety and clinical efficacy of gastrointestinal endoscopy during pregnancy. Gastroenterol Clin North Am. 2003;32(1):123-179.
  22. Cappell MS. Sedation and analgesia for gastrointestinal endoscopy during pregnancy. Gastrointest Endosc Clin North Am. 2006;16(1):1– 31.
  23. American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice. Committee Opinion No. 656: Guidelines for diagnostic imaging during pregnancy and lactation. Obstet Gynecol. 2016;127(2):e75e80.
  24. Jamidar PA, Beck GJ, Hoffman BJ, et al. Endoscopic retrograde cholangiopancreatography in pregnancy. Am J Gastroenterol. 1995;90(8):1263-1267.
  25. Sharma SS, Maharshi S. Two stage endoscopic approach for management of choledocholithiasis during pregnancy. J Gastrointestin Liver Dis. 2008;17(2):183-185.
  26. Girotra M, Jani N. Role of endoscopic ultrasound/SpyScope in diagnosis and treatment of choledocholithiasis in pregnancy. World J Gastroenterol. 2010;16(28):3601-3602.
  27. Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc. 2003;57(2):156-159.
  28. Agcaoglu O, Ozcinar B, Gok AF, et al. ERCP without radiation during pregnancy in the minimal invasive world. Arch Gynecol Obstet. 2013;288(6):1275-1278.
  29. Yang J, Zhang X, Zhang X. Therapeutic efficacy of endoscopic retrograde cholangiopancreatography among pregnant women with severe acute biliary pancreatitis. J Laparoendosc Adv Surg Tech A. 2013;23(5):437-440.
  30. Akcakaya A, Ozkan OV, Okan I, Kocaman O, Sahin M. Endoscopic retrograde cholangiopancreatography during pregnancy without radiation. World J Gastroenterol. 2009;15(29):3649-3652.
  31. Shelton J, Linder JD, Rivera-Alsina ME, Tarnasky PR. Commitment, confirmation, and clearance: new techniques for nonradiation ERCP during pregnancy (with videos). Gastrointest Endosc. 2008;67(2):364368.
  32. Li S, Dargavel C, Muradali D, May GR, Mosko JD. Real-time transabdominal ultrasound-guided ERCP is feasible and effective in pregnancy: a case series. Endosc Int Open. 2020;8(10):E1504-E1507.
  33. Shah JN, Bhat YM, Hamerski CM, Kane SD, Binmoeller KF. Feasibility of nonradiation EUS-based ERCP in patients with uncomplicated choledocholithiasis (with video). Gastrointest Endosc. 2016;84(5):764-769.
  34. Sethi S, Thosani N, Banerjee S. Radiation-Free ERCP in Pregnancy: A “Sound” Approach to Leaving No Stone Unturned. Dig Dis Sci. 2015;60(9):2604-2607.
  35. Brewer Gutierrez OI, Godoy Brewer G, Zulli C, et al. Multicenter experience with digital single-operator cholangioscopy in pregnant patients. Endosc Int Open. 2021;9(2):E116-E121.
  36. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med 2012; 366:1414-1422.

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MEDICAL BULLETIN BOARD

Medical Bulletin Board

May 2022 • Volume XLVI, Issue 5

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Compulink Partners with Promptly to Provide Cutting Edge Patient Engagement

Company adds full suite of mobile patient engagement tools to its all-in-one EHR solution

Newbury Park, CA – Compulink Healthcare

Solutions, a leader in specialty specific all-in-one EHR solutions, has announced its partnership with Promptly, provider of the leading comprehensive web-based patient experience suite on the market, to deliver new mobile-friendly patient engagement tools for its Advantage SMART Practice®  solution.

Dubbed Advantage Patient Experience™, this suite is comprised of easy-to-use features providing patients with the latest in mobile device convenience, while simultaneously reducing the administrative burden on office staff. 

Some of the features of Advantage Patient Experience include:

  • Smart online scheduling allowing patients to self-schedule with real-time availability using a simple Q&A for selecting the correct appointment type.
  • Automated Waitlist functionality which reaches out to patients automatically when the system detects a cancellation on a provider’s schedule.
  • Patient kiosk accessible from mobile phone or in-office tablet for easy update of patient information, scanning of driver’s license/ insurance card, e-sign of consents, and friction-less payment. Kiosk supports over 100 languages.
  • Mobile check-in feature with geo-location services that automatically checks patient in when they arrive at the office and alerts patients to drive times to the office.
  • Multi-level patient messaging via text, email, or interactive voice response.
  • Text-to-pay supporting virtual wallets.
  • Patient cost estimator using real-time data to provide patients with price transparency and accelerate collections while satisfying the No Surprises Act.
  • Fully automated vision insurance eligibility for Ophthalmic businesses.

“We believe this suite of state-of-the-art patient engagement tools will allow our clients to provide more personalized care to their patients at a substantially lower cost to the practice”, said Link Wilson, CEO and Product Architect. “Self-serve features like online scheduling and balance alerts with text-to-pay not only provides added convenience for patients but helps improve cashflow and bottom line business profitability.”

Compulink’s Advantage SMART Practice, all-in-one database solution includes a specialtyspecific EHR, practice management, inventory management, patient engagement, ASC, E-commerce, and Optical POS (for ophthalmic practices). The company also provides an expert revenue cycle management service for its clients. Advantage is 2015 ONC Certified for MIPS. Compulink is used by more than 25,000 providers in over 4,900 locations, 70 ASCs, and 19 universities and colleges. 

“We are extremely excited about this partnership with Compulink. Adding our patient experience suite to their comprehensive solution gives these organizations all the tools they need to automate their practices,” said Dr. Anish Kapur, President of Promptly. “The feedback we have gotten from our mutual clients has been fantastic. When our two systems are implemented at a practice, they work harmoniously to alleviate staff shortages and stresses while eliminating tedious front office tasks, increasing revenue, and improving patient satisfaction.”

About Compulink Healthcare Solutions

A leader in specialty specific EHR and Practice Management for 37 years, our all-in-one solution enables today’s private practice to deliver personalized patient care more efficiently for better outcomes and financial performance. With more smart features to automate patient flow and speed documentation, Compulink offers the industry’s only EHR solution that adapts to your workflow.

About Promptly LLC

Promptly is a comprehensive web-based patient experience and automation suite designed for medical practices to enhance patient touchpoints, accelerate patient payments and automate processes to support your team while combating staffing shortages.

Find out more at: PromptlyCheckIn.com

PHATHOM PHARMACEUTICALS SUBMITS

Vonoprazan Nda to Fda for the Treatment of Erosive Esophagitis

FLORHAM PARK, N.J., March 14, 2022 –

Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a late clinical-stage biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal diseases, announced today that it has submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for the use of vonoprazan as a treatment for adults for the healing of all grades of erosive esophagitis (EE) and relief of heartburn, and maintenance of healing of all grades of EE and relief of heartburn. Erosive esophagitis, a major type of gastroesophageal reflux disease (GERD), affects approximately 20 million people in the U.S. In addition to experiencing troubling heartburn symptoms, patients with inadequately treated EE

may progress to more severe diseases including Barrett’s esophagus, a condition in which esophageal tissue changes can progress to cancer.

“The submission of this NDA is another exciting step towards bringing the first major innovation to the U.S. GERD market in over 30 years,” said Azmi Nabulsi, M.D., Chief Operating Officer at Phathom. “Proton pump inhibitors (PPIs) are currently the standard of care for EE yet approximately half of all U.S. patients progress their lines of therapy annually. We believe there is great interest among patients and healthcare providers for new treatment options to address the shortcomings of current treatment. If approved, vonoprazan has the potential to satisfy the large unmet needs of millions of patients and set a new treatment paradigm in EE.”

This NDA is based on the positive data previously announced from Phathom’s pivotal Phase 3 PHALCON-EE trial, a randomized, doubleblind, multicenter trial that enrolled 1,024 patients with EE in the U.S. and Europe and compared vonoprazan to lansoprazole, a standard of care PPI, in the healing and maintenance of healing of

EE, and heartburn symptom relief. PHALCONEE successfully met its primary endpoints and key secondary superiority endpoints.

About Erosive Esophagitis

Erosive esophagitis is a condition characterized by the presence of breaks, or erosions, in the esophageal tissue caused by constant irritation of the mucosal surface and subsequent loss of defense mechanisms against acid and digestive enzymes. Chronic erosive esophagitis can lead to complications including peptic stricture, a narrowing of the esophagus that causes difficulty swallowing, and Barrett’s esophagus, a condition in which esophageal tissue changes can progress to cancer. Uncontrolled reflux disease can also result in extra-esophageal diseases such as respiratory problems, chest pain, angina, and increased mortality.

About PHALCON-EE

PHALCON-EE was a randomized, double-blind, two-phase, multicenter, Phase 3 trial that enrolled 1,024 patients with EE in the U.S. and Europe. The first phase of the trial evaluated the efficacy and safety of vonoprazan 20 mg administered oncedaily (QD) compared to lansoprazole 30 mg QD for the healing of EE for up to eight weeks. The second phase of the trial evaluated the efficacy and safety of vonoprazan 10 mg QD and 20 mg QD compared to lansoprazole 15 mg QD for the maintenance of healing of EE for 24 weeks. Both phases also evaluated heartburn symptoms.

About Vonoprazan

Vonoprazan is an investigational, oral small molecule potassium-competitive acid blocker (P-CAB). P-CABs are a novel class of medicines that block acid secretion in the stomach. Vonoprazan has shown the potential to have rapid, potent, and durable anti-secretory effects as a single agent in the treatment of gastroesophageal reflux disease (GERD) and in combination with antibiotics for the treatment of Helicobacter pylori (H. pylori) infection. The FDA has awarded qualified infection disease product (QIDP) status and granted Fast Track designation to vonoprazan in combination with both amoxicillin and clarithromycin and with amoxicillin alone for the treatment of H. pylori infection. Phathom in-licensed the U.S., European, and Canadian rights to vonoprazan from Takeda, which completed 19 Phase 3 trials for vonoprazan and received marketing approval in Japan and numerous other countries in Asia and Latin America.

About Phathom

Phathom Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel treatments for gastrointestinal diseases and disorders. Phathom has in-licensed the exclusive rights in the United States, Europe, and Canada to vonoprazan, a novel potassium competitive acid blocker (P-CAB) in late-stage development for the treatment of acidrelated disorders. For more information about Phathom, visit the Company’s website at www. phathompharma.com and follow the Company on LinkedIn and Twitter.

Forward Looking Statements

The Company cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the Company’s current beliefs and expectations. The inclusion of forward-looking statements should not be regarded as a representation by the Company that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in the Company’s business, including, without limitation: we may not obtain regulatory approval of our NDAs for the treatment of H. pylori, erosive esophagitis, or the other indications in which we are developing vonoprazan; even if we receive regulatory approval, the Company may experience delays in its plans to commercially launch vonoprazan in particular as we currently have a limited marketing and no sales organization and have no experience as a company in commercializing products; the Company may experience delays in designing and initiating a Phase 3 on-demand study in NERD, including in the event that the FDA does not agree with the Company’s study design or its interpretation of the data; the Company will require substantial additional financing to achieve its goals and may not be able to obtain such financing on acceptable terms, or at all; the Company’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of vonoprazan that may limit its development, regulatory approval and/ or commercialization, or may result in recalls or product liability claims; previously granted QIDP and Fast Track designations may be withdrawn or not actually lead to a faster development or regulatory review or extended exclusivity, and would not assure FDA approval of vonoprazan; the Company’s ability to obtain and maintain intellectual property protection for vonoprazan; the Company’s ability to comply with its license agreement with Takeda; the Company’s ability to maintain undisrupted business operations due to the ongoing presence of the COVID-19 coronavirus, including delaying or otherwise disrupting its clinical trials, manufacturing and supply chain, and other risks described in the Company’s prior filings with the Securities and Exchange Commission (“SEC”), including under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and the Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Evoendo Announces Us Fda 510(K) Clearance for Single-use Unsedated Transnasal Endoscopy (Tne) System

EvoEndo’s Single-Use Endoscopy System or the “EvoEndo System” eliminates the need for general anesthesia or conscious sedation during routine upper endoscopic procedures •            The EvoEndo System is being distributed by Micro-Tech Endoscopy USA with commercial sales slated to begin following completion of first clinical cases at several pediatric facilities

DENVER, CO – EvoEndo®, Inc. (“EvoEndo”), a medical device company developing systems for Unsedated Transnasal Endoscopy (TNE), has announced the receipt of 510(k) clearance from the U.S. Food and Drug Administration (FDA) to begin marketing and sale of the EvoEndo® SingleUse Endoscopy System. The clearance follows EvoEndo’s distribution agreement with MicroTech Endoscopy USA, Inc. (“Micro-Tech”), which will begin a phased distribution of the EvoEndo System into hospitals and ASCs in the United States.

EvoEndo was founded in 2017 by Dr. Joel Friedlander, a Pediatric Gastroenterologist at Children’s Hospital of Colorado, and is led by Chief Executive Officer Dr. Heather Underwood, an experienced medical device and technology entrepreneur, and alumna of the Stanford University Biodesign Program. While traditional endoscopy requires patients to undergo general anesthesia or sedation, the EvoEndo System combines sterile, single-use, flexible endoscopes, a portable video controller, and a take-home “comfort kit” containing virtual reality (VR) goggles for patient entertainment and distraction during the procedure to allow for unsedated transnasal endoscopy. The EvoEndo System ultimately enables safer and more cost-effective upper endoscopic procedures for patients, doctors, and hospitals. The FDA clearance is the latest milestone for EvoEndo, who also announced the completion of a $10.1M equity financing round last June.

Heather Underwood, Chief Executive Officer at EvoEndo, commented, “Receiving FDA 510(k) clearance for the EvoEndo System will allow us to execute on our mission of enabling a safer, faster, and more affordable alternative to sedated endoscopy for both pediatric and adult patients. This is an exceptional accomplishment for our team and validates our ongoing commitment to transform best practices in endoscopy and support the broader adoption of unsedated procedures throughout the U.S.” “With today’s announcement, we are one step closer towards making unsedated endoscopies the standard of care within the medical community,” said Joel Friedlander, Chief Medical Officer and Co-Founder of EvoEndo. “We are thrilled to receive this clearance and proud to be on the forefront of a new and innovative system to help diagnose and treat pediatric and adult patients.”

“The EvoEndo® Model LE Single-Use

Gastroscope addresses critical clinical needs in current pediatric and adult endoscopy practice and is a prime example of the innovative medical technology we strive to provide to our network,” stated Micro-Tech USA President Chris Li. “A combination of the smaller scope size, larger biopsy channel, coupled with a sterile single-use device can help save valuable procedure time and cost. We look forward to further growing our partnership with EvoEndo and to the successful completion of initial clinical cases.”

The EvoEndo System is only intended for use by medical professionals. Physicians and other medical providers interested in learning more about EvoEndo’s TNE system or to schedule demonstrations and training can contact the company here.

About EvoEndo®

EvoEndo®, Inc. is a medical device company developing systems that enable unsedated endoscopic procedures through a combination of sterile single-use, flexible endoscopes and VRbased patient distraction. EvoEndo’s technology allows pediatric patients and adults alike to receive routine endoscopies in a clinic setting without the use of general anesthesia or sedation, while reducing complexity, cost, and patient/provider apprehension.

To learn more, please visit: evoendo.com/

About Micro-Tech Endoscopy USA

Since 2000, Micro-Tech Endoscopy has been focused on creating top-quality products for endoscopic diagnosis, and therapeutic medical devices that allow physicians to provide the highest level of care. By partnering with doctors dedicated to innovation, Micro-Tech is committed to bringing better devices to market, with unparalleled speed, at an economical price, and without the burden of contracts. Micro-Tech does not compromise on quality and does not believe customers should either.

Micro-Tech Endoscopy has operations in America, Asia, and Europe and leverages this global reach to rapidly commercialize and refine the products it brings to its clinician partners. Micro-Tech’s team has a wealth of experience in the field and in-depth understanding of both product and use cases.

With the health care industry transforming rapidly, Micro-Tech Endoscopy is dedicated to setting the pace as a disruptor. Micro-Tech is more than a medical technology company, it is building a community of healthcare innovators and making health care more value-driven.

Smart Medical Systems’ G-eye® Colonoscope Is Now Fda Cleared on Olympus’ Pcf Colonoscope Series, Making It Available in the United States on the Commonly Used Models of All Leading Endoscopy Brands Fda has approved the use of G-EYE® with Olympus’ 510(k) cleared PCF colonoscopes

RA’ANANA, Israel, – SMART Medical Systems Ltd., a developer and manufacturer of innovative endoscopy products, announced an additional FDA clearance for its G-EYE® Colonoscope, based on Olympus’ 510(k) cleared PCF colonoscope series. With this additional FDA clearance, G-EYE® is now available for use in the U.S. market on the commonly used colonoscope models of all three leading endoscopy brands – OLYMPUS, FUJIFILM, and PENTAX Medical.

“The ability to offer G-EYE® on colonoscope brands and models commonly used and widely available in the United States is an important milestone for SMART Medical, patients, and endoscopists,” said Gadi Terliuc, Chief Executive Officer of SMART Medical. “The majority of U.S. endoscopists now have the option to utilize our cutting-edge technology, which has been shown in clinical studies to improve visualization compared with standard colonoscopy, while using their preferred brand and model of colonoscope. We are very excited to have completed our portfolio of U.S. G-EYE® offerings and believe that the widespread availability of the technology on the commonly used colonoscope models has the potential to accelerate adoption of G-EYE® colonoscopy as the standard of care.”

The G-EYE® Colonoscope is a 510(k) cleared colonoscope, remanufactured by SMART to include a proprietary balloon at its distal bending section. Withdrawal of the G-EYE® Colonoscope with the balloon moderately inflated during colonoscopy assists in controlling the colonoscope’s field of view and positioning. A published study (GIE 2019; 89: 545-53) demonstrated that G-EYE® can improve colonoscopy outcomes compared with standard colonoscopy across several metrics, including increasing adenoma detection rate (ADR) by 28%, detecting 47% more adenomas per patient (APP), 62% more advanced and large adenomas, and 142% more flat adenomas.

“We expect that this FDA clearance of the G-EYE® Colonoscope based on Olympus’ PCF scopes, which many Olympus users prefer over traditional adult-sized colonoscopes, will enhance our ability to capture a substantial portion of the U.S. colonoscopy market,” said Brian Cochrane, Chief Commercial Officer of SMART’s U.S. subsidiary. “We are committed to becoming the standard of care in colonoscopy, and this FDA clearance is an important step toward achieving this critical goal.”

About SMART Medical Systems

SMART Medical Systems is a pioneer in the development and manufacture of innovative medical devices in the field of gastro-intestinal (GI) endoscopy. SMART’s unique approach is to address key challenges in contemporary endoscopy while using available brand name endoscopes. SMART’s CE Marked and FDAcleared NaviAid™ and G-EYE® product families are commercially distributed in key global markets. With its partnership with FUJIFILM and PENTAX Medical, SMART’s G-EYE® colonoscopy solution is currently adopted by two of the three industry leaders in GI endoscopy imaging. SMART is headquartered in Israel, and operates in the United States through its wholly-owned subsidiary, SMART GI Inc.

For more information, please visit: smartmedsys.com/us/

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #45

Screening for Hepatocellular Carcinoma: Who, What, When, and Why

May 2022 • Volume XLVI, Issue 5
Bilal A. Asif,Elliot B. Tapper,Neehar D. Parikh

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Hepatocellular carcinoma (HCC) is one of the fastest growing causes of cancer worldwide. Two interventions are proven to improve HCC outcomes: early detection of HCC and treating the underlying cause of liver disease. In this review, we present best practices for HCC screening and evaluation. We highlight patient selection (namely patients with hepatitis B virus infection and anyone with cirrhosis), modality (ultrasound with alfa-fetoprotein with mention of alternatives), and the ideal sequence of events for patients from diagnosis to curative therapy.

Introduction

Hepatocellular carcinoma (HCC) is a growing public health threat.1 Its global incidence has increased rapidly with incidence rates expected to climb further particularly among Black and Hispanic persons.2 The median survival of HCC is 11 months, however morbidity and mortality vary by stage of disease and management strategies.3

Crucially, less than half of HCC is discovered at an early stage, reducing the possibility of curative therapy.4 While there are limited randomized controlled trials on HCC screening, existing studies have shown HCC detection and subsequent curative therapy is significantly increased in patients undergoing screening with ultrasound and serum biomarkers, than those not screened.5 This review aims to describe the at-risk populations and mechanisms for HCC screening in accordance with the American Association for the Study of Liver Diseases guidelines.

Epidemiology

Cirrhosis is the primary risk factor for HCC, accounting for 80-90% of HCC with an annual incidence of 2-4%.6,7 HCC is more common among men and older persons.8 The highest incidence is among people with uncured/viremic hepatitis C and uncontrolled hepatitis B infections.9,10 Globally, however, Asia and sub-Saharan Africa still comprise the majority of HCC due to endemic Hepatitis B infection (HBV), a major risk factor for HCC.11 Concurrently, the rising tide of nonalcoholic fatty liver disease (NAFLD), considered the hepatic component of metabolic syndrome, has eclipsed hepatitis C in its contribution to the burden of HCC.

Prevention of HCC

HCC prevention is limited to prevention of chronic liver disease in general, including HBV vaccination. Much like cervical cancer, HCC can arise from an oncogenic viral infection. In areas where HBV is endemic, approximately 70% of HCC patients test positive for hepatitis B surface antigen (HBsAg).12 HCC in children is generally the result of perinatal transmission.13 The HBV vaccine has reduced transmission. The United States adopted a universal HBV infant vaccination policy in 1991 including testing of all pregnant patients for HBsAg and prophylaxis for their infants, infant vaccination, and vaccination of adults in high risk groups.14 While this program hasn’t been optimally implemented in America, evaluation of universal childhood HBV vaccination programs in countries like Taiwan show a significant reduction in HCC in postvaccine birth cohorts compared to prevaccine cohorts.15

HBV Treatment

In general, therapeutic control of HBV can both reduce but not eliminate the risk of HCC.16 A large RCT from Taiwan assigned patients with HBVrelated cirrhosis or advanced fibrosis to receive lamivudine or placebo to evaluate liver disease progression, including HCC. While the study was terminated early due to major differences between the treatment and placebo group, HCC was noted to occur in significantly fewer patients in the lamivudine group (3.4%) compared to those receiving placebo (8.8%).17

Hepatitis C Treatment

Cure, or sustained virologic response (SVR), of hepatitis C is associated with a lower risk HCC. HCV eradication also reduces the risk of HCC,18,19 but the risk of HCC can remain elevated, particular among older persons with low platelets or albumin, high liver stiffness or Fibrosis-4 indices, and those who are actively drinking alcohol.18,20

Lifestyle Considerations

There is limited data regarding diet and lifestyle interventions for HCC risk. A number can be inferred, however, from observational data. A study using the Surveillance, Epidemiology, and End Results (SEER) database found the population attributable fraction of diabetes and obesity (hallmarks of NAFLD), to have a 37% contribution to HCC development.21 As metabolic syndrome is a pro-carcinogenic state, targeting metabolic risk factors may be an important part in HCC risk mitigation.

Use of greater than 80g of alcohol per day can increase risk of HCC nearly 5-fold.22 Alcohol is a multiplier of risk, even for persons with viral hepatitis.23

Why Screen for HCC?

Early HCC diagnosis remains difficult for many reasons. There are neither symptoms nor physical exam findings early in the disease course specific to HCC. Liver enzyme or function testing is similarly inadequate.24 Symptomatic disease is often locally advanced or metastatic with few therapeutic options that have limited efficacy, despite recent advances in systemic HCC therapeutics. Whereas patients detected at late stages have a median survival less than one year, patients detected at an early stage can undergo curative therapy and achieve 5-year survival exceeding 70%.4,25 Early stage HCC can be cured through ablation, surgical resection, or liver transplantation. Given that late-stage HCC is associated with reduced survival, poor quality of life, and can only be treated with expensive systemic therapies, efforts to identify early-stage HCC are cost-effective.26

As the principal risk factors for HCC are identifiable – cirrhosis and hepatitis B – screening can be targeted towards those most likely to benefit. Competing risks, such as life-limiting comorbidities and frailty, may play a role in deciding to enroll a patient in a screening. Among those with HBV, men >40 years old, females >50 years old, and those with a family history of HCC should be screened.27

How to Screen? (Table 1.)

First, while many patients with cirrhosis have subspecialists who assume responsibility, most do not. In evaluation of primary care physician (PCP) practices, a recent survey study demonstrated nearly a third of PCPs defer HCC screening to subspecialists.28 Effective cancer screening is a balance of accuracy of the test, ease of utilization, and cost effectiveness. Early screening algorithms proposed screening with alpha-fetoprotein (AFP). However, limitations with AFP soon became obvious, including serum elevations in the absence of HCC, remaining normal in setting of HCC, and inability for AFP to necessarily detect early stage tumors.29 A seminal study by Sheu et al. noted normal AFP in nearly half of patients presenting with hepatomas less than 5cm, which would have otherwise been missed.30 Ultrasound (US) was later introduced as a cost effective imaging modality for screening; the first RCT for HCC screening with US and AFP showed close to 40% reduction in HCC associated mortality compared to those with no screening, with a mortality rate ratio of 0.63 (95% CI 0.41, 0.98) with a 58% adherence rate. Given limitations of AFP alone, the AASLD recommends using ultrasound (with or without AFP) every 6 months. Computerized tomography (CT) and magnetic resonance imaging (MRI) have been investigated mainly as diagnostic modalities for HCC, and data for their use in HCC screening are limited. Not only are CT and MRI more costly than US, but radiation exposure and availability, respectively, have precluded their inclusion in national guidelines. However, they may be considered for screening in patients with central obesity or hepatic parenchymal heterogeneity secondary to cirrhosis.27 Recently, some centers have adopted ‘abbreviated MRI’ as a way of screening for HCC using contrast-enhanced sequences with data suggesting high sensitivity and patient acceptability.31 Finally, there are emerging data regarding novel blood-based biomarkers for screening but these are not ready for practice implementation.

What to do When I Find Something?

Prompt diagnostic evaluation is the cornerstone of HCC screening effectiveness, as tumor stage at diagnosis is the single strongest prognostic indicator.4 Unlike many other cancers, HCC diagnosis can be established with imaging without definitive need for biopsy. However, not all nodules seen by ultrasound are HCC. When a suspicious lesion is found, patients should undergo crosssectional diagnostic imaging with a multiphasic CT or MRI. Owing to the differential blood supply of the liver (primarily portal veinous blood) and HCC (primary arterial), the timing of contrast phase can identify lesions as HCC or not. Liver lesions are categorized and interpreted according to the American College of Radiology criteria for Liver Imaging Reporting and data system (LI-RADS).32 Lesions are classified from definitely benign (LIRADS 1) to definitely HCC (LI-RADS 5), as well as non-HCC malignancy (LI-RADS M) and noncategorizable (LI-RADS NC). For LI-RADS 4 lesions and above, the AASLD recommends a multidisciplinary discussion, with biopsy in select cases, or follow up imaging in 3 months. Treatment options for HCC include curative therapies such as surgical resection, locoregional therapy (ablation or radiation), palliative therapies (chemoembolization, radioembolization), or organ transplantation. Each stage of the evaluation from diagnosis to selection of treatment options to follow-up benefits from the coordination of a multidisciplinary team.

Conclusion

HCC is increasingly common and the best available tool to reduce its morbidity and mortality is screening. Screening should be performed for patients with cirrhosis and/or hepatitis B. At this time, best practice includes semi-annual ultrasound and AFP. Nodules should be evaluated using multiphasic cross-sectional imaging. Diagnosed HCC should be evaluated by multidisciplinary clinics.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 2018;68(6):394-424
  2. Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of Hepatocellular Carcinoma Incidence in the United States Forecast Through 2030. Journal of Clinical Oncology 2016;34(15):1787-94 doi: 10.1200/jco.2015.64.7412[published Online First: Epub Date]|.
  3. Greten T, Papendorf F, Bleck J, et al. Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. British journal of cancer 2005;92(10):1862-68
  4. Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology 2015;61(1):191-99
  5. Zhang B-H, Yang B-H, Tang Z-Y. Randomized controlled trial of screening for hepatocellular carcinoma. Journal of cancer research and clinical oncology 2004;130(7):417-22
  6. Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011;140(4):1182-88. e1
  7. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5):S35-S50
  8. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: A Cancer Journal for Clinicians 2011;61(2):69-90 doi: 10.3322/caac.20107[published Online First: Epub Date]|.
  9. Jhaveri R. Screening for hepatitis C virus: how universal is universal? Clinical therapeutics 2020;42(8):1434-41
  10. Owens DK, Davidson KW, Krist AH, et al. Screening for hepatitis C virus infection in adolescents and adults: US Preventive Services Task Force recommendation statement. Jama 2020;323(10):970-75
  11. El-Serag HB. Hepatocellular Carcinoma. New England Journal of Medicine 2011;365(12):1118-27 doi: 10.1056/ nejmra1001683[published Online First: Epub Date]|.
  12. Okuda K, Ishak KG. Neoplasms of the Liver: Springer Science & Business Media, 2013.
  13. Chang MH, Chen DS, Hsu HC, Hsu HY, Lee CY. Maternal transmission of hepatitis B virus in childhood hepatocellular carcinoma. Cancer 1989;64(11):2377-80
  14. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recommendations and Reports 2018;67(1):1
  15. Chang M-H, You S-L, Chen C-J, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. Journal of the National Cancer Institute 2009;101(19):1348-55
  16. Papatheodoridis GV, Chan HL-Y, Hansen BE, Janssen HL, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. Journal of hepatology 2015;62(4):956-67
  17. Liaw Y-F, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. New England Journal of Medicine 2004;351(15):1521-31
  18. Ioannou GN, Beste LA, Green PK, et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology 2019;157(5):1264-78. e4
  19. Nahon P, Layese R, Bourcier V, et al. Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs.
    Gastroenterology 2018;155(5):1436-50.e6 doi: 10.1053/j. gastro.2018.07.015[published Online First: Epub Date]|.
  20. Semmler G, Meyer EL, Kozbial K, et al. HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease. J Hepatol 2021 doi: 10.1016/j. jhep.2021.11.025[published Online First: Epub Date]|.
  21. Welzel TM, Graubard BI, Quraishi S, et al. Populationattributable fractions of risk factors for hepatocellular carcinoma in the United States. The American journal of gastroenterology
    2013;108(8):1314
  22. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004;127(5):S87-S96
  23. De Bac C, Stroffolini T, Gaeta GB, Taliani G, Giusti G. Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: a multicenter Italian study. Hepatology 1994;20(5):1225-30
  24. Attwa MH, El-Etreby SA. Guide for diagnosis and treatment of hepatocellular carcinoma. World journal of hepatology
    2015;7(12):1632
  25. De Toni EN, Schlesinger-Raab A, Fuchs M, et al. Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study. Gut 2020;69(1):168-76
  26. Parikh ND, Singal AG, Hutton DW, Tapper EB. Cost-effectiveness of hepatocellular carcinoma surveillance: an assessment of benefits and harms. Official journal of the American College of Gastroenterology| ACG 2020;115(10):1642-49
  27. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, S taging, and M anagement of H epatocellular C arcinoma: 2018 P ractice G uidance by the A merican A ssociation for the S tudy of L iver D iseases. Hepatology 2018;68(2):723-50
  28. Simmons OL, Feng Y, Parikh ND, Singal AG. Primary care provider practice patterns and barriers to hepatocellular carcinoma surveillance. Clinical Gastroenterology and Hepatology 2019;17(4):766-73
  29. Lok AS, Lai CL. α-Fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma. Hepatology 1989;9(1):110-15
  30. Sheu JC, Sung JL, Chen DS, et al. Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective study. Cancer 1985;56(3):660-66
  31. Woolen SA, Singal AG, Davenport MS, et al. Patient preferences for hepatocellular carcinoma surveillance parameters. Clinical Gastroenterology and Hepatology 2022;20(1):204-15. e6
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    2018;286(1):29-48

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FROM THE PEDIATRIC LITERATURE

From The Pediatric Literature

May 2022 • Volume XLVI, Issue 5

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ECMO and the Risk of Cholestasis in Children

Extracorporeal membrane oxygenation (ECMO) is a life-saving procedure which provides oxygen while removing carbon dioxide to critically ill patients by removing blood from a patient before returning it via a circuit. The returning blood is not pulsatile which can lead to hepatic injury and direct hyperbilirubinemia (DHB), and the occurrence of DHB in the setting of ECMO is associated with increased patient mortality. The authors of this study looked at risk factors for pediatric patients on ECMO developing DHB or experiencing mortality.

This single-center retrospective study at a tertiary medical center evaluated all pediatric patients under eight years of age who received ECMO over a 10-year period (2010-2020). Children on ECMO for less than 48 hours duration were excluded from the study, and DHB was defined as a direct bilirubin level greater than 1 mg / dL. Causes for ECMO and ECMO duration were determined, and risk factors for DHB which included total parenteral nutrition (TPN), continuous renal replacement therapy (CRRT), and central cannulation were evaluated. Illness severity while on ECMO included two scores: the vasoactive-ionotropic score (VIS) and Acute Physiology and Chronic Health Evaluation (APACHE II) score. Finally, outcomes were compared between patients with DHB on ECMO and a control group consisting of patients without

DHB on ECMO.

A total of 106 patients in the intensive care unit (ICU) were included in the study, and 51% of patients were male while 46% of patients were neonates. The median age at time of ECMO was 0.2 years (range 0-2.3 years), and the most common cause leading to ECMO was post-surgical care for congenital heart disease (39%). The median time spent on ECMO was 8 days (range 5-19 days), and 34% of patients on ECMO developed DHB. None of the patients with DHB while on ECMO had underlying previous liver disease. Serum AST and ALT were not significantly different between patients with DHB and the control group at the time of ECMO initiation. Neonates were not at a higher risk of developing DHB while on ECMO. TPN was utilized in 83% of patients, and central cannulation was utilized in 34% of patients; neither therapeutic was a risk factor for DHB. However, patients who developed DHB while on ECMO spent a significantly longer time on ECMO (19 days (interquartile range or IQR 8-30 days)) versus 6 days (IQR 4-13 days, P<0.001) and were significantly more likely to require CRRT (50% versus 13%, P<0.001). A total of 46 of the 106 patients (43%) died, and patients with DHB were statistically more likely to die while on ECMO compared to the control group (72% versus 29%, P<0.001). Although the APACHE II score was not significantly different between study groups at the time of ICU admission, logistic regression analysis demonstrated that DHB development during ECMO was associated with a significantly higher mortality rate independent of the VIS score or CRRT use (P=0.006).

This retrospective study provides some initial insight as to potential causes of mortality for children with DHB undergoing ECMO. The simple presence of DHB was a risk factor for mortality in this study, and CRRT was a possible aggravating risk factor. The authors state that more work is needed to prevent DHB from occurring in children receiving ECMO.

Alexander E, O’Sullivan D, Aganga D, Hassan S, Ibrahim S, Absah I. Clinical implications for children developing direct hyperbilirubinemia on extracorporeal membrane oxygenation. Journal of Pediatric Gastroenterology and Nutrition 2022; 74: 333-337.

Malnutrition in Children with Congenital Heart Disease

Congenital heart disease (CHD) is a common pediatric congenital disorder worldwide, and malnutrition can be a co-morbidity in children with CHD leading to poor health outcomes. The authors of this study performed a meta-analysis to determine the prevalence of malnutrition in children with CHD before and after cardiac surgery. This meta-analysis followed the guidelines of the PRISMA statement (http://www.prisma-statement. org/), and the authors searched for several CHD terms utilizing an “or” for combination wording through several large medical databases. Crosssectional or cohort studies were identified through September 2021 with an emphasis on preoperative and postoperative malnutrition. Malnutrition (underweight, stunting, and wasting) was defined by using World Health Organization z-scores in which “underweight” was defined as a weight-forage z-score less than -2; “stunting” was defined as a height-for-age z-score less than -2; and “wasting” was defined as a weight-for-height z-score of less than -2.  

The authors initially found 3415 publications; however, only 39 studies fit all inclusion criteria (33 studies on malnutrition in the preoperative period; 17 studies on malnutrition in postoperative period). Using these specific studies, the metaanalysis determined that 79,719 patients were evaluated preoperatively for underweight status; 78,572 patients were evaluated for stunting; and 77,249 patients were evaluated for wasting. The Newcastle-Ottawa Scale demonstrated that all such studies were of moderate to high quality. Pooled estimate analysis determined that 27.4% (95% CI, 21.7-34.0) of children with CHD were underweight, 24.4% (95% CI, 19.5-30.0) of children with CHD had stunting, and 24.8% (95% CI, 19.3-31.3) of children with CHD had wasting. Q testing further demonstrated that children with CHD had significantly more malnutrition compared to healthy children with no CHD (for underweight, Q = 16.24, P < .0001; for stunting, Q = 6.21, P = .013 for stunting; for wasting Q = 66.82, P < .0001).

Post-operative CHD repair improved malnutrition prevalence from 33.1% (95% CI, 26.2-40.8) at one month to 7.2% (95% CI, 4.7-10.8) at 12 months; improved stunting prevalence from 18.2% (95% CI, 10.8-29.0) at one month to 8.9% (95% CI, 4.5-16.7) at 12 months; and improved wasting prevalence from 22.1% (95% CI, 13.2-24.5) at one month to 5.4% (95% CI, 2.4-11.7) at 12 months. Of note, significant heterogeneity between studies using I2 testing was present when a pooled analysis was done for patients with underweight, stunting, and wasting. The main cause of heterogeneity depended on the continent where the study was performed. Funnel plot and Egger test analysis demonstrated no publication bias for the factors of overweight and stunting although this effect was seen for wasting.

This study demonstrates that malnutrition is a significant issue in pediatric patients with CHD, and surgical correction of CHD may improve malnutrition. However, this study also demonstrates significant outcome heterogeneity when studies throughout the world are considered. Welldefined definitions of outcomes in the setting of malnutrition and CHD are sorely needed, and better research is needed for preoperative malnutrition management (supplemental feedings, dietician management, etc.).

Diao J, Chen L, Wei J, Shu J, Li Y, Li J, Zhang S, Wang T, Qin J. Prevalence of malnutrition in children with congenital heart disease: a systematic review and meta-analysis. Journal of Pediatrics 2022; 242: 39-47.

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FROM THE LITERATURE

From The Literature

May 2022 • Volume XLVI, Issue 5

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Sleep Position and Gastroesophageal Reflux

The purpose of this study was to investigate the effect of spontaneous sleep positions on the occurrence of nocturnal gastroesophageal reflux in patients referred for ambulatory pH impedance reflux monitoring, including the concurrent sleep position measured using a sleep position measurement device that measured left, right, supine, and prone positions.

A total of 57 patients were evaluated, observing a significantly shorter acid exposure time in the left (median 0.0%, P25-P75, 0.0%-3.0%), compared with the right lateral position (median 1.2%, 0.0%-7.5%), and the supine position (median 0.6%, 0.0%-8.3%). The esophageal acid clearance time was significantly shorter in the left lateral decubitus position (median 35 seconds, 16115 seconds), compared with the supine (median 76 seconds, 22-257 seconds), and the right lateral positions (median 90 seconds, 26-250 seconds).

It was concluded that the left lateral decubitus position was associated with shorter nocturnal esophageal acid exposure time and faster esophageal acid clearance, compared with the supine and right lateral decubitus positions, as clinically suspected.

Schuitenmaker, J., van Dijk, M., Renske, N., et al.  “Association Between Sleep Position and Nocturnal Gastroesophageal Reflux: A Study Using Concurrent Monitoring of Sleep Position and Esophageal pH and Impedance.” American Journal of Gastroenterology, Vol. 112, February 2020, pp. 348-351.

IBD Treated Patients with Anti-TNFa Response to Vaccination for COVID-19

Patients with IBD treated with anti-tumor necrosis factor (TNFa biologics), are at high risk for vaccine-preventable infections. To study and assess the serologic responses to messenger RNACoronavirus Disease 2019 vaccine and its safety profile in patients with IBD stratified according to therapy, and compared with healthy controls (HCs), a prospective, controlled multicenter Israeli study was carried out. Those enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFa levels and adverse events (AEs) were detected longitudinally.

Overall, 258 subjects: 185 IBD (67 with antiTNFa, 118 non-anti-TNFa, and 73 HCs) were studied. After the first vaccine dose, all HCs were seropositive. Approximately 7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive. However, anti-spike levels were significantly lower than anti-TNFa treated, compared with non-anti-TNFa treated patients and HCs. 

Neutralizing and inhibitory functions were both lower in anti-TNFa treated, compared with non-anti-TNFa treated patients and HCs. AntiTNFa drug levels and vaccine responses did not affect anti-spike levels. Infection rate and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. 

It was concluded that in this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of vaccine; however, its magnitude was significantly lower in patients treated with antiTNFa, regardless of administration timing and drug levels. The vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

Edelman-Klapper, H., Zittan, E., Shitrit, A., et al. on behalf of the “Responses to Covid19 vaccine Israeli IBD Group (RECOVER).” Gastroenterology 2022; Vol. 152, pp. 454-467.

Viremia in Chronic HBV with DNA Less than 2000 IU/mL

From 3 tertiary hospitals, untreated patients were enrolled with compensated cirrhosis with persistent serum HBV DNA levels less than 2000 IU/mL; LLV was defined as having at least 1 detectable serum HBV DNA (20-2000 IU/mL) episode, whereas maintained virologic response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/ mL). When serum HBV-DNA was >2000 IU/ mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE), or hepatocellular carcinoma (HCC). 

Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years and was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7% and 17.3% vs 7.2%, 15.5%, and 19.4%), respectively. CCE risk was also comparable between 2 groups (7.5%, 12.8% and 13.7% vs 7.8%, 12.3% and 14.6%), respectively. By multivariate analysis, LLV (vs MVR), was not associated with HCC or CCE risks, with adjusted HR of 1.422 and 1.816, respectively.

Inverse probability of treatment weighting analysis yielded comparative outcomes between the 2 groups, regarding HCC and CCE risks, with HR ratios of 0.903 at 1.192, respectively.

It was interpreted that episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Need for AVT for episodic LLV should be reevaluated. 

Lee, H., Park, S., Lee, Y., et al.  “Episodic Detectable Viremia Does Not Affect Prognosis in Untreated Compensated Cirrhosis with Serum Hepatitis B Virus DNA <2000 IU/mL. American Journal of Gastroenterology 2022; Vol. 117, pp. 288-294.

BMI Association with Early-Onset Colorectal Cancer

There is an established association of body mass index (BMI) with colorectal cancer (CRC), and with the increasing obesity prevalence among younger generations. An attempt to evaluate the association of BMI at different ages during early adulthood with early onset CRC was carried out among 6602 patients with CRC and 7950 matched controls who were recruited in 2003 to 2020 in a population-based, case-controlled study from Germany, with 747 patients and 621 controls younger than 55 years and included in the analysis.

Self-reported height and weight at ages 20 years and 30 years and at approximately 10 years before diagnosis were recorded in personal interviews. Associations of BMI with early-onset CRC were estimated using multiple logistic regression. 

Compared with participants with BMI less than 25, those with BMI greater than 30 (obesity) at ages 20 years and 30 years and approximately 10 years before diagnosis were interviewed at 2.56, 2.06, and 1.88-fold risk of early onset CRC. The association of BMI with early-onset CRC risk was particularly pronounced among and essentially restricted to the majority of participants with no previous colonoscopy.

It was concluded that obesity at early adulthood is strongly associated with increased risk of early-onset CRC. 

Hengjing, L., Boakye, D., Chen, X., et al. “Associations of Body Mass Index at Different Ages with Early-Onset Colorectal Cancer.” Gastroenterology, 2022; Vol. 162, pp. 1088-1097.

Symptoms after Acute Gluten Exposure in Celiac Disease and NCGS

Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS), report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure.

A total of 60 subjects (n = 20 treated, healed CeD; n = 20 treated NCGS; n = 20 controls) were block randomized to a single, double-blind sham (rice flour), or 3-g gluten challenge with 72-hours followup. Twelve serial questionnaires (pain, bloating, nausea, and fatigue), and 10 serial plasma samples were collected. Mucosal permeability was assessed using both urinary lactose-13C mannitol ratios and endoscopic mucosal impedance.

A total of 35 of 40 (83%) subjects with CeD and NCGS reported symptoms with gluten (8 CeD, 9 NCGS), and sham (9 CeD and 9 NCGS), compared with 9 of 20 (45%) controls after gluten (n = 6) and sham (n = 3). There was no significant difference in symptoms among groups. Only 2 of 10 subjects with CeD and 4 of 10 NCGS identified gluten, whereas 8 of 10 subjects with CeD and 5 of 10 NCGS identified sham. A significant plasma IL-2 increase occurred only in subjects with CeD after gluten, peaking at 3 hours and normalizing within 24 hours postchallenge, despite no significant intestinal permeability change from baseline. 

It was concluded that symptoms did not reliably indicate gluten exposure in either subjects with CeD or NCGS. IL-2 production indicates rapid onset, gluten-induced T-cell activation in CeD, despite longstanding treatment. The effector site is unknown, given no increased intestinal permeability after gluten.

Cartee, A., Choung, R., King, K., et al.  “Plasma IL-2 and Symptoms Response After Acute Gluten Exposure in Subjects with Celiac Disease or Non-celiac Gluten Sensitivity.” American Journal of Gastroenterology 2022; Vol. 117, pp. 319-326.

Early Onset Colorectal Neoplasia

To determine the prevalence of colorectal neoplasia in individuals between 45 and 49 years old or even younger in the United States, an analysis was carried out using a large, nationally represented data set of almost 3,000,000 outpatient colonoscopies to determine the prevalence of, and risk factors for colorectal neoplasia among patients aged 18 to 54. 

High quality colonoscopies were analyzed from AMSURG ambulatory endoscopic centers

(ASCs) that report the results from the GI Quality Improvement Consortium (GIQuIC). Logistic regression was used to identify risk factors for EOCRC (early onset colorectal cancer).

Increasing age, male sex, white race, family history of CRC, and examinations for bleeding or screening were all associated with higher odds of APLs (advanced premalignant lesions) and CRC (colorectal cancer). Among patients aged 45-49, 32% had any neoplasm, 7.5% had APLs and 0.5% had CRC. Rates were almost as high in those aged 40-44. Family history of CRC portended neoplasia rates 5 years earlier. Race of APLs were higher in American Indian/Alaskan Natives, but lower among Blacks, Asians and Hispanics, compared with White counterparts. Prevalence of any neoplasia and APL gradually increased between 2014 and 2019 in all age groups.

It was concluded that these data provide support for lowering the screening age from 45 for all average-risk individuals. 

Trivedi, P., Mohapatra, A., Morris, M., et al. “Prevalence and Predictors of Young Onset Colorectal Neoplasia: Insights from a Nationally Representative Colonoscopy Registry.”  Gastroenterology 2022;  Vol. 162, pp. 1136-1146.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #221

More than Just Weight Loss: Understanding the Toll of Malnutrition on the Body

May 2022 • Volume XLVI, Issue 5
Christie L. Moulder,Matthew Stotts

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Protein-calorie malnutrition is associated with a variety of adverse clinical outcomes including delayed wound healing, nosocomial infections, hospital readmissions, and increased hospital length of stay. Identifying malnutrition is vital to prevent these adverse outcomes and to hasten recovery. Starvation and inflammation affect muscle mass and adipose tissue as well as the body’s ability to utilize nutrition and hydration. Changes to body cell mass alone do not explain the profound impact that malnutrition has on clinical outcomes. This paper will explore the impact that malnutrition has on different organ systems and how treatment may need to be modified for the malnourished patient.

INTRODUCTION

Malnutrition in the hospitalized patient is of this article, the term “malnutrition” shall be associated with a variety of adverse clinical synonymous with adult undernutrition or, more outcomes, including increases in infectious specifically, protein-calorie malnutrition , which is defined by inadequate energy intake required for proper tissue growth and maintenance.4 For the purposes malnutrition, one must first be able to identify it. A variety of assessments exist for diagnosing malnutrition, most of which focus on both the etiology of malnutrition and its phenotypic presentation. Examples of these assessments include the Subjective Global Assessment (SGA), the Malnutrition Clinical Characteristics (MCC), and the Global Leadership Initiative on Malnutrition (GLIM) criteria (see Table 1).4–6 All three assessment tools recognize that inflammation can expedite the loss of muscle, fat, and body cell mass beyond what one would expect from starvation alone. As the degree of inflammation increases, protein-calorie malnutrition accelerates. The SGA breaks down the metabolic demand of illness into four simple categories: no stress (starvation without illness), low stress, moderate stress, and high stress. The GLIM criteria present four similar categories: starvation, chronic disease with minimal or no inflammation, chronic disease with inflammation, and acute disease or injury with severe inflammation. The MCC also follows this theme, but with three categories instead of four: starvation, chronic disease-related, and acute disease or injury-related. In addition to the disease burden of inflammation, these assessments describe criteria related to the etiology of malnutrition, which include reduced food intake and/or gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia) persisting greater than 2 weeks. These assessments also describe criteria related to phenotypic presentations of malnutrition, including involuntary weight loss, loss of subcutaneous fat, loss of muscle mass, fluid accumulation, and diminished functional capacity. Table 1 highlights the differences between SGA, MCC, and GLIM criteria along with questions and observations clinicians should consider when determining if malnutrition is present.

The fact that malnutrition and illness often appear in concert complicates the clinical picture of an individual with malnutrition. Inflammatory responses induced by illness or injury can alter metabolism in such a way that shorter durations of limited intake can result in a profound decrease in weight and protein stores. Systemic inflammation also induces anorexia, meaning that these individuals often avoid nutrition at a time when the body would benefit most from consistent ingestion of nutrients, particularly protein. Given that modern medicine can keep people alive much longer than naturally anticipated, it is not uncommon to encounter individuals with malnutrition as a result of prolonged illness and inflammation. This clinical picture can result in a variety of deleterious effects on many different organ systems.

Malnutrition and the Musculoskeletal System


The most apparent changes seen in the setting of malnutrition are often related to the loss of skeletal muscle and protein stores. Protein is integral to survival due to its involvement in cell structure, red blood cells, enzymes, antibodies, and collagen.7 In addition to being the body’s major source of amino acids, skeletal muscle also plays a key role in metabolic regulation.8,9 In homeostasis, and even during starvation in the absence of illness, the body works to preserve protein. During illness or after injury, however, the body adapts to fight infection and heal wounds at the expense of protein storage.7

Sarcopenia is the progressive loss of skeletal mass and function due to a combination of factors including a reduction in anabolic hormones, decreased physical activity, and low protein intake.9,10 Cachexia is the presence of weight loss and rapid muscle atrophy in the absence of simple starvation.11 Patients with underlying sarcopenia or cachexia are at a significant disadvantage if they also develop malnutrition. Weight loss and skeletal muscle loss as a result of malnutrition will likely respond to adequate nutrition. However, muscle atrophy due to decreased mobility, hormonal changes, or illness-induced inflammation will not improve with nutrition alone. As such, treatment of sarcopenia and cachexia requires not only adequate nutrition, but also physical therapy, weight bearing exercise, treatment of illness or infection, and potentially medication management to offset hormonal changes.11

Malnutrition and the Immune System

During systemic inflammation, metabolism is altered due to an increased secretion of cytokines, catecholamines, glucocorticoids, and cortisol, among other substances. These changes increase resting energy expenditure and change how the body utilizes fat and protein stores (Table 2). Triglycerides from adipose tissue provide the dominant energy source and protein is catabolized for gluconeogenesis and for the synthesis of acute phase proteins.12 These acute phase proteins are involved in regulating the immunoinflammatory response.13

Inadequate intake of protein and calories, while simultaneously catabolizing protein and mobilizing lipid, results in a rapid loss of lean body mass and subcutaneous fat. The reliance on adipose tissue to provide energy and skeletal protein as the source of amino acids to mount an immune response places the malnourished patient at a disadvantage. The malnourished obese patient with ample adipose tissue but limited lean body stores may have the energy stores to stay alive, but the inability to fight infections or heal wounds. The severely underweight patient, with limited stores of both protein and fat, would be even further disadvantaged.

Advances in critical care allow patients to survive previously deadly injuries or infections, leading to patients who now suffer from chronic critical illness. The term Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) has been proposed as a new phenotype to define this subset of patients.14 There is ongoing investigation into the mechanism of PICS with some evidence suggesting that these patients experience an innate and adaptive suppression of their immune system which causes persistent low grade inflammation, immunosuppression, and chronic protein catabolism. Those suffering from PICS need a combination of physical therapy and nutrition support to improve clinically.14

A wide range of hormonal changes have been described in the setting of malnutrition. Insulinlike growth factor (IGF), one of the major anabolic hormones responsible for tissue growth, has been demonstrated to be low in severe forms of malnutrition.15 Serum cortisol levels are elevated, in part related to the presence of infections and the stress of the malnourished state. In the absence of a *REE = Resting Energy Expenditure need to metabolize carbohydrates during prolonged fasting, insulin levels are decreased.15

These alterations in hormone levels function to defend the body against malnutrition.15 Lipolysis is stimulated by elevated cortisol levels and lipogenesis is inhibited by low insulin-like growth factor, resulting in an increased supply of fatty acids to provide fuel to the brain and peripheral organs. The low insulin/glucagon ratio results in decreased glucose uptake by muscle and adipose tissue as well as increased muscle protein catabolism and increased lipolysis. Similarly, the reduction in anabolic activity (in part related to reduced insulin-like growth factor) and the increase in protein catabolism (mediated in part by the elevated cortisol level) ensure that an adequate supply of amino acids to the liver and protein synthesis continues.  When nutrition is reintroduced, especially carbohydrate, the body responds by secreting insulin. The secretion of insulin drives carbohydrate into the previously starved cells, along with potassium, phosphorus, and magnesium, causing serum levels to drop (refeeding syndrome).16 As such, nutrition should be delivered cautiously in individuals at risk for refeeding syndrome, with careful monitoring and repletion of electrolytes and vitamins.

Malnutrition and the Heart

Specific micronutrient deficiencies are well known to cause direct deleterious effects on the heart.

Severe thiamine deficiency can cause a dilated cardiomyopathy that leads to a high-output heart failure.17 Electrolyte deficiencies, especially in the setting of refeeding syndrome, can result in reduced cardiac contractility, severe arrhythmias, and rapid cardiac decompensation.17–21 The effects of proteincalorie malnutrition and starvation on the heart, however, is also notable and profound. 

In the 1940s, large autopsy studies performed on individuals with starvation showed a proportional decrease in cardiac muscle mass to the degree of muscle wasting in the rest of the body.22,23 A separate study of healthy conscientious objectors during World War II who lost an average of 25% of their body weight on a low-energy and low-protein diet for 6 months were found to have markedly decreased heart sizes on radiographs.24 Similar studies have shown reduced heart size in individuals with anorexia nervosa and kwashiorkor.25,26 Despite this reduced mass, however, a variety of compensatory mechanisms usually maintains the needs of circulation. While cardiac output and stroke volume fall with reduced myocardial mass, a reduction in body size often preserves the cardiac index and a reduction in blood volume and blood pressure also occurs.27,28 Although these compensatory mechanisms make heart failure rare in simple starvation-related malnutrition, they may not be adequate in the setting of systemic inflammation and malnutrition. As previously stated, refeeding syndrome can cause electrolyte imbalances that lead to rapid cardiac decompensation via arrhythmia. the shifts of electrolytes into cells, resulting in Moreover, carbohydrate and fat intake can lead to cardiac dysfunction and dysrhythmias.29 The the release of catecholamines and activation of the increase in energy consumption also corresponds renin-angiotensin-aldosterone axis which increase to an increase in oxygen demand driving cardiac blood pressure and blood volume and augment output at a much faster pace than the atrophied cardiac muscle can accommodate. As such, cardiac failure and refeeding must remain a consideration in severely malnourished individuals.In this setting, care should be taken to slowly increase caloric intake with careful attention to electrolyte deficiencies that can rapidly develop; intravascular fluids, if needed, should be provided with caution and close monitoring.

Malnutrition and the Gut

The gastrointestinal mucosa plays a major role in preventing bacterial translocation into the systemic circulation, and failure of this intestinal barrier is increasingly recognized to play a role in the development of organ failure and infectious complications. A range of evidence argues that the intestinal barrier function is compromised in malnourished individuals.30–32

Poor dietary intake and environmental exposures in children can lead to a vicious cycle in which an alteration in gut microbiota triggers gut barrier dysfunction, pathogen translocation, and impaired absorption.30 In malnourished adults, gut barrier dysfunction is also present. One study indirectly suggested altered mucosal immunity in malnutrition, after reporting higher levels of systemic antibodies to food proteins (gliadin and B-lactoglobulin) in malnourished individuals.31 A follow up study assessing gastrointestinal permeability using the lactulose mannitol test and endoscopic biopsies showed that intestinal barrier function was severely impaired in malnourished patients compared to healthy controls.32

Malnutrition and the Lungs

Malnutrition has several potential deleterious effects on the respiratory system, including reduced exercise capacity, loss of respiratory muscle function, and reduced lung defense mechanisms.33,34 The loss of muscle mass that occurs with sarcopenia and malnutrition has important implications for the respiratory system as inspiration and expiration rely on the diaphragm, external intercostal muscles, and abdominal muscles. In this setting, malnutrition can clearly impair respiratory function through reduced respiratory muscle mass and contractile force.

Additionally, malnutrition can also depress lung defense mechanisms. Respiratory muscles described above are important to generate effective coughing.33,34 Recent weight loss, reduced respiratory muscle strength, and a clinical diagnosis of malnutrition have all been associated with an increased risk of pneumonia.35–38 Higher rates of post-operative pneumonia and atelectasis have been noted in protein-depleted patients.39 Furthermore, the prevalence of malnutrition has been prospectively shown to be associated with expiratory muscle weakness and decreased chest wall expansion after upper abdominal surgery, with an associated higher chance of postoperative pulmonary complications.40

Malnutrition and the Brain

The energy demands of the brain are high relative to the size of the organ, accounting for at least 20% of the body’s energy consumption.41 Imaging studies have demonstrated that individuals with anorexia nervosa can have smaller brain volumes and less grey matter.42 After treatment and weight gain, some studies report full recovery of this brain atrophy,42–45 while other studies report partial recovery.46,47

In adult patients, the association between malnutrition and cognitive function is largely studied in the context of cognitive decline and post-operative delirium. In the geriatric population, malnutrition has been associated with cognitive decline,48–50 early stage Alzheimer’s disease, and behavioral psychiatric symptoms of dementia.49 Rosted et al. found that for patients admitted to a geriatric department, delirium is associated with malnutrition and individuals with both had four times the mortality risk in one month follow-up, a seven fold risk of discharge to a nursing home, and a longer length of hospital stay by 3 days.51 Due to the nature of these studies, it is not possible to conclude if decreased nutritional status is an early result of cognitive decline or if malnutrition exacerbates cognitive decline.

Post-operative delirium is associated with increased hospital length of stay, decreased health related quality of life, lower functional abilities, increased post-operative resources, higher readmission rates, and increased mortality.52–54 Developing delirium after hip fracture repair was found to be independently associated with being at

risk of malnutrition or being frankly malnourished.55 The same was found to be true for post-operative coronary artery bypass graft patients, where those with severe malnutrition were nearly three times more likely to develop post-operative delirium.52 Malnutrition and the Skin

Malnutrition is associated with an increased risk of pressure ulcer development56–58 and delayed wound healing.59 This is partly because nutrition is necessary to support cell metabolism and collagen formation. Collagen, the most abundant protein in the human body, is the main structural protein found in the extracellular matrix.60 In order for a wound to heal, the body needs protein either from an exogenous source or from the breakdown of lean body mass. Providing adequate carbohydrate and fat for energy can spare protein for cell structure and collagen synthesis. Insufficient energy intake will force the body to turn to muscle as a source of amino acids for gluconeogenesis.60

The patient presenting with malnutrition will struggle to heal wounds until their nutritional status is improved. Furthermore, the presence of a wound increases energy and protein needs, so that established malnutrition, if not properly attended to, worsens. The malnourished obese patient may be the most at risk for wound healing complications. In a state of low LBM, there is competition between using protein to heal wounds and using protein to rebuild LBM.7,58 In addition, adipose tissue is hypo-perfused and skin folds provide moist areas for bacterial growth.58 This combination means wounds are ripe for infection, dehiscence, and ischemia.

Lastly, vitamin, mineral, and trace element deficiencies often coincide with malnutrition and these deficiencies may impair wound healing. Vitamin C is necessary for synthesizing collagen, improving activation of leukocytes and macrophages, and increasing wound tensile strength.7,58 Vitamin A is involved in protein synthesis, epithelization, and fibroblast deposition of collagen.7,58 Zinc is a cofactor for collagen formation that liberates vitamin A from the liver and serves as a potent antioxidant.7,58 Vitamin E, copper, and iron also have roles in collagen formation.58 Current guidelines do not recommend routinely supplementing these micronutrients for wound healing, but do recommend checking for and correcting deficiencies if clinical signs and symptoms warrant.58 It is also important to ensure patients receive adequate vitamins and minerals throughout their hospital course.

CONCLUSION

While malnutrition alone can be detrimental to the body, it can be especially costly when combined with acute and chronic illness. The interplay between malnutrition and inflammation can create a cascade of physiological changes that hasten the loss of lean body mass, increase nutritional requirements, and affect the function of vital organ systems. These changes require careful consideration during treatment. Nutrition and hydration should be introduced early, but cautiously; electrolytes and vitamin levels should be monitored and corrected as appropriate, and physical therapy should be incorporated to preserve lean body mass. Identifying and treating malnutrition in cooperation with medical management reduces the risk of complications and improves patient outcomes.

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FRONTIERS IN ENDOSCOPY, SERIES #81

Ablation of Barrett’s Esophagus via Endoscopic Methods

May 2022 • Volume XLVI, Issue 5
Michael G. Harris,Douglas G. Adler

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INTRODUCTION

Ablation of Barrett’s Esophagus (BE) has been a continuously changing field of study over the past two decades. Radiofrequency ablation (RFA) is the dominant technology for ablation as of this writing. Spray cryotherapies and older techniques including argon plasma coagulation (APC) continue to undergo scientific review to determine their place in the current landscape of tools and techniques for the ablation of BE. This article will review available technologies for performing ablation of Barrett’s esophagus.

Who to Ablate?

Non-Dysplastic Barrett’s Esophagus (NDBE)

The American Gastroenterology Association (AGA), American College of Gastroenterology (ACG), and The British Society of Gastroenterology (BSG) clinical guidelines recommend against routine endoscopic ablation for NDBE due to low risk of annual progression (0.2-0.5%) to esophageal adenocarcinoma (EAC).1,2,3 There are valid concerns about the cost-effectiveness and safety of ablating NDBE. A comparative study published in Gastroenterology found it was more cost effective to perform endoscopic surveillance supplemented with RFA upon biopsy confirmation of HGD than to perform RFA before surveillance.1 Adverse events following ablation of BE are usually mild. Serious complications are infrequent.1 In clinical practice, some endoscopists will still ablate NDBE as it has been shown to be effective in reducing risk for progression to EAC.6,7 Patients with NDBE often ask to undergo ablation if they have significant concerns about progression of their underlying Barrett’s esophagus.

Low-Grade Dysplasia (LGD)

Patients with Barrett’s esophagus (BE) and LGD have an annual risk of progression to EAC of approximately 0.7%.1 There is high interobserver variability when making a histopathologic diagnosis of LGD, and frequent downgrading of LGD to NDBE by expert pathologists. When biopsies showing LGD are confirmed by expert pathologists, the annual risk of progression from LGD to EAC is substantially higher than 0.7%.6 Guidelines from the AGA and ACG recommend that patients with BE and LGD undergo ablative therapy or surveillance.1,2 Current guidelines from the AGA recommend endoscopic surveillance intervals for BE with LGD at 3-6 month intervals if not ablated.2 When the endoscopist encounters a patient >3 months from initial diagnosis of LGD, it would be logical to repeat biopsies before proceeding with ablation to rule out progression.

High-Grade Dysplasia (HGD)

The management of HGD in the setting of BE is probably the least controversial. There is no question of whether to ablate these patients as data accumulated over the past decade strongly support ablation for BE with HGD. The AIM-dysplasia trial in 2011 found an 8-fold risk of progression of BE with HGD to EAC if patients did not undergo RFA.5 Given the efficacy of ablation in treatment of BE with HGD and the high rate of annual progression of BE with HGD (5-8%) to EAC, endoscopic ablation is recommended by the AGA, ACG, and BSG over endoscopic surveillance or esophagectomy.1,2,3

Esophageal Adenocarcinoma T1a

EAC T1a is an intramucosal cancer and has a low propensity for metastatic spread to lymph nodes (<2%).2 The AGA, ACG, and BSG all recommend endoscopic therapy over esophagectomy for EAC T1a.1,2,3 Endoscopic therapy includes EMR of the lesion followed by ablation. One prospective case series looking at long term outcomes of patients treated with endoscopic therapy found that onethird of all patients with EAC T1a treated with EMR alone develop recurrence.9 Given such a high rate of EAC recurrence with EMR alone, ablation is a critical component in the treatment of EAC T1a following resection.  Esophageal Adenocarcinoma T1b EAC T1b is a submucosal cancer and has a higher risk of lymph node metastasis (45%) compared to T1a.2 The AGA, ACG, and BSG are consistent in recommending that patients with EAC T1b and low risk features can be treated with endoscopic therapy.1,2,3 As with EAC T1a, EAC T1b treated endoscopically involves EMR or ESD followed by ablation. To aid the endoscopist in determining which patients are “low risk” EAC T1b amenable to endoscopic therapy, it is recommended to have a multidisciplinary discussion with surgery and oncology.3 If locoregional lymph nodes are shown to have tumor involvement, endoscopic therapy can still be considered as part of a broader treatment strategy.2

Principles of Ablation

The goal of endoscopic ablative therapy in BE is to remove the esophageal mucosal layer and completely eradicate intestinal metaplasia (CEIM), dysplasia (CE-D), or cancer. The depth of injury must be carefully controlled to avoid transmural injury, preserve the deeper layers of the esophagus, and achieve the desired effect of ablation. Superficial damage and retention of the deeper layers allows for re-epithelialization of the esophageal mucosa with a layer of neo-squamous tissue. Ablative therapies produce tissue destruction through thermal or freezing methods.10

Methods for Ablation Radiofrequency Ablation (RFA)

RFA ablation of BE tissue occurs through the generation of an alternating electrical current from a bipolar electrode array and an electrosurgical generator. The electrical current released causes a controlled thermal injury to esophageal tissue. Thermal injury leads to water vaporization, coagulation of proteins, and cell necrosis. (Figure 1) Desiccated tissue serves as an insulator and protective barrier to deeper tissues due to higher electrical resistance.11 A precise dose of thermal radiofrequency energy in the 450-500kHz range provides a consistent depth of ablation, typically down to the level of the muscularis mucosae (700-800µm).11 There are multiple catheter types available for RFA including circumferential ablation catheters (Barrx 360 Express Balloon Catheter), non-circumferential focal over-thescope ablation catheters (Barrx 60, 90, and Ultra Long RFA Focal catheters where number denotes the degrees of non-circumferential contact with mucosa), and focal through-the-scope catheters (Barrx Channel RFA Endoscopic Catheter).

Argon Plasma Coagulation (APC)

APC is an ablative method where thermal injury to BE tissue occurs by releasing argon gas from a catheter probe and igniting it with a high voltage spark, generating a stream of plasma (matter in a high energy state, wherein the electrons are very excited and are not tightly bound to individual nuclei). As the plasma contact target tissue, energy is released in the form of heat, resulting in a reliable area and depth of thermal tissue destruction. In 2016 Manner et al. introduced the method of hybrid-APC to preserve the efficacy of traditional APC but reduce adverse effects. The hybrid-APC approach involves the submucosal injection of an NaCl 0.9% solution using a flexible water-jet probe before thermal ablation with APC.

Cryotherapy Ablation

Cryotherapy ablation creates tissue destruction via alternating freeze and thaw cycles. Immediate tissue destruction occurs from ice crystal formation as water in the intracellular and extracellular tissues freezes.15 Ice crystal formation disrupts cellular membranes and denatures proteins, creating an osmotic gradient favoring water movement extracellularly, leading to cell dehydration and destruction. The extracellular matrix and architecture are maintained as they are not affected by the freezing process, which reduces scar formation. During the thawing process, intracellular ice crystals fuse together with a maximum effect reached at temperatures between -20°C to -50°C. Indirect injury to the vasculature occurs during ice crystal fusion leading to tissue necrosis and ischemia from platelet aggregation, thrombus formation, and regional hyperemia. Three forms of cryoablation have been studied for use in patients with Barrett’s Esophagus: Carbon dioxide (CO2), liquid nitrogen (LN2), and nitrous oxide (NO) based therapies.

CO2 Cryotherapy

Compressed CO2 gas is delivered to tissue via a 7F through-the-scope catheter at a rate of 6-8L/ min and a high pressure of 450-750psi. The JouleThomson effect is exploited with cryotherapy, whereby the rapid expansion of CO2 gas leads to a cooling effect with temperatures down to -78°C. The rapid expansion of CO2 gas at room temperature leads to increased intraluminal pressure inside the esophagus and stomach which can cause perforation. The catheter system for CO2 cryotherapy (Polar Wand cryotherapy device [GI Supply, Camp Hill, PA, USA]) allows for simultaneous delivery of cryogen and venting of waste CO2 gas through a cap and suction system. Delivery of CO2 cryogen at a temperature of -78°C (compared to -196°C for LN2 based cryogen) does not freeze the catheter and no heating circuit is needed to keep the catheter malleable. No FDA approved CO2 cryotherapy device is available in the USA since the Polar Wand was discontinued in 2016 by the manufacturer.

Cryotherapy with Liquid Nitrogen

Liquid nitrogen (LN2) cryogen is delivered by a through-the-scope, contact-free, low pressure (2-4 psi) catheter-based system that reaches a temperature of -196°C.6 Such a low temperature comes with challenges as the catheter can freeze, losing malleability. There is a heater circuit built into the LN2 system (truFreeze, STERIS, Mentor, OH) that allows for warm air to be delivered through the catheter and maintain catheter pliability.17 Unlike CO2 -based systems, LN2 does not have a gas ventilation system. The JouleThomson effect is a principle whereby a highly compressed gas undergoing rapid expansion at a low pressure causes a cooling effect. This is the basis for how LN2 cools tissues, but the rapid expansion of LN2 gas results in high intraluminal pressures and risks perforation. To reduce the risk of luminal perforations, a nasogastric or orogastric tube (OGT) is placed and connected to active suction for decompression. After a patient with Marfan syndrome developed a gastric perforation following three freeze-thaw cycles at 20 s duration, it is suggested to use four freeze-thaw cycles at 10 s.6

Multifocal Nitrous Oxide Cryoballoon

The multifocal nitrous oxide cryoballoon ablation system (cryoballoon focal ablation system [CbFAS]; C2 Therapeutics, Inc, Redwood City, Calif) is a novel way to deliver cryotherapy. This is a portable battery-powered contact cryotherapy system.6 A small hand-held device with an attached liquid nitrous oxide capsule is used to deliver nitrous oxide (NO) gas inside of a cryoballoon. The balloon is inflated to a pressure precisely regulated to a maximum of 3.5 psi. Once the balloon is in contact with tissues, the internal diffuser component sprays NO onto the tissues freezing the mucosa to -85°C. The diffuser system can be rotated and allows the endoscopist to target specific mucosal tissues. Dosimetry data confirmed that 10 s treatments allow for eradication of BE and subsequent squamous regeneration.

Comparative Trials

RFA is currently the first-line ablative therapy for BE. A few comparative trials on RFA vs LN2 and RFA vs APC have assessed whether these other modalities have similar efficacy, however, at of the time of writing this article non-inferiority trials against RFA do not exist.

RFA vs LN2 Cryotherapy

In a recent multicenter retrospective cohort study published in 2021, LN2 cryotherapy had similar efficacy to RFA. In the study, 162 patients with BE were treated with either LN2 cryotherapy or RFA. LN2 therapy required overall more treatment sessions, but LN2 and RFA netted similar rates of CE-D (RFA 81%, LN2 71%) and CE-IM (RFA 64%, LN2 66%).6 Another comparative trial of 94 patients undergoing LN2 or RFA for ablation of BE looked at pain intensity scores between treatment groups and found that LN2 therapy was associated with less post-procedural pain than RFA.7

RFA vs APC

The so-called BRIDE study published in 2018 is the only comparative trial between RFA vs APC for ablation among patients with BE. The BRIDE study was a randomized controlled trial (RCT) of 171 patients randomized 1:1 to receive RFA or APC as ablative therapy. Patients had some form of advanced disease, either HGD or T1a EAC. All patients underwent endoscopic resection prior to ablative therapy. The study found similar efficacy at 24 months between the treatment arms, with CE-D of 93.5% for APC and 88.2% for RFA.

There was a lower retention rate of patients in the APC arm of the study which may have been due to a lower patient acceptability of APC. Buried BE glands were found in 6.1% of patients in the RFA group and 13.3% in the APC groups. Adverse events, including stricture rates, were similar (RFA 8.3%, APC 8.1%). RFA was also more expensive, costing $27,491 more in accumulated medical bills.

Risks and Benefits of Ablation Modalities RFA

Data on the efficacy and safety of RFA is by far more abundant compared to APC and cryotherapies. ACG guidelines from 2022 recommend RFA as the first line ablative therapy of non-nodular dysplastic BE.1 Dosimetry data is well known and a precise amount of tissue destruction occurs due to the nature of balloon-based bipolar radiofrequency energy electrodes., The durability of RFA has been repeatedly proven over the years. A prospective multicenter cohort study known as the AIMdysplasia trial published in 2011 found that RFA provided durable CE-D and CE-IM following treatment as evidenced by a low rate of disease progression over three years. Furthermore, a 2017 follow up of the AIM-dysplasia trial cohort found that among patients with BE and dysplasia who maintained CE-IM at three years, only 32% experienced a recurrence of BE. The SURF trial, a RCT of 136 patients with BE and LGD comparing RFA to surveillance alone, found that RFA reduced the risk of neoplastic progression to HGD or EAC by 25% over three years.

Risks associated with RFA include buried subsquamous BE glands which have a theoretical risk of progression to neoplasia, or adverse events such as post-operative pain, esophageal strictures, bleeding, and rarely, perforation. Rates of buried BE glands after RFA have been variable. The AIM-II trial in 2010 was a prospective, multicenter US trial looking at five year follow-up after RFA ablation of NDBE. Zero cases of buried BE glands were found after five years. The BRIDE study published in 2018 found that among 76 patients with BE treated with RFA, 6.1% had buried BE glands found on biopsy at 12 months.24 None of the patients with buried BE glands developed neoplasia.

Post-procedural pain is a common complaint with all ablative therapies, but RFA is five-times more likely to be associated with post-procedural pain than LN2 cryotherapy. Perhaps one of the best datasets available for safety of RFA is a systematic review and meta-analysis from 2016 that looked at 37 articles comprised of 9200 patients that found an overall rate of adverse events to be 8.8%, with 5.6% developing strictures, 1% bleeding, and 0.6% perforation. If endoscopic resection occurred before RFA, adverse event rates were substantially higher.

APC

Despite an initial enthusiasm for APC as an ablative therapy for BE due to the ease of its use and widespread familiarity with the technique for other indications, reports of major complications such as bleeding, strictures, and perforation have led to a decline in use. The APBANEX trial in 2006 was a multicenter prospective study of 60 patients undergoing traditional APC ablation of NDBE in which 10% of patients developed serious adverse events. Although RFA had a rate of 6.1% buried BE glands in the BRIDE study, APC was found to have a rate of 13.3%.24 A RCT from 2021 looking at APC ablation in 107 patients with BE and LGD found that there was a high adverse event rate that was directly proportional to the amount of watts used. For example, the group that underwent treatment at the 90 W level experienced an 83% adverse event rate while the 60 W group had a 48% adverse event rate. The hybrid-APC method where a pillow of 0.9% NaCl is injected prior to APC has remarkably lower rates of adverse events and a reported 2% stricture rate.14

The cost of APC may be more favorable than for RFA. The BRIDE study found that RFA incurred more costs than APC, with accumulated costs of RFA on average $33,170 vs $5,678 for APC. Efficacy of APC may be comparable to RFA, with long-term ablation outcomes after APC available from two RCTs from 2013 where 129 patients with BE underwent APC vs surveillance. A new study out of Europe showed promising results for hybrid-APC. Published in January 2022, the study included 154 patients having neoplastic BE and found that among patients treated with hybrid-APC there was a 97.7% rate of CE-D and 65.9% CE-IM.

CO2 Cryotherapy

CO2 cryotherapy dosimetry is non-existent. Efficacy of CO2 cryotherapy has been variable across studies. A prospective single case series of 30 patients treated with CO2 cryotherapy was terminated early because of low CE-IM rates of 11% and CE-D rates of 44%. One conflicting study in 2015 by Canto et. al reported that among patients undergoing CO2 cryotherapy there was a CE-D rate of 89% and CE-HGD of 94%. CO2 cryotherapy did have some advantages over LN2 cryotherapy, including less freezing of the catheter and the ventilation mechanism built into the Polar Wand reduced risk of perforations. The Polar Wand was discontinued by the manufacturer in 2016.

LN2 Cryotherapy

As with CO2 cryotherapy, there is a lack of dosimetry data surrounding LN2 treatment., Rapid expansion of a highly compressed gas via the Joule-Thompson effect, the principle by which LN2 cryotherapy causes tissue cooling, can lead to perforation. In initial studies a patient with Marfan Syndrome developed gastric perforation.19 To prevent gastric perforation an OGT is utilized during the procedure, but this tube in the esophagus can impair the endoscopists maneuverability during ablation. The ultra-cold temperatures involved (-196°C) in LN2 cryotherapy reduces catheter pliability, but a heater probe built into the catheter does help prevent the catheter from freezing.

A 2010 multicenter prospective trial of LN2 ablation in BE that included 77 patients found that 52% had adverse events including chest pain (17.6%), dysphagia (13.3%), odynophagia (12.1%), sore throat (9.6%), and strictures (4%)., Stricture rates appear to vary substantially across studies, however, and are generally much higher in those who undergo EMR before LN2 cryotherapy. A multicenter 2017 study of 88 patients undergoing LN2 cryotherapy following EMR of esophageal adenocarcinoma T1a or T1b had stricture rates of 12%.

The efficacy of LN2 cryotherapy was examined in a 2019 meta-analysis that included 386 patients. The pooled CE-D rate (83.5%) was comparable to that seen with RFA, but LN2 cryotherapy had a much lower CE-IM rate (56.5%). All patients in the study received LN2 cryotherapy, a subset as a salvage therapy after RFA, and another subset were treatment-naïve patients. It was concluded that RFA may be better as a first-line therapy, with LN2 cryotherapy an acceptable salvage therapy for RFA refractory BE.

Multifocal Nitrous Oxide Cryoballoon

The nitrous oxide cryoballoon (CbFAS system) is a novel therapy still under investigation to determine its role within the current ablation landscape. A prospective clinical trial published in 2020 looked at 120 patients undergoing CbFAS ablation of BE 1-6 cm in length, with either LGD, HGD, or EAC. Findings among the 94 patients in the per-protocol analysis found a pooled CE-D rate of 97% and a CE-IM rate of 91%. Stricture rates were higher than those seen in LN2 cryotherapy (12.5%).

CONCLUSION

Ablative therapies for BE include RFA, APC, and spray cryotherapy in the form of CO2, LN2, or NO. None of these technologies are perfect. RFA has the best safety profile of all ablative modalities and high rates of CE-D and CE-IM. RFA is more expensive than LN2 cryotherapy and is associated with higher post-operative pain. CO2 cryotherapy had one study terminated early due to poor performance and the Polar Wand was discontinued by the manufacturer in 2016. LN2 cryotherapy lacks dosimetry data and can have significant adverse event rates. LN2 cryotherapy has a similar rate of CE-D as RFA, but lower rates of CE-IM making it more suitable for salvage therapy after RFA failure. The CbFAS cryoballoon system is a novel form of NO spray cryotherapy. RFA remains the first-line treatment.

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  21. Solomon SS, Kothari S, Smallfield GB, Inamdar S, Stein P, Rodriguez VA, Sima AP, Bittner K, Zfass AM, Kaul V, Trindade AJ. Liquid Nitrogen Spray Cryotherapy is Associated With Less Postprocedural Pain Than Radiofrequency Ablation in Barrett’s Esophagus: A Multicenter Prospective Study. J Clin Gastroenterol. 2019 Feb;53(2):e84-e90. doi: 10.1097/MCG.0000000000000999. PMID: 29351156.
  22. Peerally MF, Bhandari P, Ragunath K, Barr H, Stokes C, Haidry R, Lovat L, Smart H, Harrison R, Smith K, Morris T, de Caestecker JS. Radiofrequency ablation compared with argon plasma coagulation after endoscopic resection of high-grade dysplasia or stage T1 adenocarcinoma in Barrett’s esophagus: a randomized pilot study (BRIDE). Gastrointest Endosc. 2019 Apr;89(4):680-689. doi:10.1016/j.gie.2018.07.031. Epub 2018 Aug 1. PMID: 30076843.
  23. Peter S, Mönkemüller K. Ablative Endoscopic Therapies for Barrett’s-Esophagus-Related Neoplasia. Gastroenterol Clin North Am. 2015 Jun;44(2):337-53. doi: 10.1016/j.gtc.2015.02.014. PMID: 26021198.
  24. ASGE Technology Committee, Navaneethan U, Thosani N, Goodman A, Manfredi M, Pannala R, Parsi MA, Smith ZL, Sullivan SA, Banerjee S, Maple JT. Radiofrequency ablation devices. VideoGIE. 2017 Sep 28;2(10):252-259. doi: 10.1016/j.
    vgie.2017.06.002. PMID: 29905337; PMCID: PMC5992954.
  25. Shaheen NJ, Overholt BF, Sampliner RE, Wolfsen HC, Wang KK, Fleischer DE, Sharma VK, Eisen GM, Fennerty MB, Hunter JG, Bronner MP, Goldblum JR, Bennett AE, Mashimo H, Rothstein RI, Gordon SR, Edmundowicz SA, Madanick RD, Peery AF, Muthusamy VR, Chang KJ, Kimmey MB, Spechler SJ, Siddiqui AA, Souza RF, Infantolino A, Dumot JA, Falk GW, Galanko JA, Jobe BA, Hawes RH, Hoffman BJ, Sharma P, Chak A, Lightdale CJ. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology. 2011 Aug;141(2):460-8. doi: 10.1053/j.gastro.2011.04.061. Epub 2011 May 6. PMID: 21679712; PMCID: PMC3152658.
  26. Hamade N, Sharma P. Ablation Therapy for Barrett’s Esophagus: New Rules for Changing Times. Curr Gastroenterol Rep. 2017 Aug 17;19(10):48. doi: 10.1007/s11894-017-0589-2. PMID: 28819902.
  27. Pouw RE, Klaver E, Phoa KN, van Vilsteren FG, Weusten BL, Bisschops R, Schoon EJ, Pech O, Manner H, Ragunath K, Fernández-Sordo JO, Fullarton G, Di Pietro M, Januszewicz W, O’Toole D, Bergman JJ. Radiofrequency ablation for low-grade dysplasia in Barrett’s esophagus: long-term outcome of a randomized trial. Gastrointest Endosc. 2020 Sep;92(3):569-574. doi: 10.1016/j.gie.2020.03.3756. Epub 2020 Mar 23. PMID: 32217112.
  28. Fleischer DE, Overholt BF, Sharma VK, Reymunde A, Kimmey MB, Chuttani R, Chang KJ, Muthasamy R, Lightdale CJ, Santiago N, Pleskow DK, Dean PJ, Wang KK. Endoscopic radiofrequency ablation for Barrett’s esophagus: 5-year outcomes from a prospective multicenter trial. Endoscopy. 2010 Oct;42(10):781-9. doi: 10.1055/s-0030-1255779. Epub 2010 Sep 20. PMID: 20857372.
  29. Solomon SS, Kothari S, Smallfield GB, Inamdar S, Stein P, Rodriguez VA, Sima AP, Bittner K, Zfass AM, Kaul V, Trindade AJ. Liquid Nitrogen Spray Cryotherapy is Associated With Less Postprocedural Pain Than Radiofrequency Ablation in Barrett’s Esophagus: A Multicenter Prospective Study. J Clin Gastroenterol. 2019 Feb;53(2):e84-e90. doi: 10.1097/MCG.0000000000000999. PMID: 29351156.
  30. Qumseya BJ, Wani S, Desai M, Qumseya A, Bain P, Sharma P, Wolfsen H. Adverse Events After Radiofrequency Ablation in Patients With Barrett’s Esophagus: A Systematic Review and Metaanalysis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1086-1095. e6. doi: 10.1016/j.cgh.2016.04.001. Epub 2016 Apr 9. PMID: 27068041.
  31. Ventre S, Shahid H. Endoscopic therapies for Barrett’s esophagus. Transl Gastroenterol Hepatol. 2021 Oct 25;6:62. doi: 10.21037/ tgh.2020.02.04. PMID: 34805584; PMCID: PMC8573364.
  32. Manner H, May A, Miehlke S, Dertinger S, Wigginghaus B, Schimming W, Krämer W, Niemann G, Stolte M, Ell C. Ablation of nonneoplastic Barrett’s mucosa using argon plasma coagulation with concomitant esomeprazole therapy (APBANEX): a prospective multicenter evaluation. Am J Gastroenterol. 2006 Aug;101(8):1762-9. doi: 10.1111/j.1572-0241.2006.00709.x. Epub 2006 Jun 30. PMID: 16817835.
  33. Wronska E, Polkowski M, Orlowska J, Mroz A, Wieszczy P, Regula J. Argon plasma coagulation for Barrett’s esophagus with low-grade dysplasia: a randomized trial with long-term follow-up on the impact of power setting and proton pump inhibitor dose. Endoscopy. 2021 Feb;53(2):123-132. doi: 10.1055/a-1203-5930. Epub 2020 Jul 10. Erratum in: Endoscopy. 2020 Oct 01;: PMID: 32650347.
  34. Sie C, Bright T, Schoeman M, Game P, Tam W, Devitt P, Watson D. Argon plasma coagulation ablation versus endoscopic surveillance of Barrett’s esophagus: late outcomes from two randomized trials. Endoscopy. 2013 Nov;45(11):859-65. doi: 10.1055/s-00331344584. Epub 2013 Sep 9. PMID: 24019134.
  35. Knabe M, Beyna T, Rösch T, Bergman J, Manner H, May A, Schachschal G, Neuhaus H, Kandler J, Weusten B, Pech O, Faiss S, Anders M, Vieth M, Sehner S, Bisschops R, Bhandari P, Ell C, Ehlken H. Hybrid APC in Combination With Resection for the Endoscopic Treatment of Neoplastic Barrett’s Esophagus: A Prospective, Multicenter Study. Am J Gastroenterol. 2022 Jan 1;117(1):110-119. doi:10.14309/ajg.0000000000001539. PMID: 34845994; PMCID: PMC8715998.
  36. Verbeek RE, Vleggaar FP, Ten Kate FJ, van Baal JW, Siersema PD. Cryospray ablation using pressurized CO2 for ablation of Barrett’s esophagus with early neoplasia: early termination of a prospective series. Endosc Int Open. 2015 Apr;3(2):E107-12. doi: 10.1055/s0034-1390759. Epub 2015 Feb 27. PMID: 26135648; PMCID: PMC4477021.
  37. Johnston CM, Schoenfeld LP, Mysore JV, Dubois A. Endoscopic spray cryotherapy: a new technique for mucosal ablation in the esophagus. Gastrointest Endosc. 1999 Jul;50(1):86-92. doi: 10.1016/s0016-5107(99)70352-4. PMID: 10385730.
  38. Pasricha PJ, Hill S, Wadwa KS, Gislason GT, Okolo PI 3rd, Magee CA, Canto MI, Kuo WH, Baust JG, Kalloo AN.
    Endoscopic cryotherapy: experimental results and first clinical use. Gastrointest Endosc. 1999 May;49(5):627-31. doi: 10.1016/s00165107(99)70393-7. PMID: 10228263.
  39. Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus.Greenwald BD, Dumot JA, Horwhat JD, Lightdale CJ, Abrams JADis Esophagus. 2010 Jan; 23(1):13-9.
  40. Tsai FC, Ghorbani S, Greenwald BD, Jang S, Dumot JA, McKinley MJ, Shaheen NJ, Habr F, Wolfsen HC, Abrams JA, Lightdale CJ, Nishioka NS, Johnston MH, Zfass A, Coyle WJ. Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer. Dis Esophagus. 2017 Nov 1;30(11):1-7. doi: 10.1093/dote/dox087. PMID: 28881903.
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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #44

Recognizing and Managing Irritable Bowel Syndrome in Quiescent Inflammatory Bowel Disease

April 2022 • Volume XLVI, Issue 4
John A. Damianos,Aline Charabaty,Katie A. Dunleavy

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Patients with inflammatory bowel disease (IBD) commonly experience new or persistent gastrointestinal symptoms despite quiescent disease. These symptoms may be attributed to a wide range of etiologies, including IBD-associated complications, concomitant gastrointestinal or extra-intestinal pathologies, and medications side effects. Disorders of gut-brain interaction (DGBIs) – formerly termed functional gastrointestinal disorders (FGIDs) – can be seen in up to two thirds of patients with IBD, the most common being irritable bowel syndrome (IBS). DGBIs in IBD are often under-recognized and are associated with worse quality of life, impaired mental health, and greater healthcare utilization. In this article, we provide a systemic approach to assessing GI symptoms in quiescent IBD, and focus on the overlap and interplay between IBD and DGBIs, in particular IBS, and review management options for IBS in patients with IBD.

INTRODUCTION

Inflammatory bowel disease (IBD) encompasses barrier. Symptoms of luminal IBD reflect intestinal a spectrum of chronic inflammatory diseases of inflammation and include abdominal pain, diarrhea, the gastrointestinal tract, classically categorized occasional constipation, and bloody stool. In as Crohn disease (CD) and ulcerative colitis (UC). addition to extraintestinal manifestations such as arthritis, uveitis, and skin rashes, patients with IBD often report fatigue, poor sleep and particularly in CD, decreased quality of life. Treatment of IBD focuses on controlling clinical symptoms, achieving endoscopic healing, and preventing disease related disability. Unfortunately, despite effective therapies that induce and maintain remission of the intestinal inflammation, many patients with IBD continue to experience gastrointestinal (GI) symptoms. The differential diagnosis for patients with ongoing symptoms while in remission is extensive (Table 1), but a significant proportion of these symptoms can be attributed to disorders of gut-brain interaction (DGBIs, formerly functional gastrointestinal disorders) including irritable bowel syndrome (IBS).

Approach to GI Symptoms in Quiescent IBD

The first step in assessing new or ongoing GI symptoms in patients with IBD is to exclude active disease. Personalized evaluation of disease activity begins by measuring inflammatory markers (C-reactive protein, fecal calprotectin), imaging [computed tomography (CT)/magnetic resonance (MR) enterography], and/or endoscopy. In addition, the presence of enteric infections, particularly Clostridioides difficile, should be assessed. If symptoms are due to ongoing inflammation, IBD therapy needs to be adjusted accordingly. Note that non-inflammatory structural IBD complications can lead to persistent GI symptoms, such as strictures or post-operative adhesions in CD causing abdominal pain, constipation, and bloating; ileal resection causing bile acid diarrhea; or a tubular lumen in long-standing UC causing diarrhea and fecal urgency.

The differential diagnosis of new GI symptoms in quiescent IBD is wide (Tables 1 and 2). Fortunately, a detailed history, physical examination, and targeted investigation, can help lead to a diagnosis.

DGBIs in Patients with IBD

DGBIs comprise a group of disorders characterized by gastrointestinal symptoms related to any combination of the following: “motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system (CNS) processing.”1 These include 33 adult and 20 pediatric disorders defined by symptoms as delineated by the Rome IV criteria. Risk factors for DGBIs include female sex, adverse childhood events, psychological trauma and other psychosocial stressors, enteric infection, disordered eating, and antibiotic use. Approximately two-thirds of IBD patients meet criteria for at least one DGBI, which is associated with significantly decreased quality of life, anxiety, depression, and increased healthcare utilization.2

The high prevalence of DGBIs in IBD may exist due to overlapping pathophysiologic features including visceral hypersensitivity, central sensitization, gut dysbiosis, small intestinal bacterial overgrowth (SIBO), abberant immune responses, and gut dysmotility. In addition, the bidirectional impact that exists between mental health and both DGBIs in IBD plays an important role in the co-existence of these two conditions (Figure 1, 2). IBS is a DGBI characterized by abdominal pain and altered bowel habits, either diarrhea or constipation predominant or mixed (Table 3). The prevalence of IBS in quiescent IBD is estimated at 39%.3  Risk factors include younger age, female sex, antidepressant use, opioid use, anxiety, depression, somatization, IBD flares, CD (more than UC), and reported lower quality of life.4

Overlap of DGBIs, IBS and IBD Pathogenesis and Interplay between IBS and IBD

Visceral Hypersensitivity: A principal component of DGBIs is visceral hypersensitivity, characterized by a reduced threshold for pain even to physiologic stimuli.5  Visceral hypersensitivity is driven by peripheral sensitization and contributors include enteric infection (postinfectious IBS), intestinal inflammation (mediated by mast cells, substance P, vasoactive intestinal peptide, and inflammatory cytokines), and trauma and psychosocial stress (mediated in part by corticotropin releasing hormone), enterochromaffin serotonin receptors, and other cell receptors/ion channels.6 Enteric infection causes localized inflammation leading to degradation of the intestinal epithelial barrier,

inducing loss of tolerance to dietary antigens. Subsequent exposure to these food antigens causes localized immune activation manifesting symptomatically as pain and altered bowel habits, as seen in IBS.7 Chronic low grade inflammation has been documented in IBS, and mast cells may be an important mediator. IBD patients in remission who have IBS also have elevated density of mucosal mast cells, 5-HT and nerve growth factor compared to healthy controls and even to patients with IBS alone.8 Transient receptor potential vanilloid type 1 (TRPV1) expression is also increased in quiescent IBD with GI symptoms. Peripheral sensitization can in part explain why patients with IBD commonly have rectal hypersensitivity (especially during disease flares), dyspepsia, esophageal pain, and pelvic and vulvovaginal pain.9

Central Sensitization: A related but distinct phenomenon is central sensitization, where abnormal connectivity within the brain and pain modulation system leads to widespread pain, hyperalgesia, allodynia, and hypersensitivity to noise and odors. Both patients with IBS and IBD have been shown to exhibit abnormal functional connectivity of neural networks in the brain pertaining to pain perception and emotional regulation. While central sensitization has long been heralded as a key mechanism in IBS, one study identified that central sensitization is actually a stronger contributor to GI symptoms in IBD than in IBS.10

Psychological Disorders: The combination of central and peripheral sensitization, as well as traumatic experiences, are thought to contribute to IBS and the multiple overlapping comorbidities, such as psychiatric illness (anxiety, depression, and somatization), but also chronic fatigue syndrome, chronic pelvic pain, and sleep disorders. While these same physical disorders are seen in patients with IBD due to their disease, psychiatric disorders are also twice as common in IBD compared with the general population. There is also evidence of a gut-to-brain bidirectional effect in IBD, where anxiety and depression increase the risk of IBD flare, severity of disease, and health care utilization, whereas a diagnosis of IBD increase the risk of developing psychiatric comorbidities in the future.11 Anxiety and depression can affect more than half of IBD patients during times of disease flare, and in a study of adults with a diagnosis of either IBD or IBS, significant post-traumatic stress was seen in 32% of those with IBD and 26% of those with IBS, highlighting the emotional impact of IBD.12

Gut Dysbiosis and Increased Intestinal Permeability: Dysbiosis feature prominently in both IBD and IBS, characterized broadly by a decrease in microbiome diversity and an imbalance between pro- and anti-inflammatory organisms. Though not clear if dysbiosis is a cause or effect of the underlying disease process, several studies point to dysbiosis being a key component in IBD pathogenesis. Decreased diversity of the microbiome combined with enrichment of pathogenic families and genera, such as Enterobacteriaceae and Bacteroides, and depletion of beneficial genera, including Lactobacilli, contribute to abnormal immune responses inducing increased intestinal permeability and local and systemic inflammation.13 In turn, increased intestinal permeability may contribute to pain and diarrhea even when IBD is in remission.14 Enteric infections are a known environmental trigger for new-onset IBD and IBD flares,15  and up to 15% of patients develop IBS after an episode of infectious diarrhea, further highlighting the role of gut dysbiosis in both conditions. In addition, increased intestinal permeability related to dysbiosis is also seen in IBS-D and post-infectious IBS, which may contribute to visceral hypersensitivity.6

Small Intestinal Bacterial Overgrowth (SIBO): SIBO has a strong association with IBD (odds ratio 9.5). It has also been associated with IBS, but the extent and significance of the association is debated.16 SIBO can cause abdominal pain, altered bowel habits, and bloating, which can all be confused with IBD or IBS symptoms. CD portends a higher likelihood of SIBO than UC, especially in patients with bowel strictures, ileocecal resection, and prior bowel surgeries. Other risk factors for SIBO in IBD include female sex, hypoalbuminemia, and longer intestinal transit times. Testing and treating for SIBO is associated with improved symptoms and outcomes in patients with IBD.17

Dysmotility: Dysmotility has been documented in IBS, but also in IBD from the esophagus to the anorectum, likely due to the effects of inflammatory cytokines on the enteric nervous system and structural change of gastrointestinal musculature. Dysmotility can contribute to reflux, chest pain, dyspepsia, gallstones, abdominal pain, constipation, diarrhea, rectal pain, and fecal incontinence.18

Diagnosis of IBS in Patients with IBD

However in otherwise healthy patients, IBS should be a positive diagnosis based on the Rome IV criteria and not a diagnosis of exclusion. The overlap of symptomatology between IBS and IBD requires that IBD patients undergo a judicious and limited work-up to exclude active IBD and mimickers of IBS (Table 2). In patients who meet the Rome IV criteria, a diagnosis of IBS should be made (Table 3).

Other DGBIs in IBD

While IBS is the most common DGBI in IBD, patients with IBD may experience other or multiple DGBIs. In one study, 66% of patients with IBD met criteria for one or more DGBIs, and 34% had more than one disorder. After IBS, the most common types of DGBIs include functional dyspepsia, belching disorders, disorders of nausea and vomiting, functional diarrhea or constipation, fecal incontinence, and proctalgia fugax.2 These are important diagnoses to consider in patients with ongoing symptoms despite quiescent IBD.

Treatment of IBS in Patients with IBD

Reassurance is paramount for management of DGBIs in IBD.19 Patients with IBD often fear that their symptoms are reflective of ongoing IBD activity or IBD complications, including colorectal cancer. It is important to validate their symptoms, but explain that they do not reflect ongoing inflammation from IBD. Education visà-vis the gut-brain axis and the mechanisms of IBS symptoms can be helpful. When IBS treatment is needed for symptoms significantly affecting quality of life, therapy choice should target the patient’s most pressing symptom(s) and be adjusted to the severity and combination of symptoms.

In addition to simple dietary changes, such as avoiding food triggers and ensuring adequate fluid and fiber intake, reasonable first line nonpharmacologic options for IBS include peppermint oil and probiotics. Peppermint oil (taken in an enteric coated pill formulation) has various mechanisms of action which may contribute to improving global symptoms of IBS including modulation of histaminergic and cholinergic receptors in the gut, k-opioid agonist activity, serotonergic antagonism, anti-inflammatory effects, and transient receptor potential melastatin 8 agonism. In fact, peppermint oil may be superior in efficacy to soluble fiber, antispasmodics, and neuromodulators, with a number needed to treat (NNT) of 4, and is recommended for the treatment of IBS by several GI societies.20,21 Given its efficacy, favorable safety and tolerability profile, and low cost, it is a reasonable cost-effective firstline option for IBS in patients with IBD.

Probiotics are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host. While probiotics are commonly used by patients and prescribed by physicians for an array of gastrointestinal diseases, probiotics are not effective in treating active IBD (except for pouchitis and mild UC), but can help with IBS symptoms in patients with IBD.22 According to a 2018 meta-analysis, probiotics are effective in treating IBS symptoms, including abdominal pain, bloating, and flatulence. Combination probiotics may be the most effective with an NNT of 7, with specific (combination of) strains being particularly effective, such as Lactiplantibacillus plantarum299v (DSM 9843) with a NNT of 3.23 One must recognize however that probiotics can exacerbate GI symptoms in a subset of patients, and some preliminary studies show an association between probiotics use and “brain fog” in IBD patients.24

Dietary modification is one of the mainstays of IBS management. The most well studied dietary intervention in IBS is the low-FODMAP diet

(LFD). In patients with IBS, fermentable oligo-, di-, monosaccharides and polyols (FODMAPs), which are poorly digested short-chain carbohydrates, contribute to IBS symptoms via induction of dysbiosis, fermentation, and osmotic potential within the lumen. The LFD consists of three parts: elimination of FODMAPs, gradual reintroduction of FODMAPs (to identify trigger foods), and personalization (to maximize liberalization of the diet as tolerated).25 Studies have consistently demonstrated efficacy of the LFD in alleviating symptoms of IBS in patients with quiescent IBD.26 Due to the restrictive nature of the LFD and related concerns about effects on the gut microbiota, potential to promote disordered eating patterns leading to increased risk of malnutrition and social isolation in an at-risk population, there is interest in exploring more liberal diets in the treatment of IBS. The Mediterranean Diet (MD), characterized by a diet rich in fruits, vegetables, legumes, nuts, seeds, whole grains, oily fish, olive oil, and red wine and low on red meat and processed foods, has shown benefit in IBS and was recently shown to be well tolerated and to improve overall GI symptoms in patients with CD.27 With any dietary therapy and intervention, it is recommended to involve a specialized dietician to educate the patient about the diet, choose foods that are tolerated by the patient with IBD, design meals that align with the patient culture, taste and lifestyle and ensure adequate and balanced nutrient intake.

There are various pharmacologic options for the management of IBS as outlined in Table 4. Therapy should be chosen to address the predominant symptom(s).28,29,30 In patients with abdominal pain, bloating, and diarrhea, a trial of antibiotics for SIBO should be considered after testing or in the presence of predisposing anatomic factors; pancreatic enzymes can also be effective in the management of these symptoms, as exocrine pancreatic insufficiency can co-exist with IBD. Fiber supplements can be used both as bulking agent in patients with diarrhea or to treat constipation (unless symptoms are due to a CD stricture, in which case the amount and type of fiber should be carefully assessed). The judicious use of neuromodulators can treat IBS symptoms as well as associated non-GI disorders: bupropion is a good option for a patient with CD and abdominal pain, depression, or anxiety, who is attempting smoking cessation, while tricyclic antidepressants can treat abdominal pain, diarrhea, and sleep disturbances.

Several psychological interventions from simple measures including routine exercise, sleep hygiene, stress reduction, and social support, to professional techniques such as mindfulness techniques, cognitive behavioral therapy, and gut-directed hypnotherapy can benefit IBS symptoms in patients with IBD. Early referral to a psychotherapist and psychiatrist should be made in patients with concomitant anxiety, depression, somatization, or trauma.

CONCLUSION

New onset or persistent GI symptoms are common in quiescent IBD. Etiologies include immunemediated/inflammatory, infectious, malabsorptive, anatomic, dysmotility, and extra-intestinal causes. After appropriate exclusion of active IBD and IBDrelated complications, a limited workup guided by a comprehensive history often leads to the diagnosis. DGBIs, particularly IBS, are common in patients with IBD and should be appropriately recognized and treated. IBS should be treated based on the predominant symptom(s) and underlying predisposing factors, and with a multidisciplinary team. It is important however to recognize that patients with quiescent IBD often have persistent GI symptoms secondary to several concomitant and overlapping etiologies and require a multifaceted approach to control their symptoms and improve their quality of life.

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