Dispatches from the GUILD Conference, Series #67

What do Gastroenterologists Need to Know About Stomas?

April 2025 • Volume XLIX, Issue 4
Gilad Alon,Michael Goldenshluger,Stefan D. Holubar,Miguel Regueiro

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Intestinal stomas, whether from the small or large bowel, are the cornerstone of the surgical management of various gastrointestinal conditions, particularly in patients with inflammatory bowel disease (IBD) and rectal cancer. This review provides an overview of stoma types, indications, complications, and the critical role of preoperative and postoperative care. This highlights the necessity for collaboration between colorectal surgeons and gastroenterologists to optimize surgical planning, manage complex cases, and prevent complications. Stomas play a pivotal role in treating refractory diseases, high-risk surgical scenarios, and emergencies. Comprehensive care involving multidisciplinary teams that include stoma nurses, dietitians, and mental health professionals is essential for addressing stoma-related challenges, minimizing complications, and improving patient outcomes. By integrating medical and surgical expertise, healthcare teams can empower patients to adapt successfully and maintain high quality of life.

Introduction

Intestinal stomas involve the surgical exteriorization of either the small or large bowel through the anterior abdominal wall. These stomas, whether small or large, play vital roles in the treatment and management of various gastrointestinal diseases. In the United States, the estimated number of patients living with a stoma (ostomates) ranges from 750,000 to 1 million, with approximately 150,000 new ostomies constructed each year.1 A comprehensive understanding of the surgical planning and decision-making processes involved in constructing ostomies, the different types of stomas, their potential complications, and the preoperative and postoperative care required, are essential for the successful treatment of patients with ostomies.2

1. Know the anatomyExactly what kind of stoma?
How much proximal and distal bowel?
Plans for restoration of intestinal continuity?
2. Stoma complicationsPoor pouching? Refer to Ostomy nursing
Anatomic issue? Refer to surgeon
Manifestation of systemic disease?
Treat as appropriate
3. High output enterostomyAvoid sugar (diarrheogenic)
Isotonic oral rehydration solutions
Stool bulking “thicken it up”
Antimotility agents “slow it down”
Parental fluid and/or nutritional support
as needed
Table 1. Key points:
What do Gastroenterologists Need to Know About Stomas?

A summary of key points and stoma-related terms is presented in Tables 1 and 2. Stoma is the Greek word for mouth and is defined as an artificial opening of a hollow organ; an ostomy refers to an opening of the bowel brought to the skin to allow egress of intestinal fluids through the os, but “-ostomy” may also refer to tubes placed in GI organs that cannot reach the skin (i.e., duodenostomy, gastrostomy).

Types of Stomas

Large bowel stoma: colostomy

Colostomies are constructed using the large intestine, most commonly the distal transverse, descending, or sigmoid colon. The more distal the colostomy, the better the functional outcomes, as stool consistency becomes more dehydrated, and stool frequency decreases.3 Compared to small bowel ostomies, colostomies have firmer stool consistency, easier pouch management, and a lower incidence of systemic complications such as electrolyte disturbances and dehydration, which are more common in small bowel ostomies.3 Colostomies generally offer better functionality given the ability of the large bowel proximal to the colostomy to absorb water and electrolytes with a resultant neutral pH (as opposed to the mildly acidic succus from ileostomies which results in universal skin irritation and the need for maturation of the os in a budded manner). Given the neutral pH of stool from a colostomy, it may be budded (matured) and protrude a few centimeters above the skin or lie flush with the skin surface, depending on patient-specific factors, such as body habitus, surgical technique, and the bowel’s length of reach to make a tension-free colocutaneous anastomosis whenever possible. Right colonic or proximal transverse colostomies are generally avoided, resulting in feculent diarrheal output as opposed to the thicker stool from distal colostomies or non-feculent succus entericus output from an ileostomy (which is generally preferred compared to a right-sided colostomy). A rare form of large-bowel stoma is an appendicostomy which may be used for antegrade colonic irrigation (i.e., the Malone antegrade continent enema [MACE] procedure).

Colostomies (Figure 1) can be fashioned as a loop colostomy, an end colostomy, or a “double barrel” colostomy depending on the clinical indication and surgical approach. A mucus fistula is an ostomy of the defunctionalized distal segment that is matured as a complete or partial opening to allow drainage of mucus and secretions from the distal segment and is critical to decompress the distal segment when a distal obstruction is present. An end colostomy is typically chosen when making a permanent colostomy, such as during an abdominoperineal resection for low rectal cancer or may be chosen in an emergency surgery after a segmental resection (e.g., surgery for perforated diverticulitis). In contrast, a loop colostomy or double-barrel colostomy may be selected when future bowel reconstruction is anticipated or when there is a need for distal decompression. A double-barrel colostomy is distinguished from a loop colostomy by its separation into two distinct stomas, one for the proximal bowel to divert feces and the other for the distal bowel to allow mucus drainage, whereas a loop colostomy typically involves a single stoma with two openings.

CategoryOrganOstomy
OstomiesJejunumJejunostomy
IleumIleostomy
AppendixAppendicostomy
ColonColostomy
Urinary tractUrostomy
TubesStomachGastrostomy
DuodenumDuodenostomy
Intestinal anastomosesSmall bowelEnteroenterostomy
IleocolicIleocolostomy
ColonColocolostomy
ColorectumColoproctostomy
Total colectomyIleoproctostomy
(aka ileorectal anastomosis)
Table 2. Summary of Ostomy Terminology

Small bowel stoma: enterostomy (Ileostomy and Jejunostomy)

Small bowel ostomies such as ileostomies and jejunostomies are constructed using the small intestine. They are most commonly fashioned from the terminal ileum but can be created from any part of the small bowel, depending on the clinical scenario. Generally, the more proximal the small bowel ostomy, the higher the sensitivity to systemic complications.1 Ileostomies are indicated for conditions requiring bowel diversion or resection of either the small or large intestine when anastomosis to restore bowel continuity is not feasible, either temporarily or permanently. Jejunostomies are made from the more proximal jejunum and avoided as much as possible due to their morbid nature, given their significantly higher output of acidic, electrolyte-rich succus entericus resulting in total parenteral nutrition dependence and may be classified as low- or high- jejunostomies, less than or greater than 30 cm from the ligament of Treitz, respectively. 

Compared to colostomies, ileostomies result in liquid to semi-liquid stool output (ideally yogurt consistency) owing to the lack of colonic reabsorption of water and electrolytes. Consequently, patients with ileostomies are at a higher risk of dehydration and electrolyte disturbances (e.g., hypokalemia and hyponatremia), as well as local issues such as skin irritation due to frequent stool output. Therefore, ileostomies must be matured such that the os is ideally 2 cm above the skin in a “spigot” manner (Figure 2) such that the stool egresses directly into the ostomy appliance bag to minimize skin irritation. Ileostomies (and jejunostomies) may be fashioned as an end ileostomy, loop ileostomy, or end loop. 

An end ileostomy (Figure 2) involves bringing the ileum through the abdominal wall to create a single stoma and is often permanent and is typically performed after total proctocolectomy or when bowel continuity cannot be restored. End ileostomies may be fashioned in several ways (Figure 3). An end-loop ileostomy made by bringing a loop proximal to the stapled-off distal segment is brought out, often chosen when there are difficulties in getting the bowel to reach 2 cm above the surface due to the shorter divided mesentery associated with a true end ileostomy, while in an end-loop the intact mesentery supplying the loop allows for additional length. When there is a distal obstruction, an end ileostomy may be performed with a mucus fistula as an additional small opening to allow drainage of mucus and secretions from the distal bowel segment when necessary. 

A loop ileostomy (Figure 4) is commonly used for temporary bowel diversion to protect the downstream anastomosis after intestinal resection. A loop of the small bowel is brought to the surface and opened, creating a stoma with two openings; the proximal limb diverts stool to the exterior, while the distal limb allows mucus drainage from the downstream bowel. Loop ileostomies are typically easier to reverse than end ileostomies, making them the preferred choice for temporary diversion. 

Continent ileostomy (Figure 5), although less commonly performed today, involves the creation of an internal reservoir, such as a Kock pouch. This reservoir allows stool to be stored and drained via intermittent catheterization. Continent ileostomies are typically chosen by patients who wish to avoid a traditional end ileostomy and are not candidates for restorative surgery with an ileal pouch-anal anastomosis (IPAA) after total proctocolectomy or personal preference. 

Indications for Stoma Creation

Temporary diversion

Temporary bowel diversion is frequently required in specific clinical scenarios in which protecting the distal anastomosis is critical. For example, in patients undergoing low rectal anastomosis after neoadjuvant radiotherapy or after IPAA, a temporary stoma diverts the fecal stream to allow the pouch to heal. Risk factors for anastomotic leakage include high-dose/prolonged corticosteroids, malnutrition, anemia, smoking, and other risk factors.4 Of note, ileostomies do not decrease anastomotic leak rates but rather decrease the severity of leaks when they occur, thus allowing less invasive treatment and facilitating successful leak management and healing by methods such as percutaneous drains and endoluminal vacuum therapy.5-8 In cases of extensive perianal disease, such as severe perianal Crohn’s disease or complex fistulas, temporary diversion may be necessary to facilitate perineal wound healing and reduce ongoing inflammation. Similarly, in the presence of active pelvic infections and inflammation — such as colovesical and colovaginal fistulas secondary to diverticulitis or malignancy — temporary diversion before or at the time of definitive surgical repair is often required to facilitate successful restoration of intestinal continuity.9

Permanent ostomies

In some cases, a permanent ostomy is planned from the outset, whereas in others, an initial temporary ostomy may become permanent due to unforeseen clinical factors or patient preference. Abdominoperineal resection (APR) is a common indication for permanent colostomy in patients with low rectal cancer, where sphincter preservation is not feasible. Another scenario requiring permanent bowel diversion is total proctocolectomy without ileal pouch creation, typically performed in patients with ulcerative colitis or familial adenomatous polyposis who are either not candidates for or decline an ileal pouch-anal anastomosis. 

Emergencies

In emergency settings, primary bowel reconstruction is often contraindicated, which necessitates stoma creation. Emergency bowel resection, frequently required for patients presenting with perforation, obstruction, or ischemia, may necessitate a stoma when factors such as hemodynamic instability, active infection, or poor tissue perfusion preclude a safe anastomosis. Trauma, whether from penetrating or blunt abdominal injuries, may also warrant temporary or permanent stoma creation to manage bowel injuries and prevent further complications.

Stomas in Inflammatory Bowel Disease (IBD)

Despite advances in medical therapy, including biologics and small molecules, a subset of patients with IBD still require surgical intervention. Surgery remains necessary for those with refractory disease, abdominal complications such as strictures, perforations, or abscesses, and severe perianal Crohn’s disease.10-12 It is estimated that approximately 20–30% of ulcerative colitis patients will require a colectomy during their lifetime, while up to 58% of Crohn’s disease patients will undergo at least one major abdominal surgery within 20 years of diagnosis.11-13 

Stomas, typically ileostomies, are often indicated in IBD cases where anastomosis is either high-risk or should be avoided. Factors that increase the risk of anastomotic leakage include severe malnutrition, prolonged steroid use, and emergency surgical indications such as abdominal sepsis or bowel obstruction.

Stoma in Ulcerative Colitis

Total proctocolectomy is typically performed with or without IPAA for ulcerative colitis (UC). To optimize outcomes and reduce morbidity, this procedure is usually staged. The 3-staged approach is most common these days, starting with a total abdominal colectomy with end ileostomy (Stage 1), leaving the rectum intact, followed by a completion proctectomy with IPAA and temporary diverting loop ileostomy (Stage 2); finally, diverting loop ileostomy reversal (Stage 3) after pouch healing is confirmed. Other staging strategies include a 2-stage, starting with a total proctocolectomy with IPAA and temporary loop ileostomy (Stage 1), followed by ileostomy reversal, and a modified 2-stage which is similar to a 3-stage, but the diverting loop ileostomy is omitted in the 2nd stage. Of note, approximately 10% of UC patients after Stage 1 of a 3-stage will have such a dramatic improvement in their health and quality of life they choose to keep it permanently and forgo IPAA, while others who are not candidates for IPAA choose a continent ileostomy. Another 5-10% of patients will require pouch excision and end ileostomy due to treatment-refractory leaks or Crohn’s-like disease of the pouch.

AgentAdult Oral DoseMaximum Daily DoseNotes
Loperamide1 – 4 two mg tablets or caplets (not capsules)  QID 30 min. before meals & QHS16 tabsOTC but can also prescribe for some
Diphenoxylate-atropine1 – 2 2.5 mg tabs  QID 30 min. before meals & QHS 8 tabsOpioid script, non-sedating
Codeine15 – 60 mg  QID 30 min. before meals & QHS240 mgOpioid script
Deodorized tincture of opium0.3 – 0.6 mL sublingual  QID 30 min. before meals & QHS6 mLOpioid script
Octreotide300 – 1200 ug IV/day divided1200 ugProvided in TPN; monitor LFTs
Sandostatin10, 20, or 30 mg IM q28 days30 mg/ monthDepot injection; monitor LFTs & glucose
Table 4. Antimotility Agents

Stoma in Crohn’s disease

In Crohn’s disease, stomas are frequently necessary to manage complications such as strictures, fistulas, abscesses, and perforations.14,15 “Temporary” diversion with an ileostomy or colostomy may also be required in severe perianal disease to facilitate wound healing and symptom control, but become permanent in the vast majority.16,17 Additionally, in high-risk conditions such as malnutrition or sepsis, primary anastomosis carries an unacceptably high failure rate, making stoma creation the preferred surgical option.5 Ultimately, the decision to create a stoma in IBD should be guided by both the patient’s clinical status and long-term disease trajectory.

Endoscopy in Stoma Patients

Prior to performing ileoscopy or colonoscopy in ostomates, it is important for the endoscopist to focus on the exact anatomy of the ostomy and the segments that need endoscopic interrogation. For example, if a patient has undergone Hartmann’s colostomy, it also has a distal segment known as Hartmann’s pouch (rectal stump), which requires assessment prior to colostomy reversal and routine endoscopic surveillance if the stump is kept in place permanently. For ileostomies, it should be kept in mind the bowel wall is thinner and more prone to incidental perforation compared with the colon. When scoping an apparent loop ileostomy, it may be an end-loop, and in this case, excessive pressure trying to intubate the stapled distal limb may result in perforation and enterocutaneous fistula formation.

Stoma Complications

The construction of an ostomy, whether a small bowel or colonic stoma, is associated with a substantial morbidity rate, with reported complication rates ranging from 20% to 80%.1 Among the most common issues are peristomal skin complications and parastomal hernias. One large population-based study analyzing over 4,200 patients found an overall surgical complication rate of 37% in elective ostomy cases and 55% in emergency ostomy cases.18

Peristomal skin irritation, hyperplastic granulation tissue, and mucocutaneous separation

(Figure 6) Peristomal skin is particularly vulnerable to irritation and breakdown due to stool leakage or ill-fitting appliances. Contact dermatitis may occur secondary to appliance adhesive. Hyperplastic granulation tissue may result from the use of a tight-fitting appliance. Treatment involves optimizing pouching techniques, applying barrier creams, and revising the stoma if necessary. Mucocutaneous separation and peristomal ulceration (Figure 7) may be thought of as a failure of enterocutaneous anastomosis to heal, and fastidious skin care may expedite healing.

Stoma retraction and strictures

(Figure 7) Retraction below the skin level can cause a poor fit and difficulty in waste elimination. Less commonly, stenosis  may develop because of mechanical causes (such as scar formation) or inflammatory changes, leading to impaired stoma function. Management options include dietary modification, dilation, or surgical revision.

Peristomal fistulae

(Figure 8) Peristomal infections can develop due to local inflammation or stool leakage, potentially resulting in abscess or fistula formation. Management may require surgical drainage and optimization of stoma care.

Peristomal pyoderma gangrenosum

(Figure 9) Chronic irritation can lead to inflammatory skin conditions including pyoderma gangrenosum (PG), which presents as painful ulcerations around the stoma. Management typically requires topical or intralesional corticosteroids and may require surgical revision in refractory cases. Surgical repositioning of the stoma is performed in severe cases, particularly when bowel continuity cannot be restored but is prone to recurrence if the underlying inflammatory disorder is not addressed with systemic advanced therapies. A stepwise algorithmic approach for management and treatment of peristoma PG is shown in Figure 10. 

Prolapse and parastomal hernias

(Figure 11) Excessive protrusion of the stoma beyond the abdominal wall may lead to cosmetic concerns, difficulty in pouching, ischemia, or even bowel obstruction. Treatment depends on the severity and ranges from non-surgical interventions (e.g., manual reduction, application of sugar to draw out the edema from the prolapsed segment, and support belts) to surgical revision. Prolapse is typically secondary to a parastomal hernia.

A parastomal hernia is defined as an incisional hernia that occurs at the site of an abdominal wall stoma. The reported incidence of parastomal hernias varies widely, depending on factors such as the length of follow-up and the type of stoma created. The incidence of end colostomies is slightly higher, reaching up to 48%, whereas that of loop ileostomies is reported to be up to 30.8%.18,19 Although most parastomal hernias are asymptomatic and can therefore be treated conservatively, parastomal hernias can significantly impair the quality of life and cause symptoms such as pain, discomfort, and, in severe cases, bowel obstruction. Compared with other incisional hernias, parastomal hernias are more challenging to repair because of the permanent defect in the abdominal wall created by the stoma. This complexity often necessitates careful preoperative planning and use of specialized surgical techniques for hernia repair.20,21

Nutrition in Ostomates

Dietary adjustments for ostomates can be divided into the early and late postoperative phases. In the early phase, the primary considerations were the patient’s preoperative nutritional status and underlying condition. In cases of severe metabolic deconditioning, 10–14 days of enteral or parenteral nutritional therapy may be beneficial before surgery and directly affect postoperative recovery.22 Early physiological enteral nutrition after surgery improves intestinal adaptation, preserves the intestinal flora and enteric immune system, and is cost effective when compared with parenteral feeding.22,23 Postoperatively, the diet is usually introduced gradually and typically consists of low-fiber foods to minimize stool production, reduce strain, and prevent obstruction, as surgical manipulation can lead to bowel edema.24 

In the long term, dietary adjustments for ostomates should be individualized based on three key factors: type of stoma, output volume, and the patient’s underlying condition. Generally, the aim is to maintain a healthy and rich diet, including all nutrients and fibers, as long as stoma function is optimal. After the initial recovery period (typically 6-8 weeks), it is recommended that new foods be introduced slowly and in small quantities, one at a time, as it simplifies the process of eliminating them if issues arise.25 

Dietary adjustments for colostomy patients

The diet of patients undergoing colostomy tends to be easier to manage than that of patients undergoing ileostomy. For long-term management, especially for patients with a permanent colostomy, maintaining a healthy BMI is crucial, as obesity and weight gain have been associated with colostomy retraction and symptomatic parastomal hernias.15 Although no specific diet has been proven effective after colostomy formation, a diet rich in complex carbohydrates and low in fat (while incorporating medium-chain triglycerides) may be beneficial. It is important to monitor for potential deficiencies in fat-soluble vitamins (A, D, E, and K), as well as in fatty acids. After the early postoperative period, including higher-fiber foods such as brown rice or whole wheat bread for patients with colostomy may help prevent constipation.26

Dietary adjustments in patients with ileostomies

After the formation of an ileostomy and during the early postoperative period, stoma output is usually unpredictable and may remain elevated for 1–3 months. When the entire colon is absent or not in continuity, patients lose the endogenous vitamins and nutrients typically produced by the gut microbiota, including vitamins K and B, folic acid, and short-chain fatty acids.26 In addition, the absorption of fat and niacin is much lower than that in patients with a colostomy. Hence, these patients should be monitored for their fat intake and the levels of fat-soluble vitamins (A, D, E, and K), along with vitamin B12, which is absorbed in the ileum by intrinsic factors. For ileostomy patients, especially those with a high-output stoma, the energy requirements may increase by up to 30%.27 To meet these needs, it is essential to increase the caloric content of the diet, which can be achieved either through dietary modifications or oral nutritional supplements. During the first year of recovery, patients may require multivitamin supplements.25 To minimize fluid loss and reduce gastric fluid production, it is recommended that patients avoid drinking fluids 30 min before and after meals. The type of fluid consumed is also important, as carbonated beverages can increase the gas in the stoma bag, leading many patients to limit or avoid them. It is helpful to reduce the amount of food consumed per meal, while increasing the number of meals throughout the day.28 

After the first 6–8 weeks post-surgery, patients should be encouraged to introduce more fruits and vegetables, provided their stoma output has normalized in both volume and consistency.24 Tolerance to fiber varies among individuals, with some patients being able to resume a high-fiber diet, while others may need to gradually reintroduce these foods or avoid certain items altogether. For ileostomy patients, some foods should be consumed with caution, as they may pose a risk of causing stoma blockages (popcorn, apple peels, whole corn, bean sprouts, dried fruit, and nuts) and excessive gas or unpleasant odors (beans/pulses, cabbage, broccoli, cauliflower, mushrooms, onions, and alcohol).28 Additionally, patients with ileostomy may develop lactose intolerance after surgery due to changes in gut function. Therefore, they should avoid dairy products if they experience abdominal cramps or watery output.

High output enterostomy (HOE) and electrolyte management

Dehydration and electrolyte imbalances are the leading causes of hospital readmission following ileostomy formation and are responsible for up to 10% of readmissions within 60 days post-surgery; the most common postoperative losses in patients undergoing ileostomy are fluid, sodium, potassium, and magnesium.29,30 Table 3 shows electrolyte replacement options. Of note, magnesium sulfate supplements are diarrheogenic, and Mag Plus Protein (Miller Pharmaceutical Group) may be recommended to avoid obligate fluid losses associated with magnesium sulfate supplementation. During the first 6–8 weeks, patients may lose 1200–2000 ml of fluid and 120–200 mmol of sodium per day. However, after approximately eight weeks, the ileum typically undergoes adaptation, leading to a reduction in fluid losses.28 During the immediate postoperative period; therefore, close monitoring of renal function and electrolyte balance is essential. These assessments should be repeated at follow-up appointments within a month or sooner if any clinical signs arise. A stepwise algorithmic approach for managing HOE is recommended (Figure 12), which focuses on isotonic oral fluid repletion, stool bulking, and antimotility agents. A summary of antimotility agents is shown in Table 4. Patients with HOE, defined as producing >1500 ml/day after adaptation, are recommended to avoid sugary drinks and foods that cause osmotic diarrhea, avoid hypotonic fluids, and instead consume an additional 1000 ml of oral rehydration solution to replace the lost electrolytes.31 Unlike typical physiological responses, patients should be advised against increasing fluid intake of hypotonic fluids such as water, tea, or juice, as these hypotonic fluids may cause greater fluid loss from the stoma and instead use a rehydration solution. 

Role of Multidisciplinary Care

Patients with ostomies, especially IBD, who require an ostomy, should be cared for by a multidisciplinary team that includes a gastroenterologist, colorectal surgeon, dietitian, pharmacist, social worker, psychologist, and a stoma therapist. Early involvement of colorectal surgeons is crucial for discussing the procedure, setting expectations, reassessing nutritional status, and possibly offering nutritional prehabilitation through enteral or parenteral feeding.

Stoma nurses are essential for providing education, support, and managing various stoma-related complications. The involvement of a mental health specialist and an ostomy nurse has been shown to enhance ostomy acceptance, reduce complications, improve quality of life, and are associated with shorter hospital stays.32

Conclusion

Enterostomies remain a cornerstone of the surgical management of gastrointestinal conditions, particularly in patients with complex IBD. The creation of an intestinal stoma can profoundly reshape a patient’s life, often presenting unique challenges and risks, including complications and potential impacts on the quality of life. Enterostomies play a critical role in managing refractory diseases, complications, and surgical recovery in patients with IBD.

The success of stoma creation and its subsequent management relies heavily on the collaborative expertise of a multidisciplinary team that includes colorectal surgeons and gastroenterologists. This partnership ensures tailored surgical planning, precise execution, and vigilant postoperative care, which are essential for minimizing complications and supporting patients in achieving the best possible outcome. By integrating medical and surgical approaches, healthcare teams can empower ostomy patients to adapt and lead fulfilling lives, even in the face of chronic illnesses. 

References

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27. Medlin S. Nutritional and fluid requirements: high-output stomas. Br J Nurs. Mar 22-Apr 11 2012;21(6):S22-5. doi:10.12968/bjon.2012.21.Sup6.S22

28. Gasche R. Diet and stoma care. Br J Community Nurs. Sep 2 2022;27(9):444-448. doi:10.12968/bjcn.2022.27.9.444

29. Akesson O, Syk I, Lindmark G, Buchwald P. Morbidity related to defunctioning loop ileostomy in low anterior resection. Int J Colorectal Dis. Dec 2012;27(12):1619-23. doi:10.1007/s00384-012-1490-y

30. Liu C, Bhat S, Sharma P, Yuan L, O’Grady G, Bissett I. Risk factors for readmission with dehydration after ileostomy formation: A systematic review and meta-analysis. Colorectal Dis. May 2021;23(5):1071-1082. doi:10.1111/codi.15566

31. Cuerda C, Pironi L, Arends J, et al. ESPEN practical guideline: Clinical nutrition in chronic intestinal failure. Clin Nutr. Sep 2021;40(9):5196-5220. doi:10.1016/j.clnu.2021.07.002

32. Levy LC, Coburn ES, Choi S, Holubar SD. The management of the hospitalized ulcerative colitis patient: the medical-surgical conundrum. Curr Opin Gastroenterol. Jul 2020;36(4):265-276. doi:10.1097/MOG.0000000000000637

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Nutrition Reviews in Gastroenterology, SERIES #22

Nutrition Therapies for Managing Gastrointestinal Symptoms During Pregnancy 

April 2025 • Volume XLIX, Issue 4
Christine L. Scarcello,Kelly Issokson,Puja V. Khanna

Read Article

Gastrointestinal symptoms of pregnancy are common and can interfere with quality of life and the ability to consume adequate oral intake. The occurrence of symptoms varies throughout pregnancy; while nausea and vomiting predominantly affect patients during the first trimester, other symptoms may progressively worsen throughout the length of gestation without relief until the postnatal period. Common symptoms prevalent during pregnancy include nausea and vomiting, gastroesophageal reflux, constipation, and diarrhea. Clinicians can introduce nutritional interventions for the management of mild symptoms prior to pharmacologic intervention, but it is important to monitor for adequate relief. Individuals with chronic GI disorders – such as inflammatory bowel disease, gastroparesis, metabolic dysfunction-associated steatotic liver disease, and irritable bowel syndrome – face an increased risk for malnutrition and may require ongoing care from a gastroenterologist and a registered dietitian during pregnancy. 

Introduction 

The forty-week period of gestation is a time of heightened need for nutritional optimization for both the parent and developing fetus. Changes in the gastrointestinal (GI) tract result from hormonal and physiologic intra-abdominal adaptations during pregnancy and may quickly affect quality of life as well as adequate oral nutrition. The American College of Obstetrics and Gynecology (ACOG) and former Institute of Medicine (IOM) recommendations for specific gestational weight gain ranges for pregnancy are based on pre-pregnancy Body Mass Index (BMI) (See Table 1).1 While these ranges continue to be researched and updated, clinicians should still measure adequacy of weight gain throughout gestation to avoid over- or undernutrition. A recent systematic review of over one million pregnant individuals revealed that 23% did not meet weight gain parameters and 47% exceeded them.2 Monitoring gestational weight milestones is important to prevent poor fetal development and pregnancy outcomes, such as small-for-gestational-age (SGA) infants and preterm birth when undernutrition is present.2 Pregnancy-related GI symptoms can also affect quality of life,and managing mild pregnancy GI symptoms safely and adequately through diet is the recognized first-line treatment (See Table 2).3-6 The purpose of this review is to identify the most common GI symptoms experienced during pregnancy, highlight the first-line nutrition therapies for these ailments, and discuss updates and considerations for pregnant individuals diagnosed with GI disorders. 

BMIClassificationGestational Weight
Gain Goals
<18.5Underweight28-40 lbs
18.5-24.9Normal 25-35 lbs
25-29.9Overweight15-25 lbs
>30Obese11-20 lbs
Table 1.
Gestational Weight Gain per ACOG/IOM Recommendations (2013)1

Common Gastrointestinal
Symptoms During Pregnancy

Nausea and Vomiting

Nausea and vomiting (NV) in pregnancy is the most common GI symptom that affects between 50-90% of pregnant individuals and interferes the most with adequate oral intake and ability to reach pregnancy weight goals.3,4,7 Beginning early in the first trimester and subsiding after 20 weeks, the etiology of NV can be attributed to various hormonal changes.8,9 For example, increased estrogen and human chorionic gonadotropin affect GI motility while progesterone inhibits motility and can cause delayed gastric emptying.8,9 Clinicians should be sure to rule out any other causes of nausea during pregnancy, such as gastroenteritis, biliary disease, gastroparesis (GP), gastroesophageal reflux disease (GERD), peptic ulcers, pancreatitis, hepatitis, pyelonephritis, appendicitis, and irritable bowel syndrome (IBS).4,9 

Common GI SymptomsPractical Nutrition-Related Interventions for Patients
Nausea and Vomiting Texture modification for fruits, vegetables, and proteins to soft and small particle size: fork-tender consistency, blended, steamed, stewed, slow-baked, roasted.  Smaller meals with more frequency to ensure adequate nutrient intake. Supplementation with ginger and Vitamin B6.8 Limit offending foods (based on smell, taste, or texture) that worsen nausea. The use of prenatal vitamin and mineral supplementation one month prior to conception can reduce occurrence and severity.4  
Hyperemesis GravidarumEmphasis on calories and protein at each meal.4   Electrolyte and micronutrient monitoring and replacement.  EN or PN support if intake remains inadequate.
Gastroesophageal Reflux Disorder Smaller meals with more frequency to ensure adequate nutrient intake.  Final meal or snack consumed 2-3 hours before bed. Limit offending foods that worsen symptoms. Common GERD triggers include caffeine/coffee, spicy foods, greasy or high-fat foods, chocolate, peppermint, acidic fruits, heavy creams or gravies, and vinegar. Limit high-volume intake and over-eating. Separating fluids from meals may help reduce the volume of items entering the stomach at one time.
ConstipationIncreased fiber intake if inadequate. Aim for 25-35 grams per day and increase slowly by a few grams each day.  Increased hydration if inadequate. Aim for 60-64 ounces per day.
DiarrheaIncreased soluble fiber intake (e.g., oatmeal, banana, potato). Use of oral rehydration solutions (ORS) if diarrhea is severe/persistent. Review all medications and supplements as some may cause or worsen diarrhea (such as certain antibiotics, laxatives, motility agents, magnesium citrate or oxide).
Table 2. Nutrition-Related Applications for Common GI Symptom Management 

• Nutritional remedies that can be implemented for NV during pregnancy include: 4,7,8,9
• Identifying triggering foods (based on smell, taste, or texture)
• Eating smaller and more frequent meals
• Modifying textures of foods to a smaller particle size
• Choosing bland foods and snacks that are generally higher in protein and lower in fat
• Supplementing with ginger (250 mg capsules four times per day) or vitamin B6 (10-25 mg every eight
hours) before advancing to pharmacologic treatments

If nutrition interventions to reduce NV are unsuccessful, next-line treatment includes H1-receptor antiemetics such as doxylamine, promethazine, and dimenhydrinate.8 Additional pharmacological intervention should be used on a case-by-case basis after identifying the certain risks and benefits of medication use in this population. The use of prenatal vitamin and mineral supplementation at least one month before conception may reduce the occurrence and severity of NV in pregnancy.4 Clinicians should encourage patients to do so, especially in the preconception visit and fertility clinic setting. 

Hyperemesis Gravidarum

Intractable and sustained vomiting – hyperemesis gravidarum (HG) – can lead to severe complications such as metabolic disturbances, dehydration, micronutrient deficiencies, Wernicke’s encephalopathy, and even death from thromboembolism or cardiac arrest.4,10 HG affects a much smaller percentage of pregnancies with various estimates placing its prevalence at approximately 1- 3%.4,7 Research by Fezjo et al. in recent years has shown a causative genetic etiological component of worsening NV and HG related to a hypersensitivity to increased levels of growth and differentiation factor 15 (GDF15) from which future therapies may one day be derived.10,11 Other contributing factors that have shown to be related to HG onset include changes to the amount of progesterone, estrogen, thyroid hormones, and leptin during pregnancy.4 Physiological changes during pregnancy include abnormalities with gastric transit and lower esophageal sphincter (LES) resting pressure, which may increase the severity of NV and risk of developing HG.4  

Manifestations that may present in a clinical exam and that are used to diagnose HG include weight loss (5% or greater), dehydration, ketonuria, orthostasis, micronutrient deficiencies, inadequate oral intake (usually consuming less than 50% of needs), and electrolyte imbalances.4,7 Some severe cases require hospitalization and parenteral administration of fluids and electrolytes. In the acute inpatient setting, a regular diet should be the primary goal with modifications as needed, with the supplementation of enteral nutrition (EN) reserved for those who continue to experience weight loss and are refractory to medical interventions.4 

Malnutrition and inadequate gestational weight gain are concerning consequences of HG.4 It is important to consult a registered dietitian (RD) to monitor for these clinical repercussions and assess when escalation to EN is important. Nasogastric tubes with use of antiemetic medication are preferred first, as post-pyloric feeding tube placement requires imaging for placement confirmation that will expose the fetus to radiation.4 Dietitians should start with polymeric enteral formulas and evaluate tolerance before considering a transition to a semi-elemental enteral formula or an alternative access method. If vomiting remains intractable and there is persistent intolerance to oral and EN support, parenteral nutrition (PN) may become necessary to provide the adequate caloric and protein needs for fetal development and prevention of malnutrition. In lieu of clinical guidelines for this population subset, the decision to escalate to PN must be managed on a case-by-case basis.4 Providing treatment early for NV in pregnancy may help delay the progression to HG, and it is important for clinicians to recognize when escalation of care is essential before severe metabolic disturbances arise.7,8

Gastroesophageal Reflux  

Instances of heartburn, regurgitation, and epigastric pain during pregnancy are often related to GERD, though it is important to rule out other GI disorders that may present with similar symptomatology.9 GERD is a common GI disorder that currently affects 1 in 3 U.S. adults and during pregnancy it has an even higher prevalence of 50-85%with symptoms usually persisting until delivery.8,9,12 Clinical manifestations are diagnosed just as with nonpregnant individuals, with an important note that barium imaging studies should be avoided in pregnant patients due to fetal radiation exposure.9 

The etiology of GERD in pregnancy may be attributed to hormonal changes (for example, progesterone can affect the LES) or physiological changes to intra-abdominal pressure and motility due to an enlarging uterus.8,9,13 The first-line treatment for reflux and associated symptoms includes changes to diet, meal planning, and sleep position.9 Recommendations include:9

• Ceasing intake a few hours before bed
• Eating smaller meals with increased frequency
• Identifying triggering and offending foods and avoiding them
• Raising head of bed during sleep
• Lying on the left side

Schuitenmaker et al. investigated sleep positions on non-pregnant individuals while measuring esophageal pH in 57 adult participants and determined that sleeping in the left lateral decubitus position offered a shorter esophageal acid exposure time and increased acid clearance when compared to right lateral or supine sleep positioning.14 The clinical practice update from the American Gastroenterological Association (AGA) lists modifications to lifestyle and diet as best practice advice.15  Weight loss is the traditional recommendation to reduce GERD symptoms but would not be appropriate to recommend during pregnancy.15 

If the first-line treatment of altered diet and lifestyle change does not improve symptoms, physicians may consider antacids as a second-line therapy.14 Antacids containing aluminum, calcium, and magnesium are considered an acceptable treatment in normal doses, but those containing sodium bicarbonate or magnesium trisilicate are not.16,17 Additional pharmacologic therapy is needed if prior interventions are not effective at managing symptoms on a case-by-case basis. There is a paucity of human study data for GI medications during pregnancy, but some medications have been classified by the Food and Drug Administration (FDA) to be acceptable or lower risk.9,16 The FDA currently does not have a classification for antacids during pregnancy. While antacid use may be beneficial at treating GERD symptoms for 30-50% of pregnant patients, for the rest it may not be sufficient.17 After approaching symptom management with lifestyle change and antacids, clinicians can use histamine-2 receptor blockers, which are classified by the FDA as Category B and have been shown in studies to be safe during pregnancy.17 If unsuccessful, the next approach involves proton pump inhibitors; while classified as Category C, studies have largely indicated their safety during pregnancy even though there is a lack of research around their efficacy at treating symptoms in pregnant patients.17 

Constipation  

Constipation during pregnancy is one of the more common GI symptoms with a global prevalence of 32.4% per recent meta-analysis data.18  Contributing factors in the complex etiology may include decreasing motility and smooth muscle contractility from progesterone production, increased intra-abdominal pressure from an expanding uterus, decreased physical activity level, iron supplementation, and changes to diet such as including more fat- and protein-rich foods to meet nutritional needs during pregnancy.18,19 

Treatment for constipation during pregnancy differs based on the severity of symptoms; mild cases may be improved with lifestyle modifications involving increased dietary fiber intake and adequate hydration.9,18 Clinicians can discuss safe bulking agents such as psyllium fiber or methylcellulose.8 Additionally, education and counseling on how to consume fiber in the diet can be achieved with a referral to an RD. After addressing nutrition and lifestyle changes, further medical management to include osmotic laxatives or stimulants should be started only under the discretion of a physician and for more severe cases.8,18,19 For those suffering with co-occurring GI ailments during pregnancy, osmotic laxatives can worsen bloating, cramps, flatulence, and nausea and therefore may not be a welcomed method of constipation treatment.19  

Hemorrhoids are a common complication of constipation and are prevalent in up to 80% or more of pregnancies.5,8 The etiology can be attributed to the third trimester compression of the rectum from the expanding uterus, prolonged straining during constipation, and inadequate fiber intake to regulate bowel movements.5,8,19The first-line treatment for hemorrhoid prevention include:5

• Increased fiber
• Increased fluid intake
• Improved toileting regimen to limit the amount of time and straining during defecation

Poskus et al. conducted a clinical trial researching the inclusion of dietary strategies for prevention of hemorrhoids in 260 randomized pregnant patients across three medical centers.20The intervention group received education on drinking adequate fluid, increased fiber intake from bran, fruits, vegetables, and nuts, exercising 3-5 times per week for at least 30-60 minutes, spending less than three minutes on the toilet, not ignoring any urgency to use the bathroom, attempting a bowel movement 30-40 minutes after eating, and washing after bowel movements.20 This group showed a significantly reduced occurrence of hemorrhoids by about 50% after receiving the education.20 

Diarrhea

Diarrhea and fecal incontinence are much less common GI symptoms that can occur during pregnancy compared to nausea, vomiting, reflux, and constipation.21 Acute infection is the most common cause for diarrhea during pregnancy so it is important to rule out viral, bacterial, or parasitic infectious etiologies first.21 If acute infection is not present, the noninfectious causes or factors leading to diarrhea during pregnancy may include hormonal changes, changes to diet, increased intra-abdominal pressure, and side effects of prenatal vitamins.21 Clinicians should also consider preexisting conditions such as pelvic floor dysfunction, inflammatory bowel disease (IBD), IBS, lactose intolerance, overflow diarrhea from constipation, a history of anorectal surgeries, or ileal pouch anal anastomosis (IPAA).21  Pregnant individuals with fecal incontinence may benefit from certain lifestyle modifications, which can include pelvic floor muscle training (PFMT) with or without biofeedback therapy.21 A referral to a specialized physical therapist for a PFMT assessment may be useful.21

 The first-line intervention for diarrhea includes a slow introduction and increase in dietary intake of soluble fiber (e.g., banana, oatmeal, potato) or use of psyllium fiber supplementation.21 Important nutrition interventions include consuming smaller and more frequent meals and adequate hydration with electrolytes via oral rehydration solutions (ORS) if diarrhea is frequent and signs and symptoms of dehydration are detected. Intravenous electrolytes and hydration may be necessary for prolonged diarrhea if metabolic abnormalities are present. Excluding whole food groups or overly restrictive diets are not indicated during pregnancy as this may lead to inadequate gestational weight gain or nutritional deficiencies. A consultation with an RD can help ensure patients are consuming adequate nutrition by finding alternatives for any nutrients that are being excluded. 

Pharmacologic intervention for diarrhea during pregnancy should only be used in the most persistent and severe cases, and loperamide is the antidiarrheal most preferred.9,21 It is important to know that diphenoxylate with atropine and bismuth preparations (Pepto-Bismol® and Kaopectate®) are contraindicated during pregnancy due to adverse fetal effects and that probiotics and empiric antibiotics are not routinely used in this population.9,21 

Special Considerations
for Gastrointestinal Disorders

Pregnant individuals with chronic GI disorders may benefit from intervention by their healthcare team during preconception or early pregnancy. The nutrition interventions discussed above for nausea, vomiting, reflux, constipation, and diarrhea would be appropriate for those who have these symptoms superimposed upon their chronic disease, but it warrants a discussion with their healthcare provider and case-by-case evaluation. Below are special considerations during pregnancy for chronic GI disorders (See Table 3).

GI Disorder  Considerations During Pregnancy 
Inflammatory Bowel DiseasePregnancy in active IBD can include increased risks of miscarriage, premature delivery, inadequate gestational weight gain, complications during labor and delivery, and SGA infants.22,23  The AGA recommends remission for 3-6 months prior to conception to reduce flare risk during pregnancy.22  PEN and EEN are safe nutritional interventions during pregnancy. 29,30 Working with an IBD-focused RD can help manage adequate intake and weight gain goals. 
GastroparesisPreconception planning is prudent as GP during pregnancy can lead to nutritional consequences and deficiencies for the patient and fetus.31  Small particle size, low-fat, and low insoluble fiber diets.32  RD consultation to recommend more easily tolerated foods, supplements, and oral nutrition shakes to ensure adequate nutrition. 
Metabolic Dysfunction-Associated Steatotic Liver DiseasePregnancy outcomes with MASLD include higher rates of GDM, gestational hypertension, hypertensive complications, Caesarean sections, preterm births, and postpartum hemorrhage compared to other chronic liver diseases or no liver disease.33  Weight loss is not recommended during pregnancy, but patients can adhere to ACOG/IOM gestational weight gain goals.  Reduction of sugar-sweetened beverages, added sugars, and ultra-processed foods.34
Irritable Bowel Syndrome IBS is a common DGBI that may worsen during pregnancy, theoretically, due to increased hormone production or stress.36  An RD during preconception is beneficial to assess diet quality and liberalization prior to becoming pregnant if currently on a restricted diet. Initiating restrictive diets, such as the high-FODMAP elimination phase if appropriate, should be done under the close guidance of an RD and if no response, then discontinued.36
Table 3. Considerations for Gastrointestinal Disorders During Pregnancy 

Inflammatory Bowel Disease

Risks associated with pregnancy in active IBD include miscarriage, increased risk of premature delivery, inadequate gestational weight gain, complications during labor/delivery, and SGA infants.22,23 Adequacy of nutrition can play a vital role in reducing complications from inadequate gestational weight gain or decreased intake that may occur with active disease, GI complications, or surgical changes in GI anatomy from IBD.22 In one recent cohort study, the risk of inadequate gestational weight gain was higher among those with Crohn’s disease (34.3%) and ulcerative colitis (26.7%) compared to those without IBD (19.4%).24 Twenty percent of participants with IBD in a second cohort study experienced inadequate weight gain and had increased risk for preterm birth, intrauterine growth restriction (IUGR) and SGA.25Poor nutrition in early pregnancy can further affect fetal development from insufficient vitamin and mineral intake, and those with active IBD flaring are at a higher risk of food intolerance and inadequate intake. 

Guidelines from the 2019 AGA IBD Parenthood Project Workgroup recommend women with IBD to be in remission for 3-6 months prior to conception to reduce the risk of flare during pregnancy.22 IBD-trained RDs can help patients navigate dietary concerns, ensure quality nutrition and micronutrient intake, and monitor for appropriate gestational weight gain if flares occur during pregnancy. Many organizations’ recent clinical guidelines and practice updates have recognized the importance of having specialized RDs as part of an IBD interdisciplinary team.26-28 A thorough nutrition assessment can determine whether certain interventions, such as steroid-sparing exclusive enteral nutrition (EEN) or other nutrition therapies, would be beneficial and safe during pregnancy. A recent case report of a 35-year-old woman eight weeks pregnant with moderately severe ileal Crohn’s disease showed clinical remission and weight gain after 6 weeks of the Crohn’s Disease Exclusion Diet (CDED) and partial enteral nutrition (PEN).29 The patient gained appropriate gestational weight (10.3 kg), delivered at 40 weeks, and sustained remission up to 12 weeks postpartum.29 A retrospective observational study of fifteen women with active CD showed that peptide-based EEN was effective at inducing remission in 85.7% of participants without any changes in pregnancy outcomes compared to a non-EEN group.30 The women in the study were pregnant or preparing for pregnancy and had experienced a relapse or complication for which they were refractory to or contraindicated for other treatment modalities.30 In addition to PEN or EEN, specialized therapeutic diets for IBD may also be beneficial for patients as long as they are robust enough to provide adequate micronutrients; monitoring and evaluation by an RD can determine on a case-by-case basis whether a specialized diet is too restrictive for a pregnant individual based on their recall of usual intake. A list of IBD-specific nutrition resources in Table 4 may be beneficial for helping patients expand their diets healthfully during pregnancy.

IBD-Specific ResourcesOrganization
Gut-Friendly RecipesCrohn’s & Colitis Foundation:
gutfriendlyrecipes.org
2020 Consensus Guidelines
for Nutrition		International Organization for the Study of Inflammatory Bowel Disease:
ioibd.org
MyIBDLife Parenthood ProjectAmerican Gastroenterological Association:
myibdlife.gastro.org
Evidence-Based Nutrition TherapiesNutrition Therapy for Inflammatory Bowel Disease:
nutritionaltherapyforIBD.org
Table 4. Resources for Inflammatory Bowel Disease 

Gastroparesis

GP is a chronic disorder of delayed gastric emptying that presents nutritional consequences for the patient and fetus during pregnancy. It is prudent to conduct preconception multidisciplinary planning – including diet education – for those with pre-existing disease who wish to become pregnant.31 There is a lack of data on the efficacy and safety of medications used to treat GP in the pregnant population.31 The 2022 guidelines on gastroparesis from the American College of Gastroenterology (ACG) provide nutrition interventions that include small particle size, low-fat, and low insoluble fiber diets.32 These are appropriate interventions during pregnancy so long as they are not overly restrictive and remain varied enough to provide adequate nutrition for appropriate gestational weight gain. 

Nausea, vomiting, and pain associated with GP may often lead to decreased intake.31 A referral to an RD can help to manage suboptimal intake, oral food intolerances, micronutrient deficiency that may result, and recommendations for whether nutrition support therapies are needed. An RD can provide education on the importance of smaller meals in higher frequency, texture modification for better tolerance, and the use of oral nutrition supplements; an RD can evaluate a patient’s diet pattern and quality to ensure adequacy and recommend the best-absorbed supplements (such as liquids or chewable tablets) that will be better tolerated. 

Metabolic Dysfunction-Associated
Steatotic Liver Disease 

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD or MASH) would benefit from preconception interdisciplinary intervention for management of this chronic disease. Over the last decade, there has been an increase in the incidence of fatty liver diseases among the U.S. population under 40 years old.33 One study looking at 18 million U.S. pregnancies between 2012-2016 identified over 5600 pregnancies with MASLD (previously known as NAFLD) and found significantly more cases of gestational diabetes mellitus (GDM), gestational hypertension, hypertensive complications, Caesarean sections, preterm births, and postpartum hemorrhage compared to other chronic liver diseases or no liver diseases.33 

Weight loss is not recommended during pregnancy but adherence to the ACOG/IOM gestational weight gain is an appropriate intervention. Nutritional interventions include the reduction of sugar-sweetened beverages, added sugars, and ultra-processed foods as these are associated with worsened MASLD status.34 The addition of a Mediterranean-style dietary pattern (which is high in dietary fiber and monounsaturated fatty acids), and reduction of red meat have also been related to a reduced incidence of MASLD.34

Irritable Bowel Syndrome 

IBS is classified as a disorder of gut-brain interaction (DGBI) and characterized by recurrent abdominal pain and altered bowel habits.35 The subgroups of this DGBI are based on bowel status and include IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and IBS with mixed or alternative bowel habits (IBS-M).35 While there is a lack of extensive study on the effect of pregnancy on IBS, a theoretical association to explain how IBS symptoms may worsen during pregnancy is the change in hormones.36 Increased estrogen during pregnancy can affect gut-brain axis regulatory mechanisms, visceral hypersensitivities, and gut motility.36 Luteal hormone production, which is highest in the first trimester, can affect the migrating motor complex and increase risk of both constipation and small intestinal bacterial overgrowth.36 Increased stress could also play a role in IBS status during pregnancy.36 Regarding pregnancy outcomes, having IBS during pregnancy was associated with increased risks of miscarriage and ectopic pregnancy compared to individuals without IBS, although this information is based on a retrospective trial and more studies of this population are needed.36

A majority of patients with IBS report that their symptoms are food-related, and dietary modification for the exclusion of offending foods (such as gas-producing foods, high lactose content, or foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols known as FODMAPs) remains as first-line treatment for the general IBS population.36,37 In a survey of over 1500 gastroenterologists in the U.S., 60% reported that their patients associate their symptoms with food and were inclined to restrict foods on their own, using dietary modifications that included reducing lactose (33%), eliminating gluten (24%), lowering fat content (6%), or trying low FODMAP diet (2%).37 Half of patients used ‘trial and error’ to determine which foods were problematic.37 Over half of the gastroenterologists reported that they use dietary modification as a first-line treatment strategy to 75% of their patients.37 The most common dietary therapy recommended to patients was a low FODMAP diet (77% of respondents), with high-fiber and lactose-reduced as the next most common (both at 45%).37

The dietary modifications and recommendations for the general IBS population should involve careful consideration during pregnancy to ensure adequacy of nutrient intake.36 Prior to conception, patients with IBS would benefit from consulting with an RD to evaluate baseline adequacy of their diet and to trial diet liberalization. Ongoing follow-ups during pregnancy is recommended if worsening IBS symptoms develop or affect oral intake. Restrictive diets, such as the high-FODMAP elimination phase, should only be started under the close supervision of a registered dietitian.36 If no improvement is observed, the diet should be discontinued. Patients who are on restricted diets for IBS management and become pregnant should also be closely observed for appropriate gestational weight gain and micronutrient adequacy.36 

Conclusion

Clinicians can implement nutritional interventions as useful first-line therapies during pregnancy for many common GI symptoms. Involving an RD during early pregnancy can help those who are experiencing weight loss and inadequate intake from common ailments like nausea, vomiting, reflux, diarrhea, and constipation. Nutrition education during the preconception stages is a beneficial option for those with chronic GI disorders such as IBD, GP, MASLD, and IBS. Patients who are not meeting their gestational weight gain milestones will benefit from frequent RD follow-ups throughout gestation, particularly during the second and third trimesters. There remain gaps in knowledge with a myriad of research opportunities within the pregnant population, especially regarding disease etiology, pharmacologic management, and the role of nutrition in GI disease management. 

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24. Bengtson MB, Aamodt G, Mahadevan U, Vatn MG.
Inadequate Gestational Weight Gain, the Hidden
Link Between Maternal IBD and Adverse Pregnancy
Outcomes: Results from the Norwegian Mother and
Child Cohort Study. Inflamm Bowel Dis. 2017 Jul;
23(7): 1225-1233.
25. Bengston MB, Martin CF, Aamodt G, Morten HV,
Mahadevan U. Inadequate Gestational Weight Gain
Predicts Adverse Pregnancy Outcomes in Mothers
with Inflammatory Bowel Disease: Results from a
Prospective US Pregnancy Cohort. Dig Dis and Sci.
2017; Mar. 62:2063-2069.
26. Hashash JG, Elkin J, Lewis JD, Binion DG. AGA
Clinical Practice Update on Diet and Nutritional
Therapies in Patients with Inflammatory Bowel
Disease: Expert Review. Gastroenterology. 2024 Mar;
166(3): p521-532.
27. Bischoff SC, Bager P, Escher J, Bender DV, Wierdsma
N, Weimann A et al. ESPEN guideline on Clinical
Nutrition in inflammatory bowel disease. Clin Nutr.
2023, Mar; 42(3):352-379.
28. Lamb, CA et al. British Society of Gastroenterology
consensus guidelines on the management of inflammatory
bowel disease in adults. Gut. 2019, Dec; 68(Suppl
3): s1-s106.
29. Ukovic B, Chapman B, Schulberg J, De Cruz P, Choy
MC. Novel Use of the Crohn’s Disease Exclusion Diet
Plus Partial Enteral Nutrition for the Treatment of
Crohn’s Disease During Pregnancy. ACG Case Rep J.
2023; 10: e01078.
30. Yang Q, Tang J, Ding N, Chao K, Li M, Huang Z, Guo
H, Chen J, Zhi M, Hu P, Gao X. Twelve-week peptidebased
formula therapy may be effective in inducing
remission of active Crohn disease among women who
are pregnant or preparing for pregnancy. Nutr Clin
Pract. 2022, Apr; 37(2): 366-376.
31. Moosravi S, Won YM, Wong M, Rezaie A.
Gastroparesis in pregnancy. Am J Obstet Gynecol.
2023, Apr; 228(4):382-394.
32. Camilleri M, Kuo B, Nguyen L, Vaughn VM, Petrey
J, Greer K, Yadlapati R, Abell TL. ACG Clinical
Guideline: Gastroparesis. Am J Gastroenterol. 2022,
Aug; 117(8):1197-1220.
33. Sarkar M, Grab J, Dodgr JL, Gunderson EP, Rubin J,
Irani RA, Cedars M, Terrault N. Non-alcoholic fatty
liver disease in pregnancy is associated with adverse
maternal and perinatal outcomes. J Hepatol. 2020
Sept;73(3):516-522.
34. European Association for the Study of the Liver
(EASL), European Association for the Study of
Diabetes (EASD), and European Association for
the Study of Obesity (EASO). EASL-EASD-EASO
Clinical Practice Guidelines on the management of
metabolic dysfunction-associated steatotic liver disease
(MASLD). J Hepatol. 2024, Sep; 81(3):492-542.
35. Lacy, BE, Pimentel M, Brenner DM, Chey WD,
Keefer LA, Long MD, Moshiree B. ACG Clinical
Guideline: Management of Irritable Bowel Syndrome.
Am J Gastroenterol. 2021; 116(1):17-44.
36. Moosavi S, Pimentel M, Wong M, Rezaie A. Irritable
Bowel Syndrome in Pregnancy. Am J Gastroenterol.
2021; 116:480-490.
37. Lenhart A, Ferch C, Shaw M, Chey WD. Use of
Dietary Management in Irritable Bowel Syndrome:
Results of a Survey of Over 1500 United States
Gastroenterologists. Journal of Neurogastroenterol
Motil. 2018; 24(3): 437-451.

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A CASE REPORT

Granulomatosis with Polyangiitis Presenting as Crohn’s Disease

March 2025 • Volume XLIX, Issue 3

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by Eliseo Garcia, Kurt B. Schaberg, Angel A. Herrera Guerra, Arthur J. de Lorimier

Granulomatosis with Polyangiitis (GPA) is a systemic necrotizing vasculitis associated with antineutrophil cytoplasmic antibody (ANCA) that often presents with multiorgan involvement, frequently affecting the upper and lower respiratory tracts and kidneys.1 While bowel involvement can occur, this is rare. Here, we describe a case of GPA with bowel involvement where the endoscopic appearance was like the “skip” lesions one may see in Crohn’s disease (CD) with biopsies confirming the former diagnosis.

Case Presentation

An 11-year-old male presented to the emergency department with anorexia, a 5.48 kg weight loss over the past 5 months, persistent weakness, mouth ulcers, cough, persistent right acute otitis media (AOM), and bilateral testicular pain. His medical history included allergic rhinitis, recurrent AOM, malnutrition, and right epididymitis. Over the past two months, he exhibited a normal bowel pattern, but experienced increasing fatigue and weakness, decreased oral intake, and intermittent abdominal pain.

His physical exam revealed a cachectic adolescent with unexpected weight loss who weighed 21.82 kg (0.01 percentile); physical exam also demonstrated a purulent effusion in the right ear and a serous effusion in the left ear. Laboratory results exhibited normocytic anemia (Hgb 9.6 g/dL, MCV 85.1 fl), elevated inflammatory markers (WBC 17.7 K/mm3, ESR 62 mm/hr, CRP 10.6 mg/dL, calprotectin 1690 ug/g), elevated eosinophils (0.8 K/mm3), and a positive c-ANCA pattern with a high ANCA IFA titer (>1:1280). Nasal endoscopy revealed significant scarring and stenosis of the bilateral nasal cavities with minimal nasal patency. CT of the head and sinus revealed pansinusitis sequelae, while chest X-rays and CT demonstrated perihilar opacities and bilateral perihilar infiltrates/masses with necrotic foci, respectively. On upper endoscopy, two large esophageal ulcers were visualized adjacent to one another with biopsies showing normal surrounding mucosa. Colonoscopy revealed aphthous lesions reminiscent of “skip” lesions in the ascending and transverse colon (Figure 1). Colon biopsies demonstrated submucosal vasculitis with associated poorly formed granulomas that lacked cryptitis (ie. inflammation that did not span the entire mucosal width) (Figure 2). There were also areas of fibrinopurulent exudate consistent with ulceration throughout the gastrointestinal tract and ischemic changes in the duodenum. 

Based on these findings, the patient was diagnosed with granulomatosis with polyangiitis and treated with a methylprednisolone pulse (22 mg/kg on day one followed by 17.5 mg/kg after two days), three doses of rituximab (375 mg/m2 at approximately one-week intervals), and an oral prednisolone taper (20 mg BID for seven days, weaned down to 25 mg once daily). 

In subsequent follow up over a 6-month period, the patient demonstrated signs of clinical improvement, with resolution of anemia, normal inflammatory markers (i.e. ESR, CRP, and calprotectin), and a weight gain of 12.8 kg (22nd percentile); the patient continues to receive appropriate follow up care.

Discussion

This case explores a unique situation where GPA, previously Wegener’s granulomatosis, manifested similarly to CD. CD is a chronic inflammatory bowel disease characterized by full-thickness inflammation of the bowel that impairs the lining of the digestive tract and can lead to abdominal pain, diarrhea, fatigue, weight loss, and malnutrition.2 Of importance, CD may also present with various extraintestinal manifestations, including respiratory tract involvement, although this is uncommon.3

In our patient’s case, the presentation was primarily gastrointestinal, characterized by symptoms such as decreased oral intake, early satiety, intermittent abdominal pain, and weight loss, which are more commonly associated with CD.2 Histologically, the colon biopsies most prominently showed submucosal changes, including vasculitis and granulomas with what appeared to be secondary mucosal changes like ischemia and erosion (Figure 2). This contrasts with the transmural mucosal acute and chronic inflammation characteristic of inflammatory bowel disease. Additionally, laboratory results revealed normocytic anemia, elevated inflammatory markers, elevated eosinophils, and a positive c-ANCA pattern with a high ANCA IFA titer, indicative of GPA.1

While there have been reports of GPA with gastrointestinal symptoms similar to CD,3,4 the occurrence of such symptoms is relatively low, being described in about 10-24% of GPA patients.4 When juxtaposed with previous studies, our patient’s presentation is distinct because our case involves a pediatric patient with both systemic and significant gastrointestinal symptoms,3,4 which is highly atypical in a pediatric population, with an occurrence of GPA in this population being 1:1,000,000.5 Furthermore, the presence of CD or GPA manifesting as a mimic of the other condition has generally only been reported in adults (two previously published case reports with patients aged 29 and 41),6,7 potentially making this case, to the best of our knowledge, the second instance of a pediatric patient who’s diagnosed GPA presents as CD without also having a concurrent diagnosis of CD.8

Conclusion

In conclusion, this case underscores the importance of considering GPA in the differential diagnosis when a patient presents with gastrointestinal symptoms akin to CD, especially when accompanied by systemic symptoms, respiratory symptoms, and a positive c-ANCA pattern.3,4 Further research is warranted to understand the relationship between GPA and CD and to enhance the diagnosis and treatment of these conditions. 

References

1. Csernok E, Gross WL. Current understanding of the pathogenesis of
granulomatosis with polyangiitis (Wegener’s). Expert Rev Clin Immunol.
2013;9(7):641-648. doi:10.1586/1744666X.2013.811052
2. Dolinger M, Torres J, Vermeire S. Crohn’s disease. Lancet. Published
online March 1, 2024:S0140-6736(23)02586-2. doi:10.1016/S0140-
6736(23)02586-2
3. Vaszar LT, Orzechowski NM, Specks U, et al. Coexistent pulmonary granulomatosis
with polyangiitis (Wegener granulomatosis) and Crohn disease. Am
J Surg Pathol. 2014;38(3):354-359. doi:10.1097/PAS.0000000000000135
4. Jóźwiak L, Ławnicka I, Książek A. Coexistence of granulomatosis with polyangiitis
(GPA) and Crohn’s disease or multiorgan manifestation of the same
disease? Reumatologia. 2016;54(2):86-90. doi:10.5114/reum.2016.60219
5. Bohm M, Gonzalez Fernandez MI, Ozen S, et al. Clinical features of childhood
granulomatosis with polyangiitis (wegener’s granulomatosis). Pediatr
Rheumatol Online J. 2014;12:18. doi:10.1186/1546-0096-12-18
6. Sinnott JD, Matthews P, Fletcher S. Colitis: an unusual presentation of
Wegener’s granulomatosis. BMJ Case Rep. 2013;2013:bcr2012007566.
doi:10.1136/bcr-2012-007566
7. Schneider A, Menzel J, Gaubitz M, Keller R, Lügering N, Domschke W.
Colitis as the initital presentation of Wegener’s granulomatosis. Journal of
Internal Medicine. 1997;242(6):513-517. doi:10.1111/j.1365-2796.1997.
tb00025.x
8. Sokol RJ, Farrell MK, McAdams AJ. An unusual presentation of Wegener’s
granulomatosis mimicking inflammatory bowel disease. Gastroenterology.
1984;87(2):426-432. doi:10.1016/0016-5085(84)90724-8

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Dispatches from the GUILD Conference, Series #66

Diagnosis and Managementof Gastroparesis

March 2025 • Volume XLIX, Issue 3
Michael Camilleri

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This review appraises the symptoms associated with gastroparesis and the optimal measurement to identify delayed gastric emptying. The diagnosis requires differentiation from functional dyspepsia, iatrogenic disease (e.g., opiates and GLP-1 agonists), and conditions associated with vomiting including rumination and cannabinoid hyperemesis. Management includes normalization of hydration and nutrition and relief of symptoms which typically requires pharmacological treatment predominantly with prokinetics and antiemetics. Metoclopramide is the only FDA-approved medication for treatment of gastroparesis, but there are restrictions for its use. Targeting the fundus and visceral sensation may also provide symptom relief. Treatment of abnormal pyloric contractility or poor distensibility may be targeted with intra-pyloric botulinum toxin injection or, increasingly in practice, gastric per-oral endoscopic myotomy. This is increasingly applied for patients not responding to dietary and pharmacological approaches. There is significant unmet need in the treatment of gastroparesis.

Introduction

The overall objectives are to review the definition, optimal measurement of gastric emptying (GE) of solids, and differential diagnosis and management of gastroparesis. It is important to distinguish between gastroparesis and functional dyspepsia which affects about 8% of people in the community in 26 countries,1 whereas definite gastroparesis (symptoms plus delayed gastric emptying) is reported in 13.8 to 267.7 per 100,000 adults.2,3 

Definition

Gastroparesis is identified in clinical practice through recognition of the clinical symptoms and documentation of delayed GE in the absence of gastric outlet obstruction. Symptoms resulting from gastroparesis include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain.4

Diagnosis

A sine qua non for diagnosis of gastroparesis is an accurate, reliable assessment of emptying of solid, digestible food, appraisal for at least 3 and preferably 4 hours, robust normative data, and reproducibility. This excludes radiopaque markers and wireless motility capsule (not digestible), water or nutrient liquids as food substrates. Three available tests (2 scintigraphic and 1 stable isotope) are approved: 

a. The egg-substitute 250kcal with 2% fat Eggbeaters® meal is the most widely used; the cut-off for delayed GE is >60% retention at 2 hours, and >10% retained at 4h,5 based on 95th percentile of a study of 123 healthy volunteers.6 This meal has an emptying profile almost identical to that of the liquid nutrient meal, Ensure.®7 Moreover, the reproducibility on replicate testing 48 weeks apart was ~40%.8

b. The Mayo two scrambled real egg meal (320kcal, 30% fat) has reproducibility rate of >80%,9 with 95%ile of GE T1/2 >174min; GE at 2h <25% emptied; GE at 4h <75% emptied, based on 319 healthy controls.10

c. The 13C-spirulina stable isotope breath test using reconstituted real egg 238kcal, 42% fat meal, was validated with simultaneous scintigraphy,11 and effects of pharmacological acceleration and delay of GE.12

Other tests infrequently used in the diagnosis of gastroparesis are antropyloroduodenal manometry (to diagnose antral hypomotility,13 pylorospasm,14 differentiate neuropathy from myopathy based on amplitude of contractions15), or EndoFLIP of the pylorus (to identify pyloric diameter and distensibility16,17). 

Gastrointestinal symptoms such as nausea or vomiting are significantly correlated with GE measured optimally (solid meal over >3h)18 based on a systematic review and meta-analysis.19  

Differential Diagnosis

The main considerations are functional dyspepsia (differentiation based on a reliable GE test), rumination syndrome (predominantly through classical effortless regurgitation within 20 minutes after every meal20,21), cyclic vomiting or cannabinoid hyperemesis syndrome (CHS) and iatrogenic disease (predominantly GLP-1 receptor agonists22,23, opiates24, tetrahydrocannabinol25, and cannabidiol26). CHS is associated with chronic (typically years) and heavy (typically daily or near-daily) cannabis use and predominance in males.27 

Management

Management of gastroparesis should include correction of nutritional state, relief of symptoms, improvement of GE and glycemic control in those with diabetes,28 and identifying and treating the underlying pathophysiology.

A. Hydration and nutrition

When patients with gastroparesis have significant fluid or metabolic derangements (e.g., ketoacidosis, renal insufficiency, hyperglycemia) due to nausea and vomiting or underlying metabolic diseases such as diabetes, restoration of hydration and electrolyte balance (especially K+, Ca++, Mg++) is essential through per-oral or intravenous routes.29  

Nutritional deficiencies are highly prevalent among patients with gastroparesis; up to 64% of patients with gastroparesis consume <60% of the estimated total kcal needs, and vitamin (A, B6, C, K) and mineral (iron, potassium, zinc) deficiencies are common.30

The first dietary modifications, that is, homogenizing solids to smaller particle size, reducing fat, and cooking of nondigestible fibers, reduced the severity of nausea, vomiting, postprandial fullness, bloating, and regurgitation/heartburn in patients with diabetic gastroparesis.31 If these are not tolerated, stepwise nutritional interventions include liquid meals, oral nutrition supplements, enteral nutrition, and parenteral nutrition.32 Enteral feeding should be directly into the jejunum, rather than via jejunal extension from gastrostomy tube; it is safe and leads to weight regain.33 Parenteral nutrition is used temporarily for severe nutritional deficiency, is rarely required long term in those with intolerance of jejunal feeding, and it may be associated with complications such as infections and thromboses.34  

B. Pharmacologic agents

Figure 1. shows a conceptual summary of pharmacological approaches to treat gastroparesis directed at vomiting center receptors and neurons in the enteric nervous system.

B. i. Prokinetics

The 2022 gastroparesis guideline35 recommended therapies that target GE and symptoms of idiopathic and diabetic gastroparesis, while weighing the benefits and risks of the agent. Prokinetic agents enhance GE and reduce symptoms. In a systematic review of randomized, blinded, parallel, or crossover trials with optimal GE tests, meta-regression showed a positive association between accelerated GE T1/2 by at least 20.4 minutes and upper gastrointestinal symptoms.19 This conclusion was independently confirmed.36  

B. ii. Dopaminergic modulation

Metoclopramide approved by FDA for gastroparesis in 1979, functions through antagonism of central and peripheral dopamine receptors. Central antiemetic effects are mediated by inhibition of dopamine D2 and 5-HT3 receptors in the area postrema (vomiting center), located outside the blood–brain barrier and a target of several antiemetics.37 Peripherally, metoclopramide exerts prokinetic effects through agonism on 5-HT4 receptors on cholinergic neurons and antagonism of D2 receptor.38 Metoclopramide crosses the blood-brain barrier and can cause anxiety, agitation, somnolence, and reversible extrapyramidal symptoms including tremors. In 1 in 1000-10,000 patients, irreversible tardive dyskinesia occurred.39,40 Because of risk of neurological adverse effects, metoclopramide is only approved for a maximum of 12 weeks and carries a black box warning. 

Routes of administration are oral (tablet or liquid preparation), nasal spray,41 and parenteral (e.g., i.v. or subcutaneous) formulations.42 As the only approved medication for gastroparesis, practitioners should prescribe lowest effective dose of liquid, nasal, or tablet formulation, 5-10 mg t.i.d. 15 minutes before meals for 12 weeks. If tolerated, there should be “drug holidays” between prescription cycles, with symptomatic remedies such as liquid or blenderized diet, antiemetic agents (e.g., ondansetron 4-8 mg b.i.d.), or short-term (to avoid tachyphylaxis) erythromycin, 40-200 mg t.i.d. as tolerated.43 

B. iii.
Other marketed agents used off-label in gastroparesis

Other marketed agents used off-label include domperidone, macrolides, and 5-HT4 receptor agonists such as cisapride and prucalopride.

B. iii. a. Domperidone 

Domperidone is a peripherally acting dopamine D2 receptor antagonist that is available through the FDA’s Program for Expanded Access to Investigational Drugs. The recommended dose of domperidone is 10-20 mg t.i.d. at bedtime. Its efficacy for the treatment of gastroparesis is comparable to metoclopramide.44 A systematic review of 28 trials showed symptomatic reduction (64%), decreased hospitalization (67%), and accelerated GE (60% of the studies).45 Domperidone does not cross the blood-brain barrier. Domperidone was associated with corrected QT interval (QTc) prolongation, and it should be avoided in patients with prolonged QTc (>470 ms in males, >450 ms in females).46

B. iii. b. Motilin agonists

Macrolides such as erythromycin, azithromycin, and clarithromycin are motilin receptor agonists with a prokinetic property. In a systematic review of 5 small-scaled, short-term studies, erythromycin accelerated gastric emptying and improved symptoms in 43% of patients with gastroparesis.47 Oral erythromycin is associated with tachyphylaxis within days to weeks due to down-regulation of the motilin receptor.48 Although erythromycin may prolong the QTc, a systematic review and network meta-analysis of 33 studies (22.6 million subjects) found no association with risk of arrhythmia or cardiovascular mortality.49

There are no randomized, placebo-controlled trials of azithromycin and clarithromycin to assess efficacy of symptoms in patients with gastroparesis.

B. iii. c. 5-HT4 agonists used off-label

Prucalopride is highly selective for 5-HT4 receptors. Two available randomized, placebo-controlled, cross-over trials of prucalopride in gastroparesis50,51 showed greater benefit in patients with idiopathic gastroparesis than in gastroparesis secondary to underlying diseases (diabetes or connective tissue diseases).

Cisapride accelerated GE and improved symptoms in placebo-controlled trials conducted in short-term or medium-term trials (e.g., 6- or 8-week duration) in gastroparesis.35 Cisapride is a potent inhibitor of the human ether-à-go-go-related gene (hERG) potassium channel and with reports, extremely rarely, of cardiac arrhythmias. It is also only available for compassionate use in selected cases in the USA. 

B. III. d. Cholinesterase inhibitors used off-label for gastroparesis

Neostigmine is a short-acting (15-30min) parenteral acetylcholinesterase (ACE) inhibitor that induces fasting gastroduodenal motor activity,52 accelerates GE of liquids in critically ill patients with delayed GE,53 and should only be used in hospital, as it induces vagotonia and bradycardia; EKG monitoring and atropine 0.6-1.2mg should be available while neostigmine is administered. 

Pyridostigmine has longer duration of action (4h), is available as liquid or tablet, and is prescribed at a dose of 60mg t.i.d. In an open-label series in children with gastrointestinal dysmotilities, pyridostigmine was beneficial in relief of symptoms.54  

B. III. e. Ghrelin receptor agonist

Ghrelin is a 28-amino acid orexigenic hormone found primarily in the stomach. A pharmacological dose of ghrelin increased proximal gastric tone through central and peripheral effects.55 Relamorelin, a pentapeptide ghrelin receptor agonist, increased the frequency of distal antral contractions without inhibiting gastric accommodation or inducing satiation.56 

Relamorelin had proven clinical efficacy and safety in phase 2A and 2B, randomized, controlled trials in patients with diabetic gastroparesis but not in subsequent phase III trials.57

C. Antiemetics

C. i. 5-HT3 antagonists

Ondansetron targets stomach distention, alleviating nausea without affecting gastric compliance, volume, or accommodation.58 Ondansetron is available as oral tablet, oral dissolution, and intravenous formulations, and is dosed at 4-8mg every 8 hours as needed. Ondansetron can cause QTc prolongation and rarely cardiac arrhythmia. Baseline EKG is recommended. Granisetron is also available orally and i.v., and the sustained release transdermal patch of granisetron significantly improved nausea and vomiting in an open-label study of 51 patients with gastroparesis.59 Tropisetron, effective for cancer or chemotherapy-induced nausea and vomiting, has potential in gastroparesis based on a dog study.60

Constipation is a known adverse effect of this class of medications.

C. ii. Agents targeting multiple receptors

Prochlorperazine is primarily a D2 receptor antagonist, with ability to block histaminergic, cholinergic, and noradrenergic receptors. Promethazine primarily acts as an antagonist for histamine receptors (H1), with additional antagonism at dopamine, adrenergic, N-methyl-D-aspartate, and muscarinic cholinergic receptors. 

Scopolamine competes for binding at muscarinic (M1) receptors, inhibiting cholinergic nerve stimulation. 

All these antiemetics are available in orally disintegrating tablets, dermal, or rectal formulations for patients with gastroparesis. Cholinergic side effects like sedation, dry mouth, and constipation are frequent. Promethazine may be habit forming and is reserved as a “rescue” agent.

Mirtazapine acts on several receptors: presynaptic α2 adrenergic receptors, several 5-HT receptor subtypes, and H1 receptor. Agonist effects on central and peripheral 5-HT1A receptors influence gastric receptive fundic relaxation. In a 4-week trial in gastroparesis, mirtazapine improved nausea, vomiting, retching, loss of appetite, and patient grading assessment compared with pretreatment.61

C. iii. Neurokinin-1 antagonists

Aprepitant (approved for chemotherapy-induced emesis) affects the vomiting center in the brainstem and enhances gastric accommodation without slowing GE.62 In a randomized, double-blind, placebo-controlled trial of 126 patients with chronic nausea and vomiting of presumed gastric origin, aprepitant, 125mg daily, significantly reduced severity of nausea, vomiting, and overall symptoms.63  

Tradipitant is an investigational agent which was demonstrated to decrease nausea score, increase nausea-free days, and improve the GCSI score in patients with gastroparesis compared to placebo.64 Benefit was documented when controlling for drug exposure, rescue medications, and baseline severity inflation.65  

C. iv. Cannabinoid agents

The primary ingredient in marijuana is tetrahydrocannabinol (THC), a nonselective cannabinoid receptor agonist. Although THC delays gastric emptying of solids,66 a database of 506 patients with gastroparesis, showed 12% used medical or recreational marijuana for symptomatic relief.67  

Cannabidiol (CBD), a low-THC extract from Cannabis sativa approved for seizure disorders, blocks CBR1 and CBR2 receptors. CBD twice daily (Epidiolex® escalated to 20mg/kg/d) in 44 patients68 was efficacious in gastroparesis, with reduction in total GCSI score, ability to finish a normal-sized meal, vomiting, and overall symptom severity, despite slower GE of solids. CBD’s effectiveness was attributed to anxiolytic and visceral analgesic properties.69  

D. Neuromodulators for pain relief

Patients frequently experience abdominal pain with gastroparesis; however, those primarily presenting with abdominal pain should be evaluated for alternative diagnoses. In a randomized trial involving 130 patients diagnosed with idiopathic gastroparesis, nortriptyline did not demonstrate superiority over placebo in alleviating symptoms, as measured by the GCSI score.70 

E. Targeting the fundus 

About  20%  of   284 patients with proven  gastroparesis have increased gastric accommodation.71 Erythromycin (motilin and cholinergic receptor agonism) stimulates both fundic contraction and antral motor function and accelerates GE.72,73 Erythromycin was tested in an open-labeled study: at 4 weeks, there was acceleration of GE and reduced symptoms, but efficacy was lost over time,74 reflecting tachyphylaxis.48

For dyspeptic symptoms with both reduced GE and reduced accommodation,75 buspirone, a 5-HT1A agonist with anxiolytic properties, improved aggregate symptoms and nausea in response to a nutrient challenge meal in healthy controls.76 On the other hand, patients with moderate-to-severe early satiety or postprandial fullness and other symptoms of gastroparesis did not benefit from treatment with buspirone.77   

Although mirtazapine has 5-HT1A effects, the improvements in nausea, vomiting, retching, and loss of appetite61 appear unrelated to alteration in gastric accommodation.78  

F. Targeting the pylorus

In a subset of patients with gastroparesis, pyloric dysfunction, characterized by abnormally prolonged and intense tonic contractions of the pylorus, was noted.14 After excluding iatrogenic dysfunction (e.g. opiates),24 open-label studies showed intrapyloric injection of botulinum toxin had short-term (<6 months) efficacy in accelerating GE and improving symptoms.79 However, two randomized, placebo-controlled trials did not confirm efficacy in achieving symptom improvement.80,81 Measurements of pyloric diameter and distensibility index may predict response to therapy, particularly post–G-POEM (discussed below)82 or after botulinum toxin injection for relief of vomiting.83  

G. Electrical approaches 

Gastric electric stimulation (GES) may be considered for control of gastroparesis symptoms as a humanitarian use device. Randomized, crossover trials of gastric electric stimulation have shown mixed results, sometimes with improvement in symptoms but no differences in gastrointestinal quality of life, nutritional parameters, or GE, suggesting possible effects on visceral afferents rather than the motor function of stomach (trials reviewed elsewhere35).

H. Endoscopic or surgical approaches 

In patients with gastroparesis with symptoms refractory to medical therapy, pyloromyotomy (nowadays almost exclusively through G-POEM) is recommended over no treatment for symptom control,35 based predominantly on open-label studies. One sham-controlled study of 6 months’ duration documented relief of symptoms and improved GE with G-POEM procedure.84  

In 177 patients with gastroparesis, laparoscopic pyloroplasty improved GE in 90% of patients and induced short-term improvement of nausea, vomiting, bloating, and abdominal pain. However, morbidity rate was 6.8%, including leaks requiring further surgery.85

Conclusion

A careful appraisal of symptoms is necessary in suspected gastroparesis: “If patient has predominant pain, think again”. A solid GE test is essential. Normalization of hydration and nutrition, and relief of symptoms typically requires pharmacological treatment. G-POEM is increasingly applied for patients not responding to dietary and pharmacological approaches. 

References

1. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study. Gastroenterology 2021;160:99-114.

2. Dilmaghani S, Zheng T, Camilleri M. Epidemiology and healthcare utilization in patients with gastroparesis: a systematic review. Clin Gastroenterol Hepatol 2023;21:2239–2251.e2.

3. Ye Y, Yin Y, Huh SY, Almansa C, Bennett D, Camilleri M. Epidemiology, etiology, and treatment of gastroparesis: real-world evidence from a large US national claims database. Gastroenterology 2022;162:109-121.e5. 

4. Camilleri M, Parkman H, Shafi M, Abell T, Gerson L, American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18-37.

5. Maurer AH, Camilleri M, Donohoe K, et al. The SNMMI and EANM practice guideline for small-bowel and colon transit 1.0. J Nucl Med 2013;54:2004-2013. 

6. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol 2000;95:1456-1462.

7. Sachdeva P, Kantor S, Knight LC, Maurer AH, Fisher RS, Parkman HP. Use of a high caloric liquid meal as an alternative to a solid meal for gastric emptying scintigraphy. Dig Dis Sci 2013;58:2001-2006.

8. Pasricha PJ, Grover M, Yates KP, et al. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathologic features. Gastroenterology 2021;160:2006-2017.

9. Camilleri M, Zheng T, Vosoughi K, Lupianez-Merly C, Eckert D, Busciglio I, Burton D, Dilmaghani S. Optimal measurement of gastric emptying of solids in gastroparesis or functional dyspepsia: evidence to establish standard test. Gut 2023;72:2241-2249.

10. Camilleri M, Iturrino J, Bharucha AE, Burton D, Shin A, Jeong I-D, Zinsmeister AR. Performance characteristics of scintigraphic measurement of gastric emptying of solids in healthy participants. Neurogastroenterol Motil 2012;24:1076–e562.

11. Szarka LA, Camilleri M, Vella A, Burton D, Baxter K, Simonson J, Zinsmeister AR. A stable isotope breath test with a standard meal for abnormal gastric emptying of solids in the clinic and in research. Clin Gastroenterol Hepatol 2008;6:635-643.

12. Viramontes BE, Kim DY, Camilleri M, Lee JS, Stephens D, Burton DD, Thomforde GM, Klein PD, Zinsmeister AR. Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying. Neurogastroenterol Motil 2001;13:567-574.

13. Camilleri M, Malagelada J-R, Stanghellini V, Fealey RD, Sheps SG. Gastrointestinal motility disturbances in patients with orthostatic hypotension. Gastroenterology 1985;88:1852-1859.

14. Mearin F, Camilleri M, Malagelada J-R. Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology 1986;90:1919-1925.

15. Thumshirn M, Bruninga K, Camilleri M. Simplifying the evaluation of postprandial antral motor function in patients with suspected gastroparesis. Am J Gastroenterol 1997;92:1496-1500.

16. Malik Z, Sankineni A, Parkman HP. Assessing pyloric sphincter pathophysiology using EndoFLIP in patients with gastroparesis. Neurogastroenterol Motil 2015;27:524-531.

17.  Desprez C, Chambaz M, Melchior C, Basile P, Prevost G, Jacques J, Leroi AM, Gourcerol G. Assessment of pyloric sphincter distensibility and pressure in patients with diabetic gastroparesis. Neurogastroenterol Motil 2021;33:e14064.

18. Vijayvargiya P, Jameie-Oskooei S, Camilleri M, Chedid V, Erwin PJ, Murad MH. Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis. Gut 2019;68:804-813.

19. Vijayvargiya P, Camilleri M, Chedid V, Mandawat A, Erwin PJ, Murad MH. Effects of promotility agents on gastric emptying and symptoms: a systematic review and meta-analysis. Gastroenterology 2019;156:1650-1660.

20. O’Brien MD, Bruce BK, Camilleri M. The rumination syndrome: clinical features rather than manometric diagnosis. Gastroenterology 1995;108:1024-1029. 

21. Chial HJ, Camilleri M, Williams DE, Litzinger K, Perrault J. Rumination syndrome in children and adolescents: diagnosis, treatment, and prognosis. Pediatrics 2003;111:158-162.

22. Camilleri M, Lupianez-Merly C. Effects of GLP-1 and other gut hormone receptors on the gastrointestinal tract and implications in clinical practice. Am J Gastroenterol 2024;119:1028-1037. 

23. Camilleri M, Carlson P, Dilmaghani S. Prevalence and variations in gastric emptying delay in response to GLP-1 receptor agonist liraglutide. Obesity (Silver Spring). 2024;32:232-233. 

24. Camilleri M, Sanders KM. Opiates, the pylorus, and gastroparesis. Gastroenterology 2020;159:414-421.

25. McCallum RW, Soykan I, Sridhar KR, Ricci DA, Lange RC, Plankey MW. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther 1999;13:77-80. 

26. Jehangir A, Parkman HP. Cannabinoid use in patients with gastroparesis and related disorders: prevalence and benefit. Am J Gastroenterol 2019;114:945-953.  

27.  Rubio-Tapia A, McCallum R, Camilleri M. AGA clinical practice update on diagnosis and management of cannabinoid hyperemesis syndrome: commentary. Gastroenterology 2024;166:930-934.   

28. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L, American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18-37.

29. Camilleri M. Diabetic gastroparesis. New Engl J Med 2007;356:820-829.

30. Parkman HP, Yates KP, Hasler WL, Nguyen L, Pasricha PJ, Snape WJ, Farrugia G, Calles J, Koch KL, Abell TL, McCallum RW, Petito D, Rees Parrish C, Duffy F, Lee L, Unalp-Arida A, Tonascia J, Hamilton F, NIDDK Gastroparesis Clinical Research Consortium. Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. Gastroenterology 2011;141:486-498.e1-e7.

31. Olausson EA, Storsrud S, Grundin H, Isaksson M, Attvall S, Simren M. A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized controlled trial. Am J Gastroenterol 2014;109:375-385.

32. Limketkai BN, LeBrett W, Lin L, Shah ND. Nutritional approaches for gastroparesis. Lancet Gastroenterol Hepatol 2020;5:1017-1026.

33. Fontana RJ, Barnett JL. Jejunostomy tube placement in refractory diabetic gastroparesis: a retrospective review. Am J Gastroenterol 1996;91:2174-2178.

34. Bharadwaj S, Meka K, Tandon P, Rathur A, Rivas JM, Vallabh H, Jevenn A, Guirguis J, Sunesara I, Nischnick A, Ukleja A. Management of gastroparesis-associated malnutrition. J Dig Dis 2016;17:285-294.

35. Camilleri M, Kuo B, Nguyen L, Vaughn VM, Petrey J, Greer K, Yadlapati R, Abell TL. ACG Clinical Guideline: Gastroparesis. Am J Gastroenterol 2022;117:1197-1220.

36. Goelen N, Jones M, Huang IH, Carbone F, Janssen P, Tack J. Do prokinetic agents provide symptom relief through acceleration of gastric emptying? An update and revision of the existing evidence. United European Gastroenterol J 2023;11:146-162.

37. Sanger GJ. Translating 5-HT4 receptor pharmacology. Neurogastroenterol Motil 2009;21:1235-1238.

38. Tonini M, Cipollina L, Poluzzi E, et al. Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther 2004;19:379-390.

39. Rao AS, Camilleri M. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther 2010;31:11-19. 

40. Al-Saffar A, Lennernas H, Hellstrom PM. Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited. Neurogastroenterol Motil 2019;31:e13617.

41. Parkman HP, Carlson MR, Gonyer D. Metoclopramide nasal spray reduces symptoms of gastroparesis in women, but not men, with diabetes: results of a phase 2b randomized study. Clin Gastroenterol Hepatol 2015;13:1256-1263.e1251.

42. McCallum RW, Valenzuela G, Polepalle S, Spyker D. Subcutaneous metoclopramide in the treatment of symptomatic gastroparesis: clinical efficacy and pharmacokinetics. J Pharmacol Exp Ther 1991;258:136-142.

43. Camilleri M. Beyond metoclopramide for gastroparesis. Clin Gastroenterol Hepatol 2022;20:19-24.

44. Patterson D, Abell T, Rothstein R, Koch K, Barnett J. A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol 1999;94:1230-1234. 

45. Sugumar A, Singh A, Pasricha PJ. A systematic review of the efficacy of domperidone for the treatment of diabetic gastroparesis. Clin Gastroenterol Hepatol 2008;6:726-733.

46. Dumitrascu DL, Weinbeck M. Domperidone versus metoclopramide in the treatment of diabetic gastroparesis. Am J Gastroenterol 2000;95:316-317.

47. Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am J Gastroenterol 2003;98:259-263.

48. Thielemans L, Depoortere I, Perret J, Robberecht P, Liu Y, Thijs T, Carreras C, Burgeon E, Peeters TL. Desensitization of the human motilin receptor by motilides. J Pharmacol Exp Ther 2005;313:1397-1405.

49. Gorelik E, Masarwa R, Perlman A, Rotshild V, Muszkat M, Matok I. Systematic review, meta-analysis, and network meta-analysis of the cardiovascular safety of macrolides. Antimicrob Agents Chemother 2018;62:e00438-e00518.

50. Carbone F, Van den Houte K, Clevers E, Andrews CN, Papathanasopoulos A, Holvoet L, Van Oudenhove L, Caenepeel P, Arts J, Vanuytsel T, Tack J. Prucalopride in gastroparesis: a randomized placebo-controlled crossover study. Am J Gastroenterol 2019;114:1265-1274. 

51. Andrews CN, Woo M, Buresi M, Curley M, Gupta M, Tack J, Wilsack L, Nasser Y. Prucalopride in diabetic and connective tissue disease-related gastroparesis: Randomized placebo-controlled crossover pilot trial. Neurogastroenterol Motil 2021;33:e13958.

52. Bortolotti M, Cucchiara S, Sarti P, Brunelli F, Mazza M, Bagnato F, Barbara L. Comparison between the effects of neostigmine and ranitidine on interdigestive gastroduodenal motility of patients with gastroparesis. Digestion 1995;56:96-99.

53. Lucey MA, Patil V, Girling K, Jacques T, O’Leary M. Does neostigmine increase gastric emptying in the critically ill-results of a pilot study. Crit Care Resusc 2003;5:14-19.

54. Manini ML, Camilleri M, Grothe R, Di Lorenzo C. Application of pyridostigmine in pediatric gastrointestinal motility disorders: a case series. Pediatr Drugs 2017;20:173-180. 

55. Peeters TL. Central and peripheral mechanisms by which ghrelin regulates gut motility. J Physiol Pharmacol 2003;54(Suppl 4):95-103.  

56. Nelson AD, Camilleri M, Acosta A, Busciglio I, Linker Nord S, Boldingh A, Rhoten D, Ryks M, Burton D. Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers. Neurogastroenterol Motil 2016;28:1705-1713.

57. Camilleri M, Jencks KJ. Pharmacological treatments for gastroparesis. Pharmacological Reviews (2025, in press).

58. Janssen P, Vos R, Van Oudenhove L, Tack J. Influence of the 5-HT3 receptor antagonist ondansetron on gastric sensorimotor function and nutrient tolerance in healthy volunteers.  Neurogastroenterol Motil 2011;23:444-449, e175.  

59. Midani D, Parkman HP. Granisetron transdermal system for treatment of symptoms of gastroparesis: a prescription registry study. J Neurogastroenterol Motil 2016;22:650-655.

60. Gullikson GW, Loeffler RF, Viriña MA. Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. J Pharmacol Exp Ther 1991;258:103-110.

61. Malamood M, Roberts A, Kataria R, Parkman HP, Schey R. Mirtazapine for symptom control in refractory gastroparesis. Drug Des Devel Ther 2017;11:1035-1041.

62. Jacob D, Busciglio I, Burton D, Halawi H, Oduyebo I, Rhoten D, Ryks M, Harmsen WS, Camilleri M. Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant. Am J Physiol Gastrointest Liver Physiol 2017;313:G505-G510.

63. Pasricha PJ, Yates KP, Sarosiek I, McCallum RW, Abell TL, Koch KL, Nguyen LAB, Snape WJ, Hasler WL, Clarke JO, Dhalla S, Stein EM, Lee LA, Miriel LA, Van Natta ML, Grover M, Farrugia G, Tonascia J, Hamilton FA, Parkman HP, NIDDK Gastroparesis Clinical Research Consortium (GpCRC). Aprepitant has mixed effects on nausea and reduces other symptoms in patients with gastroparesis and related disorders. Gastroenterology 2018;154:65-76.e11.

64. Carlin JL, Lieberman VR, Dahal A, Keefe MS, Xiao C, Birznieks G, Abell TL, Lembo A, Parkman HP, Polymeropoulos MH. Efficacy and safety of tradipitant in patients with diabetic and idiopathic gastroparesis in a randomized, placebo-controlled trial. Gastroenterology 2021;160:76-87.e74.

65. Carlin JL, Polymeropoulos C, Camilleri M, Lembo A, Fisher M, Kupersmith C, Madonick D, Moszczynski P, Smieszek S, Xiao C, Birznieks G, Polymeropoulos MH. The efficacy of tradipitant in patients with diabetic and idiopathic gastroparesis in a phase 3 randomized placebo-controlled clinical trial. Clin Gastroenterol Hepatol 2024;22:2506-2516.

66. McCallum RW, Soykan I, Sridhar KR, Ricci DA, Lange RC, Plankey MW. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther 1999;13:77-80.

67. Parkman HP, Sharkey EP, Nguyen LA, et al. Marijuana use in patients with symptoms of gastroparesis: prevalence, patient characteristics, and perceived benefit. Digest Dis Sci 2020;65:2311-2320.

68. Zheng T, BouSaba J, Taylor A, Dilmaghani S, Busciglio I, Carlson P, Torres M, Ryks M, Burton D, Harmsen WS, Camilleri M. A randomized, controlled trial of efficacy and safety of cannabidiol in idiopathic and diabetic gastroparesis. Clin Gastroenterol Hepatol 2023;21:3405-3414.e4.

69. de Almeida DL, Devi LA. Diversity of molecular targets and signaling pathways for CBD. Pharmacol Res Perspect 2020;8:e00682. 

70.  Parkman HP, Van Natta ML, Abell TL, McCallum RW, Sarosiek I, Nguyen L, Snape WJ, Koch KL, Hasler WL, Farrugia G, Lee L, Unalp-Arida A, Tonascia J, Hamilton F, Pasricha PJ. Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial. JAMA 2013;310:2640-2649.

71. Yang D, Abdelnaem N, Matar A, Camilleri M. Gastric accommodation and impact on emptying of solids in gastroparesis. Neurogastroenterol Motil (submitted)

72. Liau SS, Camilleri M, Kim DY, Stephens D, Burton DD, O’Connor MK. Pharmacological modulation of human gastric volumes demonstrated noninvasively using SPECT imaging. Neurogastroenterol Motil 2001;13:533-542.  

73. Coulie B, Tack J, Peeters T, Janssens J. Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans. Gut 1998;43:395-400.

74. Richards RD, Davenport K, McCallum RW. The treatment of idiopathic and diabetic gastroparesis with acute intravenous and chronic oral erythromycin. Am J Gastroenterol 1993;88:203-207.

75. Park S-Y, Acosta A, Camilleri M, Fox J, Szarka LA. Gastric motor dysfunction in patients with functional gastroduodenal symptoms. Am J Gastroenterol 2017;112:1689-1699.

76. Chial HJ, Camilleri M, Burton D, Thomforde G, Olden KW, Stephens D. Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health. Am J Physiol Gastrointest Liver Physiol 2003;284: G130-G137.

77. Parkman HP, Yates KP, Sarosiek I, Bulat RS, Abell TL, Koch KL, Kuo B, Grover M, Farrugia G, Silver P, Abdullah A, Maurer AH, Malik Z, Miriel LA, Tonascia J, Hamilton F, Pasricha PJ, McCallum RW; NIDDK Gastroparesis Clinical Research Consortium. Buspirone for early satiety and symptoms of gastroparesis: A multi-centre, randomised, placebo-controlled, double-masked trial (BESST). Aliment Pharmacol Ther 2023;57:1272-1289.

78. Carbone F, Vanuytsel T, Tack J. The effect of mirtazapine on gastric accommodation, gastric sensitivity to distention, and nutrient tolerance in healthy subjects. Neurogastroenterol Motil 2017 Dec;29(12). doi: 10.1111/nmo.13146. Epub 2017 Jul 11.  

79. Thomas A, de Souza Ribeiro B, Malespin M, de Melo SW Jr. Botulinum toxin as a treatment for refractory gastroparesis: a literature review. Curr Treat Options Gastroenterol 2018;16:479-488.

80. Friedenberg FK, Palit A, Parkman HP, Hanlon A, Nelson DB. Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol 2008;103:416-423. 

81. Arts J, Holvoet L, Caenepeel P, Bisschops R, Sifrim D, Verbeke K, Janssens J, Tack J. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther 2007;26:1251-1258.

82. Vosoughi K, Ichkhanian Y, Jacques J, et al. Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy. Gastrointest Endosc 2020;91:1289-1299.

83. Desprez C, Melchior C, Wuestenberghs F, et al. Pyloric distensibility measurement predicts symptomatic response to intrapyloric botulinum toxin injection. Gastrointest Endosc 2019;90:754-760.e1.  

84. Martinek J, Hustak R, Mares J, Vackova Z, Spicak J, Kieslichova E, Buncova M, Pohl D, Amin S, Tack J. Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial. Gut 2022;71:2170-2178.

85. Shada AL, Dunst CM, Pescarus R, et al. Laparoscopic pyloroplasty is a safe and effective first-line surgical therapy for refractory gastroparesis. Surg Endosc 2016;30:1326-1332.

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Dispatches from the GUILD Conference 2025

Introduction: Dispatches from the GUILD Conference 2025

March 2025 • Volume XLIX, Issue 3
Uma Mahadevan

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Welcome to the ninth annual Dispatches from the GUILD Conference series. The Gastrointestinal Updates-IBD-Liver Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February (GUILD 2025: February 16 -19) and a new meeting in the Caribbean, this year in St. Thomas, in January 2025. We are delighted to offer a hybrid meeting with over 250 health care providers attending live. GUILD again provides cutting edge updates in gastroenterology by world class speakers. Our topics this year include 2 days of IBD updates, a day of hepatology and a day devoted to general gastroenterology including eosinophilic esophagitis, gastroparesis and obesity. We understand that trainees are our future. Ten Gastroenterology fellows were selected to attend the meeting and receive daily mentoring and networking from our star faculty. GUILD also recognizes the role played by nurse practitioners and physician assistants in the care of IBD and liver patients and introduced a boot camp in 2019, awarding 10 scholarships to APPs to attend the meeting.

To share our learning with the gastroenterology community at large, we are happy to continue our series beginning with the following article,
“Diagnosis and Management of Gastroparesis”.

We look forward to providing informative and educational articles covering IBD, Hepatology, and key topics in general gastroenterology in Practical Gastroenterology over the following months. We hope to see you all in person for GUILD 2026 in Puerto Rico (January 11-14, 2026) and in Maui (February 14 -18, 2026). 

For more information on the
GUILD Conference, visit:

guildconference. com

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Frontiers in Endoscopy, Series #94

Endoscopic Management of Esophageal and Gastric Anastomotic Strictures

March 2025 • Volume XLIX, Issue 3
Michael B. Andrews,Douglas G. Adler

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Introduction

Esophageal and gastric anastomotic strictures can be challenging to treat. Minimally-invasive therapeutic endoscopic intervention has overtaken surgical re-intervention as first-line therapy. This literature review aims to assess the technique, efficacy, and adverse events of the many currently available options for endoscopic management.

Esophageal Anastomotic Strictures

Etiology

Esophageal anastomotic strictures (EAS) are most commonly a post-operative adverse event following esophagectomy and esophageal atresia repair. The most common indication for esophagectomy is treatment of malignancy, but rarely, it may be indicated for treatment of benign esophageal disease in cases of severe obstruction, perforation, or dysmotility. EAS remains a common problem. The reported rate of EAS following esophagectomy ranges between 5-46% with a large retrospective cohort study performed by Honkoop et al. demonstrating EAS development in 114 out of 269 (42%) patients.2,3

Esophageal atresia is a rare congenital anomaly affecting 1 in 3,500 births.4 There are four types (A-D) of esophageal atresia of which type C is seen in 80-85% of cases and presents anatomically with a closed off upper esophagus and aberrant connection of the lower esophagus to the trachea.5,6 Surgical repair is required, but post-operative EAS has been reported to develop in approximately one-third to one-half of patients.4,7,8

Risk Factors

Patient risk factors for EAS include pre-operative cardiovascular disease and diabetes.2,9 Mendelson et al. reported lower risk for EAS in patients who had previously received neoadjuvant chemotherapy when esophagectomy was performed for malignancy.

Surgical risk factors have been more extensively studied with data supporting post-operative anastomotic leakage as a driver of tissue ischemia, inflammation and eventual stricture development.2,9 Anastomotic closure techniques, hand-sewn versus stapled, have also been analyzed without clear evidence to suggest one increases risk for EAS more than the other.11,12

Clinical Manifestations

Dysphagia is the most common clinical manifestation of EAS, described by patients as the inability to swallow, food becoming stuck in the throat, or regurgitation of food.13 Dysphagia can be graded using the Atkinson’s classification: grade 0 (ability to tolerate normal diet), grade 1 (ability to swallow some solids), grade 2 (ability to swallow semi-solids), grade 3 (ability to swallow liquids), and grade 4 (inability to swallow anything).14

Bougie and Endoscopic Balloon Dilation

Technique – Bougie Dilation

Bougie dilators are reusable push-type dilators available in various sizes with a fixed diameter exerting radial and longitudinal forces simultaneously as they pass through the stricture.15 Hurst and Maloney bougie dilators (Medovations, Milwaukee, Wisc, and Teleflex Medical, Research Triangle Park, NC) do not use a guidewire and are instead pushed blindly with gravity assistance from tungsten within the dilator.15 Savary-Gillard (Cook Medical, Winston-Salem, NC) and American Dilation System bougie dilators (ConMed, Utica, NY) utilize a guidewire placed endoscopically followed by passage of the bougie dilator over the wire, with or without fluoroscopic guidance.15 Available diameters range from 16-60 French (Hurst), 36-54 French (Maloney), and 15-60 French (Savary-Gillard and American Dilation System).15

Technique – Endoscopic Balloon Dilation

Balloon dilators are single-use, inflatable dilators of various diameters (6-20mm) designed to supply a radial force against the stricture.15 The most common technique utilizes a through-the-scope (TTS) balloon dilator passed over a guidewire to position the balloon within the stricture prior to inflation with injection of saline or contrast.15 Others are designed to be placed through the scope under endoscopic visualization without a guidewire, but these are rarely used in modern clinical practice.15

Efficacy

Results across multiple studies are similar for both bougie and endoscopic balloon dilation (EBD) with initial clinical success rates ranging from 70-90% following a median of two to nine dilation sessions, emphasizing how refractory some of these strictures can be.2,14,16,17  van Halsema et al., in a retrospective cohort study of 179 patients, reported a stricture recurrence rate of 73.7%.18 Risk factors for recurrence include diabetes and strictures longer than 10mm.17 van Halsema et al. also showed significantly increased dilation-free days (92 vs. 41 days) and decreased recurrence rates (68.1% vs. 79.5%) with dilation >16mm diameter compared to 16mm.18 There were no significant differences in adverse events including perforation between the two groups.18

Adverse Events

van Halsema et al. reported an overall adverse event rate of 5.3% per patient and 1.0% per procedure.18 The most notable adverse events were perforation rates of 3.6% per patient and 0.6% per procedure with bleeding in <1% of patients.18

Adjunctive Triamcinolone Injection

Technique

Intralesional injection of triamcinolone acetonide has been studied in multiple randomized control trials as adjunctive therapy to dilation of EAS.19,20  Local steroid injection is thought to inhibit fibrotic healing and scar contracture following dilation.21 While widely employed, steroid dosages and injection techniques vary based on operator preference and institutional experience. A meta-analysis by Dasari et al. reported dosages ranging from 40-50mg with multiple intralesional injections using a 25-gauge needle.19,22

Efficacy

Hanaoka et al. performed a randomized control trial of 65 patients and observed a two-fold reduction in the median number of dilation sessions required to achieve clinical success with adjunctive steroid injection compared to dilation alone.19 The patients in the treatment arm also had a significantly higher six-month recurrence-free rate of 39% compared to 16% in the control arm (p-value < 0.01).19 Pereira-Lima et al., in a randomized control trial limited by a small sample size of only 19 patients, had previously reported similar findings with a significantly higher six-month recurrence-free rate of 62% in the treatment arm compared to 0% in the control arm (p-value <0.01).20

Adverse Events

Neither Hanaoka et al. nor Pereira-Lima et al. reported any adverse events in their 84 combined patients including bleeding, pain, perforation, or Candida esophagitis.19,20 However, in a more recent meta-analysis published in 2020, Dasari et al. reported a perforation rate of 1.4% and a Candida esophagitis rate of 5.5%.22 

Self-Expandable Metal Stents

Technique

The first endoscopic stent type used to treat EAS was a self-expandable plastic stent (SEPS).23 SEPS required assembly, were cumbersome to place, had high migration rates, and, despite some good clinical outcomes, are essentially obsolete and have since been replaced by self-expandable metal stents (SEMS).23,24 

Modern SEMS have strong radial force and are available as uncovered (UCSEMS), partially covered (PCSEMS), or fully covered (FCSEMS) devices. Commercially available stents in the United States include WallFlex stents (Boston Scientific, Natick, Massachusetts, United States), Endomaxx and Alimaxx stents (Merit Medical, South Jordan, Utah, United States), and Evolution stents (Cook Endoscopy, Winston-Salem, North Carolina, United States).25,26 These stents are available in various lengths (6-16cm) and diameters (12-23mm) and are designed to prevent migration via proximal and/or distal flared ends with various stent designs including fins and scaling to further reduce migation.25 Stents can be placed via endoscopy, fluoroscopy, or a combination thereof. (Figure 1)

Efficacy

Four retrospective cohort studies have shown clinical success rates ranging from 21-70%, but no individual study contained more than 50 patients with EAS.27,28,29,30  Wu et al. treated EAS with PCSEMS showing a 12-month stricture-free recurrence rate of 70% and a mean improvement of one point in dysphagia grade.27 Re-stenting was required in 12 out of 13 patients treated in the retrospective study performed by Suzuki et al. using various types of SEMS, reflecting that many of these strictures can be refractory.28 Bakken et al. and Eloubeidi et al. reported use of FCSEMS with stricture recurrence rates at approximately two months of 30% and 79%, respectively.29,30

Adverse Events

Stent migration remains a common adverse event occurring in approximately one-third of patients.31  Suzuki et al. reported a similar migration rate of 38.5% in EAS patients using various types of SEMS.28 The two studies that used only FCSEMS reported migration rates of 37.3% and 60%.29,30 No perforations were reported among the four studies, but there was one incident of food impaction within the stent at day 128.27,28,29,30

It should be stressed that sometimes migration is not a true adverse event and may reflect the fact that the stricture has resolved, thus allowing the stent to migrate. This concept was highlighted by Thomas et al. in a large retrospective cohort study of 369 patients with benign or malignant esophageal strictures treated with various FCSEMS.32 They observed total migration rates of 23-30% with clinically relevant migration rates of only 14-17%.32

Migration rates can be reduced using different anchoring techniques.31 These include endoscopic suturing (which is more technically challenging and expensive) with a reported 17% migration rate.33  Other techniques include deploying TTS or over-the-scope (OTS) clips with lower reported migration rates of 13% and 6.7-15%, respectively.31,34 An FDA-approved stent fixation device on the market since 2019, the Stentfix OTS Clip System (Ovesco, AG-Tuebingen Germany), was prospectively studied by Manta et al. who reported a migration rate of only 3.2% and no adverse events when used.31

Lumen-Apposing Metal Stents

Technique

Lumen-apposing metal stents (LAMS) were originally approved by the FDA to drain pancreatic fluid collections but have since been widely used for the endoscopic treatment of a variety of other conditions, including EAS, in an off-label manner. LAMS are fully covered, short stents with wide proximal and distal flanges to reduce migration.35 The only commercially available LAMS in the United States is the AXIOS stent (Boston Scientific, Natick MA, United States) with a 10mm length, 6-15mm diameter, and flanges of 21 or 24mm diameter.35,37 A guidewire is placed across the stricture under endoscopic and fluoroscopic guidance, and the stent is deployed with or without pre-stent or in-stent dilation.35,37 (Figure 2) Stent dwell time has been commonly reported between 60-90 days, but is often individualized.38,39 

Efficacy

LAMS have been used for short (<1cm) EAS with reported clinical success rates ranging from 50-100% among two case series and two retrospective cohort studies that combined reported on 17 patients.36,37,38,39 The largest of these, an international multicenter retrospective cohort study by Santos-Fernandez, included seven patients with EAS and showed a 30-day symptom resolution rate of >80% which dropped to <50% at 90 days.36 Larger studies specifically focused on use in EAS patients are needed.

Adverse Events

Out of the 17 patients, there were three (17.6%) stent migrations, two (11.8%) angulations, and development of a new proximal stricture made of granulation tissue in one case requiring balloon dilation to remove the stent.36,37,38,39 No study reported bleeding or perforation.36,37,38,39

Biodegradable Stents

Technique

Biodegradable stents (BDS) made of synthetic polymers such as polydioxanone are designed to apply a radial force for approximately six weeks then degrade via hydrolysis over an additional six to 24 weeks.40 This eliminates the need for a removal procedure, but the currently available BDS require assembly and supply a weaker radial force than traditional SEMS.40 The SX-ELLA BDS (ELLA-CS, Hradec Kralove, Czech Republic) is the only commercially available BDS for esophageal use and is available in many lengths (60-135mm) and diameters (18-25mm).41 This device is not approved for use in the United States. Once assembled, BDS are loaded onto a delivery system, advanced over a guidewire, and deployed with endoscopic and/or fluoroscopic visualization using radiopaque markers on both ends.41

Efficacy

There are limited studies on BDS for treatment of EAS. Sanchez Munoz et al.’s case report described an ideal sequence of events with successful placement, initial stent degradation at four weeks, complete stent resorption at five months, and a patent anastomosis without symptoms at 20-month follow-up.42 Three prospective cohort studies with a combined 21 EAS patients reported clinical success rates of 25-60% with median dysphagia-free time of three to six months.43,44,45  However, several patients experienced stricture recurrence requiring up to three BDS replacements to maintain long-term patency.43,44,45

Adverse Events

Using BDS, Hirdes et al. reported bleeding, stent migration, and food impaction in 11% and pain in 7% of patients.43 van Boeckel et al. reported bleeding, pain, food impaction, and tissue overgrowth in 11% and stent migration in 22% of patients.44 van Hooft et al. reported food impaction in 10% and obstruction due to stent epithelialization in 20% of patients.45 Perforation was not reported in any of the studies.43,44,45

Endoscopic Incisional Therapy

Technique

Endoscopic incisional therapy (EIT) was first used to treat Schatzki rings and has been applied to refractory benign esophageal strictures as well.46  Radial incision and cutting (RIC) is one method using an insulation-tip (IT) knife (KD611L, IT2, Olympus, Japan) or a standard needle knife to make radial incisions around the circumference of the stricture, sometimes with removal of the fibrotic tissue in-between incisions.47,48,49,50  Radial incisions of operator-dependent length and depth are made perpendicular to the stricture.49,50

Efficacy

Clinical success of EIT ranges from 50-100% across multiple studies.46,47,48,49,50 Two retrospective cohort studies with a combined 104 patients showed 50-63% of patients remained asymptomatic at six months.46,47 In a case series of 20 patients, Hordijk et al. observed the 12 patients with strictures <1cm long remained asymptomatic at 12 months whereas 8 patients with strictures >1cm long experienced dysphagia recurrence.49

Jimoh et al. performed a meta-analysis showing EIT significantly reduced the odds (OR 0.32, p-value 0.03) of stricture recurrence in naïve EAS compared to EBD.51 Muto et al.’s retrospective cohort study showed similar results with significantly higher 6-month (65.3% vs. 19.8%, p-value <0.005) and 12-month (61.5% and 19.8%, p-value <0.005) recurrence-free rates in patients treated with EIT compared to EBD.47

Adverse Events

Chest pain (up to 26%) was a commonly reported adverse event among published studies.46,48 Bleeding was reported in 10% of patients.46 There were no reports of perforation.46,48,49,50

Gastric Anastomotic Strictures

Etiology

Gastric anastomotic strictures most commonly develop following Roux-en-Y gastric bypass (RYGB) surgery but may also result following gastric resections for benign or malignant disease.52,53  Gastric anastomotic strictures account for half of RYGB post-operative adverse events affecting 3-28% of patients.52,53

Risk Factors

Patient risk factors for gastric anastomotic strictures include pre-operative gastroesophageal reflux disease. Risk for concomitant marginal ulcers increased in patients using tobacco, alcohol, or non-steroidal anti-inflammatory drugs (NSAIDS).55

Many studies have examined the impact of anastomotic closure techniques on the risk for developing gastric anastomotic strictures with conflicting results.52,, Jiang et al. performed a meta-analysis of 13,626 patients showing no significant difference in gastric anastomotic stricture rates between hand-sewn, circularly stapled, or linearly stapled anastomoses following laparoscopic RYGB.56 However, a more recent meta-analysis by Jin et al. reported patients were at higher risk for gastric anastomotic strictures if circular stapling was used compared to linear stapling.57

Clinical Manifestations

Patients often present with obstructive symptoms including nausea, vomiting, early satiety, reflux, and/or dysphagia.52, Carrodeguas et al. performed a retrospective cohort study of 1,291 patients noting mean symptom onset at 52 days (range 20-154 days) following surgery.58 

Endoscopic Balloon Dilation

Technique

TTS EBD is the most utilized method for dilating gastric anastomotic strictures. Clinicians target a RYGB stoma diameter of 10-12mm.52 The same EBD techniques described previously apply to gastric anastomotic stricture dilation with the balloon dilator positioned with or without a guidewire prior to inflation against the stricture.15

Efficacy

Meta-analyses by Baumann et al. (N=896) and Campos et al. (N=760) showed clinical success rates of 97% and 98%, respectively.53,59 Baumann et al. noted only 38% of patients required multiple dilation sessions, and Campos et al. reported patients required a mean of 1.62 dilation sessions to achieve clinical success.53,59

Adverse Events

Perforation occurred in 1.8-2.3% of patients.53,59 Baumann et al. reported only one incidence of bleeding out of 896 patients.59

Self-Expandable Metal Stents

Technique

The main barrier to using SEMS to treat gastric anastomotic strictures is the ability to reach the stricture with the stent delivery system. Many of the previously described esophageal SEMS, especially the Endomaxx stents (Merit Medical, South Jordan, Utah, United States), can be used off-label if the stricture is within reach of the stent’s sheath.25 Cai et al. described successful use of longer FCSEMS Megastents (Taewoong Medical Industries, Kangseo-Gu Songjung-Dong, South Korea) available as 18 and 23cm to reach distal strictures.52 This stent is designed with flares to reduce migration rates.52 The Wallstent Enteral and Wallflex Duodenal stents (Boston Scientific, Natick, Massachusetts, United States) are other options available in lengths 60-120cm and diameters 20-22mm.25

Efficacy

Limited data exist regarding treatment of gastric anastomotic strictures with SEMS.60,61,62  Randhawa et al. performed a prospective cohort study with six gastric anastomotic stricture patients showing an 83.3% clinical success rate.61 Bakken et al.’s retrospective cohort study with 12 gastric anastomotic stricture patients described a clinical success rate of 75% at the time of stent removal but a 77% recurrence rate.62

Adverse Events

Stent migration is a commonly experienced adverse event seen in up to 50% of patients.61,62 Previously described SEMS anchoring techniques may be used to reduce stent migration.61 Randhawa et al. observed a decrease in migration rate from 28.6% to 0% when more than one endoscopic suture was applied to the FCSEMS.61 Only one perforation was reported out of 19 patients.60,61,62

Lumen-Apposing Metal Stents

Technique

LAMS can be used in an off-label manner to treat gastric anastomotic strictures using the same technique described above for EAS.63  (Figure 3) While operator dependent, Skidmore et al. described a case series of 14 patients where pre-stent dilation was avoided with the goal of reducing stent migration.

Efficacy

Clinical success using LAMS ranges from 60-100% across many studies including a retrospective cohort study of 109 patients performed by Mahmoud et al. who reported 98.4% of patients were asymptomatic at 30 days.63,64,65,66,67,68  However, stricture recurrence requiring re-intervention occurred in approximately half of patients.68

Adverse Events

Stent migration occurred in 10-27.3% of patients.64,67,68 Chest pain was experienced by as many as 10-14% of patients.64,68 Mahmoud et al. reported bleeding in 3.9% of patients.68 Only one perforation was reported out of 154 total patients across all studies.64,65,66,67,68

Conclusion

Treatment of esophageal and gastric anastomotic strictures remains a significant challenge despite advancement in therapeutic endoscopic options. For esophageal anastomotic strictures, bougie and endoscopic balloon dilation remain first-line therapy despite high recurrence rates which are improved with adjunctive steroid injection. Other modalities include stent placement with SEMS, LAMS, or BDS, each with varying degrees of efficacy and adverse events, as well as endoscopic incisional therapy. Endoscopic management options for gastric anastomotic strictures are similar including endoscopic balloon dilation, if technically feasible based on stricture location, and stent placement with SEMS or LAMS. 

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Hannah Freid,Mark Shneyderman,Sonia Mehra,Abigail Bacharach,David Kohler,Stephanie Gold

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Vitamin C, also known as L-Ascorbic Acid, is a water-soluble vitamin that cannot be synthesized by humans and is commonly found in many fruits and vegetables. Although vitamin C is traditionally known for its role in the immune system, this vitamin also has many other functions in the human body including as a cofactor in enzymatic reactions, supporting catecholamine production, and aiding tissue repair.1 Of interest, vitamin C plays a role in almost every organ system, including the gastrointestinal tract. From the stomach to the pancreas, small intestine, liver and colon, vitamin C plays a role in the pathophysiology of many common disorders encountered by gastroenterologists. This review will focus on the role of vitamin C in many of these diseases of the gastrointestinal tract, including, but not limited to H. pylori associated peptic ulcer disease, pancreatic cancer, metabolic associated steatotic liver disease (MASLD), constipation and inflammatory bowel disease. 

Introduction

Vitamin C, also known as L-Ascorbic Acid, is a water-soluble vitamin commonly found in many fruits and vegetables.1 Unlike many other organisms, humans lack the enzymatic ability to synthesize vitamin C endogenously and therefore they must depend on the diet to obtain their daily requirements. Although vitamin C is often highlighted for its role in immune system function, it also has many other functions in the human body including as a cofactor in enzymatic reactions, supporting catecholamine production, and aiding tissue repair.1 As a cofactor, vitamin C is involved in numerous enzymatic reactions for the biosynthesis of collagen, L-carnitine and some neurotransmitters.2 Vitamin C is also a crucial physiologic antioxidant in the human body, donating electrons and scavenging reactive oxygen species, limiting damage by free radicals and oxidative stress.1,2 With all of these properties, vitamin C is involved in the synthesis of neurotransmitters and hormones in the nervous system. Vitamin C has been shown to affect almost all of the organ systems in the body and may underly many of the pathologic conditions that impact patients today. More specifically, studies have suggested that vitamin C deficiency may play a role in cancer development, diabetes, chronic inflammatory disorders, neurodegenerative disorders and even metal toxicities.3 In this review, we will focus on the function of vitamin C in the gastrointestinal (GI) tract and its role in major GI illnesses. (Figure 1)

Absorption and Bioavailability of Vitamin C

Vitamin C is absorbed in the distal small bowel and this process is regulated by renal excretion. At doses of 100-200 mg, nearly 100% of vitamin C can be absorbed in the small bowel, however, at higher doses (>500 mg), significantly less is absorbed and the excess is excreted in the urine.4 Vitamin C is absorbed through simple diffusion and active transporters (using sodium dependent vitamin C transporters and hexose transporters). The bioavailability of naturally occurring vitamin C (from food) and synthetic vitamin C (from supplements) is thought to be identical; in a study of 68 healthy men, plasma vitamin C levels rose equally after consumption of broccoli, orange juice, and a synthetic supplement.4,5 

Food Serving SizeVitamin C (mg)
Acerola Cherries½ cup825
Bell Peppers1 cup152
Kiwi Fruit1 fruit132
Guava 1 fruit125
Grapefruit¾ cup of fruit94
Orange Juice, fresh¾ cup93
Strawberries1 cup85
Orange1 fruit65
Broccoli, cooked½ cup51
Brussels sprouts, cooked½ cup37
Potato, white
(with skin)		1 (medium)22
Tomato 1 (medium)17
Cheerios1.5 cups
(1 serving)		~8
Table 1. Food Sources of Vitamin C
Information obtained primarily from Oregon State University Linus Pauling Institute Micronutrient Information Center.4 

Vitamin C Sources and Daily Requirements  

Given that humans are unable to synthesize vitamin C, dietary consumption is incredibly important to maintain healthy levels. Fruits and vegetables are the major sources of vitamin C in the American diet. While grains are not a natural source of vitamin C, many cereals and flours in the United States are fortified for additional supplementation. Of note, animal proteins contain no vitamin C. Foods highest in vitamin C are listed in Table 1. Synthetic vitamin C supplements contain ascorbic acid in various forms, all of which have similar bioavailability. The majority of supplements contain ascorbic acid or its related sodium salt, sodium ascorbate.4 The mineral/salt forms of ascorbic acid, including sodium ascorbate and calcium ascorbate are thought to be less acidic and potentially better tolerated (fewer GI side effects).4 

The recommended dietary allowance (RDA) of vitamin C varies based on age and biologic sex as well as a patient’s smoking, pregnancy and lactation status.2,4 Ideally patients would consume the minimum amount to maintain a steady state neutrophil vitamin C concentration with minimal excess renal excretion.2 Studies have demonstrated that current and past smokers have consistently lower levels of plasma and neutrophil vitamin C levels as compared to never smokers, likely secondary to the increased oxidative stress associated with nicotine.2 Therefore, it is recommended to increase the RDA by 35 mg/day in those who are active or prior smokers.2,4 The RDA for vitamin C is listed in Table 2. Vitamin C deficiency is commonly diagnosed based on symptoms and plasma blood testing. Symptoms of vitamin C deficiency include changes in hair and nails, bleeding gums, fatigue and weakness, as well as skin changes.4 

Vitamin C Recommended Dietary Allowances
AgeMale (mg)Female (mg)Pregnancy (mg)Lactation (mg)Smoking  (mg)
0-6 months40*40*


7-12 months50*50*


1-3 years1515


4-8 years2525


9-13 years4545


14-18 years756580115110
19+ years907585120125
Table 2. Recommended Dietary Allowances for Vitamin C Across the Lifespan 
*AI: Adequate intake values   Information obtained primarily from the National Institute of Health Vitamin C Fact Sheet 2

Vitamin C and Gastric Disease 

The role of vitamin C in the pathophysiology of gastric disease has been a topic of investigation for nearly a century, and vitamin C deficiency has been identified in the most common gastric diseases including gastritis, peptic ulcer disease, and gastric cancer.6-8 Gastric cytoprotection relies on both endogenous and ingested antioxidants, including vitamin C, so the well-established association between vitamin C deficiency and gastric disease is not suprising.8 The prevalence of vitamin C deficiency in gastric diseases is currently attributed to four mechanisms: insufficient vitamin C intake, decreased vitamin C absorption, increased metabolic requirement for ascorbic acid in gastric diseases, and increased destruction of vitamin C in the diseased stomach.6 

H. Pylori Infection and Gastric Ulceration 

Reduced plasma and gastric vitamin C levels are seen in H. pylori (HP) infection. Henry et al.9 and Woodward et al.10 noted decreased dietary vitamin C in H. pylori-positive subjects relative to uninfected individuals. After correcting for the reduced dietary intake, vitamin C levels were still significantly lower in infected patients relative to controls, suggesting that HP infection impairs the bioavailability of dietary vitamin C.9-12 The correlation between low vitamin C levels and HP infection could also be explained by vitamin C’s crucial role in collagen synthesis. Vitamin C is a cofactor in the synthesis of type IV collagen, which is a component of the lamina propria within the stomach. In this way, vitamin C helps strengthen the stomach’s connective tissue, making it difficult for HP to infiltrate the gastric epithelial cells.13,14 Finally, vitamin C inactivates the HP urease enzyme, inhibiting the bacteria’s ability to survive in the stomach’s acidic environment.8

Despite our understanding of how vitamin C may impede HP’s infiltration and survival in the stomach, randomized trials have yielded inconsistent data on the effects of vitamin C supplementation on HP eradication.14,15 Many studies have demonstrated that HP eradication is improved by supplementing triple therapy with vitamin C and some even argue that vitamin C intake for extended duration after HP triple therapy is beneficial in preventing re-infection in susceptible individuals.16-21 However, other studies have found no significant therapeutic effect of vitamin C intake, suggesting that further research is needed to better understand this relationship.22 

Vitamin C supplementation may also be beneficial in preventing gastric ulcers and their complications, such as upper gastrointestinal bleeds (UGIB). Clinical trials have shown that Vitamin C is gastroprotective and attenuates non-steroidal anti-inflammatory-drug-induced gastric damage.23-28 Additionally, vitamin C deficiency is highly prevalent among patients with UGIB and is associated with worse outcomes, greater mortality risk, and longer hospital stay after UGIB.29

Gastric Malignancy 

Finally, an inverse relationship has been observed between vitamin C and gastric cancer incidence.7,15,30-32 Many studies have demonstrated that increased vitamin C intake reduces the risk of gastric cancer development.7,33 This may be due to vitamin C’s ability to reduce oxidative stress, preventing cellular and DNA damage that may be associated with the development of gastric cancer.33,34 Antineoplastic effects of ascorbic acid may also be related to its inhibition of the formation of certain carcinogens such as N-nitroso compounds.35,36 Kong et al. provides a specific dose needed to achieve vitamin C’s risk reduction effect, suggesting that 100 mg of vitamin C intake per day, a dose well under the tolerable upper intake level for vitamin C, significantly reduces the risk of gastric cancer.37 Vitamin C’s protective effects against gastric cancer may also be mediated by its interaction with HP infection, as HP is a leading cause of gastric cancer worldwide.33,38 Of interest, Kim et al. found that HP infection was a significant risk factor for gastric cancer in patients with low vitamin C intake, but not in patients with high vitamin C intake, implying that vitamin C consumptionmodifies the relationship between H. pylori and gastric cancer.39

Vitamin C and Pancreatic Disease

Pancreatitis 

Given vitamin C’s role as an important antioxidant in human blood, it has been studied as a potential mediator for acute and chronic pancreatitis. In a study comparing patients with acute pancreatitis on admission to the hospital with healthy controls, those with pancreatitis had a significantly lower plasma vitamin C level (15 μg/mL vs. 2.8 μg/mL).40 The authors suggested that in patients with acute pancreatitis, significant oxidative stress from the underlying insult denatures the vitamin C that is available and results in a significant drop in plasma vitamin C levels.40 A systematic review showed that a combined antioxidant including vitamin C, selenium, beta carotene, vitamin E and methionine improved pain in patients admitted with chronic pancreatitis.41 Similarly, a study of 84 patients with acute pancreatitis demonstrated that those who received high dose intravenous vitamin C supplementation (10 grams/day) had a shorter hospital duration and lower mortality compared to those in the standard of care group.42

Pancreatic Cancer 

Vitamin C has similarly been studied to assess its role in the pathogenesis and treatment of pancreatic malignancies. Numerous observational studies have suggested that there is an inverse relationship between vitamin C intake and the risk of developing pancreatic cancer. Given this, a meta-analysis was performed including 20 studies and roughly 5,000 cases of incident pancreatic cancer; in this study, the relative risk for developing pancreatic cancer in the highest and lowest consumption of vitamin C was 0.58 vs. 0.66.43 The authors of this study concluded that there was insufficient evidence to suggest that vitamin C consumption reduced the risk of pancreatic cancer.43 This finding was supported by a subsequent systematic review including 12 European and North American studies with 2 randomized controlled trials (RCTs) and 3 Mendelian randomization studies.44 The authors of this review concluded that there was no evidence to support an association between vitamin C intake and the development of pancreatic cancer.44

However, there is stronger evidence on the use of vitamin C in the treatment of pancreatic cancer. Numerous studies to date have demonstrated the antitumor effect of vitamin C in a variety of malignancies.45 Specifically in patients with pancreatic cancer, high doses of vitamin C have been shown to impede the growth of pancreatic ductal adenocarcinoma cells through reduction in glucose metabolism, trigger apoptosis, and suppress invasion and metastasis of pancreatic adenocarcinoma cells.45 Vitamin C is of particular interest as a treatment modality in pancreatic cancer, as it has been shown in high doses (intravenously) to selectively induce cytotoxicity in pancreatic cells while sparing normal cells.46 Research is currently being done in humans to understand the impact of high dose vitamin C on specific pancreatic cancer mutations in order to offer more personalized oncologic treatments.  

Vitamin C and Liver Disease 

Metabolic Dysfunction-Associated Steatotic Liver Disease & Metabolic Dysfunction-Associated Steatohepatitis 

The incidence and prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is increasing exponentially in the United States.47,48 Oxidative stress and gut derived lipopolysaccharides (LPS) have been shown to contribute towards the progression of MASLD to MASH.49,50 As such, the anti-inflammatory and antioxidant effects of vitamin C have been suggested to play an important role in the development of MASLD.51,52 In addition, vitamin C has been shown to activate the adiponectin pathway, a hormone that can reduce the accumulation of triglyceride levels in the liver, potentially reducing the risk of MASLD.53-55 Studying the relationship between serum vitamin C levels and the risk of MASLD, Wu et al.56 performed a cross sectional study of 5,578 participants in a large national survey study (National Health and Nutrition Examination Survey [NHANES]) and found that higher serum vitamin C levels were protective against the development of MASLD in both men and women. However, with inverse variance weighted Mendelian randomization, no causal relationship between serum vitamin C levels and MASLD risk was observed (OR = 0.82, p = 0.502).56 Two subsequent studies demonstrated that there was no difference in the vitamin C serum and plasma concentrations between those patients with MASLD and healthy controls.57,58 Looking forward, large prospective studies are necessary to better elucidate this relationship.  

Dietary intake of vitamin C has been shown to have protective effects in patients with MASLD and MASH.59 An RCT in adults with MASLD showed that high vitamin C intake in diet was associated with improved liver biomarkers including lower levels of ferritin and increased albumin.60 Another RCT including adults with MASLD found that a twelve-week course of vitamin C supplementation led to higher serum adiponectin levels as well as increased intestinal microbiota diversity, both of which may improve liver function recovery in patients with MASLD.61 Given the potential impact of vitamin C supplementation on liver disease, further studies are necessary to identify the dose and formulation of vitamin C that is most effective. A cross-sectional study of 4500 participants found that serum vitamin C levels of 50.5-67.0 µmol/L were associated with reduced liver disease risk whereas serum levels greater than 67 µmol/L were associated with a higher risk of MASLD, liver fibrosis and cirrhosis.62 Which patients would benefit from supplementation and at what doses, formulations, etc. is an area of future research. 

Hepatocellular Carcinoma 

Given the antioxidant properties of vitamin C and the impact on MASLD and MASH, researchers have studied the use of vitamin C in patients with hepatocellular carcinoma (HCC). Going back to the 1970s, Pauling and Cameron demonstrated that intravenous injections of vitamin C were effective at prolonging survival in patients with advanced malignancies.63 This same effect was not demonstrated from oral vitamin C supplementation in subsequent malignancy studies. In 2018, Lu et al.64 demonstrated that intravenous vitamin C supplementation had a significant effect on prolonging tumor free survival in patients with HCC. In a subsequent in vitro study, the effect of combined vitamin C and Lenvatinib was studied in HCC cells; in this study, vitamin C alone significantly reduced the proliferation, migration and invasion of HCC cells while vitamin C in combination with Lenvatinib showed a synergistic relationship in inhibiting cancer cell proliferation.63 This study suggested that vitamin C may have a beneficial role in the treatment of HCC; however, once again, the correct dose and method of delivery needs to be identified.63 

Vitamin C and the Small and Large Intestine 

Intestinal Permeability and Injury 

Over the last decade, there has been variability in the findings from the literature evaluating the impact of vitamin C on intestinal permeability, which may be secondary to significant heterogeneity in study design (vitamin C dose, definition of gut permeability etc.). In a recent study assessing the impact of vitamin C on intestinal permeability and absorption, Sequeira et al.65 compared the effects of oral aspirin and ascorbic acid on excretion in healthy adults, demonstrating that in the 3 hours following intake, lactulose excretion was significantly greater following ascorbic acid administration alone as compared to aspirin administration alone (p<0.05). Of interest, the authors identified that aspirin and ascorbic acid have an additive effect, with the combined administration of these two substances leading to the greatest increase in intestinal permeability.65 This study suggested that vitamin C may be useful in increasing paracellular nutrient absorption, which is a route of many nutrients, such as calcium and oxalate. 66,67 

Looking at intestinal injury, McAlindon et al.68 investigated the impact of vitamin C on gastric mucosal reactive oxygen metabolites and gastroduodenal injury as assessed on endoscopy in healthy volunteers. In this study, vitamin C administration significantly reduced duodenal injury and therefore the authors proposed that vitamin C may have a protective effect against aspirin induced duodenal injury.68-70 There are few other studies in humans assessing this effect; however, in a study assessing the protective effect of vitamin C in rats who undergo ethanol induced duodenal injury, a combination of vitamin C, vitamin E and selenium was found to be protective against duodenal damage.71 

Microbial Diversity 

Many studies have demonstrated that vitamin C supplementation has the ability to shift the intestinal microbiome and potentially increase diversity.72,73 More specifically, these studies have demonstrated an increase in the family Lachnospiraceae in the stool with vitamin C supplementation, which may result in decreased systemic inflammation through the production of anti-inflammatory short chain fatty acids.74 In a small study of 14 individuals given 1000 mg daily vitamin C supplementation for 2 weeks, Otten et al.72 found increases in Lachnospiraceae (p< 0.05) and decreases in other species, such as Bacteroidetes (p<0.01) and Enterococci (p < 0.01), when analyzing stool samples. Similarly, in a randomized control trial, Pham et al.75 found vitamin C supplementation to significantly increase population size of a specific species of Lachnospiraceae and to also increase alpha diversity, a measure of biodiversity, across 12 participants given 500 mg/day vitamin C. In a study looking at individuals already taking vitamin C supplementations for various reasons, Hazan et al.76 noted shifts in bacterial populations as well, however, the authors did not find an overall increase in microbiome diversity. The authors suggest that this variability may be secondary to differences in vitamin C dosing, route of administration and duration of supplementation.76 Ultimately, it remains unclear whether these shifts in the microbiome’s composition provide clinically meaningful health benefits. 

Osmotic Laxative 

Vitamin C has been noted to be an excellent osmotic laxative. In fact, studies have evaluated the use of vitamin C in combination with polyethylene glycol (PEG) solutions for colonic cleansing prior to colonoscopy.77 Due to the hexose structure of vitamin C, a portion of orally consumed vitamin C is absorbed in the proximal small bowel and the unabsorbed fraction can act as an osmotic agent, drawing water into the bowel. In a small pilot study of 6 healthy volunteers who were undergoing screening colonoscopy, patients who received PEG in addition to 10 grams of vitamin C had 35% greater stool volume compared to those who had the standard of care PEG alone (2.2 L vs. 1.4 L; P < 0.01).2,77 However, a subsequent study from Mouly et al.77 compared 6 colon cleansing solutions with varying amounts of PEG and vitamin C; in this study, all of the solutions had similar tolerability and no significant statistical difference in stool volume, suggesting that the presence of vitamin C did not increase the effectiveness of the bowel preparation. Future studies are needed to better understand whether added vitamin C can improve the effectiveness of bowel preparations for colonoscopy. 

Given that the unabsorbed fraction of vitamin C is not absorbed and can act as an osmotic laxative in the bowel, researchers have evaluated whether vitamin C rich foods or supplementation can be used for slow transit constipation. In a study looking at the impact of dietary factors on constipation in generally healthy adults, there was a significant positive correlation between intake of vitamin C and constipation.78 Moreover, in a community-based study assessing the prevalence of constipation in young children, the authors suggested that children with constipation had significantly lower intakes of vitamin C (p=0.041) compared to those children who did not have constipation.79 

Inflammatory Bowel Disease 

Vitamin C plays a significant role in inflammatory bowel disease (IBD), and its importance has started to come into focus over the past several years. One small study of Crohn’s patients found that administration of vitamin C had a beneficial effect on T-cell function.80 In addition, as mentioned above, vitamin C plays a role in modulation of the microbiome, which is incredibly important in patients with IBD.81 Additionally, vitamin C is a strong antioxidant that can modulate gut inflammation and may be associated with improved bone mineral density; vitamin C is crucial for wound healing in IBD patients who have had courses of steroids.81-86 Finally, vitamin C consumption is known to increase iron absorption in the small bowel, which is important for patients with IBD who are prone to iron deficiency anemia due to luminal bleeding and decreased iron absorption. 

Patients with IBD are prone to micronutrient deficiencies for a myriad of reasons, including decreased food intake, malabsorption, increased GI losses, and increased nutritional needs in the setting of systemic inflammation.86 Traditional guidance for patients with strictures, ileostomies, and those with active IBD symptoms has included restriction of fresh fruits and vegetables. However, this recommendation has changed and we now understand that modification of these foods, including peeling, cooking and pureeing is far superior to restriction, as restriction leads to a myriad of nutritional deficiencies. Unfortunately, vitamin C deficiency often goes undiagnosed in patients with IBD and the clinical implications have not been extensively studied. In one study evaluating the prevalence of vitamin C deficiency in IBD patients, 21.6% of patients in the study had a vitamin C deficiency (24.4% of Crohn’s disease patients and 16% of ulcerative colitis patients).84 In a subsequent case series of patients with IBD and vitamin C deficiency, 16 (80%) of patients had symptoms consistent with clinical scurvy including arthralgias, rash, gingivitis, and brittle hair/nails and the majority of these patients (56%) reported fruit and vegetable avoidance.83 While restriction of fruits and vegetables certainly plays a role in vitamin C deficiency, patients with IBD have been found to have polymorphisms in vitamin C transporter genes and tumor necrosis factor alpha (TNFa), an important inflammatory cytokine in IBD, which downregulates the transcription of vitamin C transporters, further reducing the capacity for vitamin C uptake.84 Furthermore, vitamin C is absorbed in the jejunum and ileum, which are commonly affected areas in Crohn’s disease.84,86 

Studies have demonstrated that vitamin C deficiency has been linked with worsened clinical outcomes and disease progression. In the aforementioned study evaluating the prevalence and impact of vitamin C deficiency in patients with IBD, patients with active disease (defined by an elevated C-reactive protein or calprotectin) were significantly more likely to have an abnormal vitamin C level ([CRP: 39.1% vs. 16.9%, P < 0.001], [Calprotectin: 50.0% vs. 20.0%, P = 0.009]).84 While this could be secondary to dietary changes in those with active disease (reduced fruits and vegetable intake for example), univariate analysis demonstrated that penetrating disease (p=0.03), obesity (p=0.02) and need for a biologic (p=0.006) were also associated with vitamin C deficiency in this study.84 Vitamin C deficiency has also been associated with sarcopenia, which is itself associated with worse clinical outcomes in IBD.86

Too Much of a Good Thing?
Toxicity of Vitamin C

Vitamin C has very low toxicity and has not been associated with significant health concerns in the general population. Given the vitamin’s water-soluble nature, excess vitamin C is excreted in the urine without complications.87 The upper intake level of vitamin C is 2 grams per day; at doses similar to this, vitamin C is poorly absorbed in the gastrointestinal tract and the unabsorbed vitamin C can cause an osmotic effect, leading to diarrhea and abdominal pain.87 Intravenous vitamin C can cause migraine headaches, flushing and nausea/vomiting when given at very high doses (above the safe upper limit).87 Of note, supplementation with more than 250 mg of vitamin C daily can interfere with fecal occult blood testing, resulting in a false negative result. In addition, vitamin C supplementation should be avoided in patients with iron overload; in those specifically with cardiac hemochromatosis, large doses of vitamin C supplementation can lead to rapid mobilization of iron from the heart, leading to potentially fatal cardiac arrythmias.88 Similarly, in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, vitamin C supplementation can lead to hemolysis and a subsequent renal injury. Finally, vitamin C plays a role in oxalate metabolism, and therefore, may increase the risk of calcium oxalate stones.89 The Nurses’ Health Studies identified that intake of over 1000 mg of vitamin C per day was associated with a 41% increased risk for developing a kidney stone.89 However, this has been an area of controversy, as other studies have not shown this relationship. A recent systematic review with meta-analysis demonstrated that supplementation with ascorbic acid was associated with a higher risk of kidney stone formation in men, but not in women.90 Future, prospective studies are needed to better delineate this risk.  

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44. Martinez-Dominguez SJ, Laredo V, Garcia-Rayado G. The role of vitamin C in the prevention of pancreatic cancer: a systematic-review. Front Nutr. 2024;11:1398147.

45. Kim JH, Hwang S, Lee JH, Im SS, Son J. Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling. Int J Mol Sci. 2022;23(20).

46. Cieslak JA, Cullen JJ. Treatment of Pancreatic Cancer with Pharmacological Ascorbate. Curr Pharm Biotechnol. 2015;16(9):759-770.

47. Liang X, Or B, Tsoi MF, Cheung CL, Cheung BMY. Prevalence of metabolic syndrome in the United States National Health and Nutrition Examination Survey 2011-18. Postgrad Med J. 2023;99(1175):985-992.

48. Arshad T, Golabi P, Henry L, Younossi ZM. Epidemiology of Non-alcoholic Fatty Liver Disease in North America. Curr Pharm Des. 2020;26(10):993-997.

49. Ferro D, Baratta F, Pastori D, et al. New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress. Nutrients. 2020;12(9).

50. Spahis S, Delvin E, Borys JM, Levy E. Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis. Antioxid Redox Signal. 2017;26(10):519-541.

51. Ellulu MS, Rahmat A, Patimah I, Khaza’ai H, Abed Y. Effect of vitamin C on inflammation and metabolic markers in hypertensive and/or diabetic obese adults: a randomized controlled trial. Drug Des Devel Ther. 2015;9:3405-3412.

52. Tamari Y, Nawata H, Inoue E, et al. Protective roles of ascorbic acid in oxidative stress induced by depletion of superoxide dismutase in vertebrate cells. Free Radic Res. 2013;47(1):1-7.

53. Gu X, Luo X, Wang Y, et al. Ascorbic acid attenuates cell stress by activating the fibroblast growth factor 21/fibroblast growth factor receptor 2/adiponectin pathway in HepG2 cells. Mol Med Rep. 2019;20(3):2450-2458.

54. Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621-2637.

55. Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol. 2013;19(6):802-812.

56. Wu H, Guo JL, Yao JJ, et al. Serum vitamin C levels and risk of non-alcoholic fatty liver disease: results from a cross-sectional study and Mendelian randomization analysis. Front Nutr. 2023;10:1162031.

57. Da Silva HE, Arendt BM, Noureldin SA, Therapondos G, Guindi M, Allard JP. A cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs healthy controls. J Acad Nutr Diet. 2014;114(8):1181-1194.

58. Madan K, Bhardwaj P, Thareja S, Gupta SD, Saraya A. Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD). J Clin Gastroenterol. 2006;40(10):930-935.

59. Ivancovsky-Wajcman D, Fliss-Isakov N, Salomone F, et al. Dietary vitamin E and C intake is inversely associated with the severity of nonalcoholic fatty liver disease. Dig Liver Dis. 2019;51(12):1698-1705.

60. Luo X, Zhang W, He Z, et al. Dietary Vitamin C Intake Is Associated With Improved Liver Function and Glucose Metabolism in Chinese Adults. Front Nutr. 2021;8:779912.

61. He Z, Li X, Yang H, et al. Effects of Oral Vitamin C Supplementation on Liver Health and Associated Parameters in Patients With Non-Alcoholic Fatty Liver Disease: A Randomized Clinical Trial. Front Nutr. 2021;8:745609.

62. Xie ZQ, Li HX, Tan WL, et al. Association of Serum Vitamin C With NAFLD and MAFLD Among Adults in the United States. Front Nutr. 2021;8:795391.

63. Wang X, Qian S, Wang S, et al. Combination of Vitamin C and Lenvatinib potentiates antitumor effects in hepatocellular carcinoma cells in vitro. PeerJ. 2023;11:e14610.

64. Lu Y, Shen H, Huang W, et al. Correction: Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance. Cell Death Discov. 2022;8(1):74.

65. Sequeira IR, Kruger MC, Hurst RD, Lentle RG. Ascorbic Acid may Exacerbate Aspirin-Induced Increase in Intestinal Permeability. Basic Clin Pharmacol Toxicol. 2015;117(3):195-203.

66. Kiela PR, Ghishan FK. Physiology of Intestinal Absorption and Secretion. Best Pract Res Clin Gastroenterol. 2016;30(2):145-159.

67. Sequeira IR. Higher doses of ascorbic acid may have the potential to promote nutrient delivery via intestinal paracellular absorption. World J Gastroenterol. 2021;27(40):6750-6756.

68. McAlindon ME, Muller AF, Filipowicz B, Hawkey CJ. Effect of allopurinol, sulphasalazine, and vitamin C on aspirin induced gastroduodenal injury in human volunteers. Gut. 1996;38(4):518-524.

69. Amasheh S, Meiri N, Gitter AH, et al. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci. 2002;115(Pt 24):4969-4976.

70. Chen G, Qiu Y, Sun L, et al. The jagged-2/notch-1/hes-1 pathway is involved in intestinal epithelium regeneration after intestinal ischemia-reperfusion injury. PLoS One. 2013;8(10):e76274.

71. Koyuturk M, Bolkent S, Ozdil S, Arbak S, Yanardag R. The protective effect of vitamin C, vitamin E and selenium combination therapy on ethanol-induced duodenal mucosal injury. Hum Exp Toxicol. 2004;23(8):391-398.

72. Otten AT, Bourgonje AR, Peters V, Alizadeh BZ, Dijkstra G, Harmsen HJM. Vitamin C Supplementation in Healthy Individuals Leads to Shifts of Bacterial Populations in the Gut-A Pilot Study. Antioxidants (Basel). 2021;10(8).

73. Li L, Krause L, Somerset S. Associations between micronutrient intakes and gut microbiota in a group of adults with cystic fibrosis. Clin Nutr. 2017;36(4):1097-1104.

74. Vacca M, Celano G, Calabrese FM, Portincasa P, Gobbetti M, De Angelis M. The Controversial Role of Human Gut Lachnospiraceae. Microorganisms. 2020;8(4).

75. Pham VT, Fehlbaum S, Seifert N, et al. Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome- a pilot study. Gut Microbes. 2021;13(1):1-20.

76. Hazan S, Dave S, Papoutsis AJ, Deshpande N, Howell MC, Jr., Martin LM. Vitamin C improves gut Bifidobacteria in humans. Future Microbiol. 2022.

77. Mouly S, Mahe I, Knellwolf AL, Simoneau G, Bergmann JF. Effects of the addition of high-dose vitamin C to polyethylene glycol solution for colonic cleansing: A pilot study in healthy volunteers. Curr Ther Res Clin Exp. 2005;66(6):486-500.

78. Rollet M, Bohn T, Vahid F, On Behalf Of The Oriscav Working G. Association between Dietary Factors and Constipation in Adults Living in Luxembourg and Taking Part in the ORISCAV-LUX 2 Survey. Nutrients. 2021;14(1).

79. Lee WT, Ip KS, Chan JS, Lui NW, Young BW. Increased prevalence of constipation in pre-school children is attributable to under-consumption of plant foods: A community-based study. J Paediatr Child Health. 2008;44(4):170-175.

80. Animashaun A, Kelleher J, Heatley RV, Trejdosiewicz LK, Losowsky MS. The effect of zinc and vitamin C supplementation on the immune status of patients with Crohn’s disease. Clin Nutr. 1990;9(3):137-146.

81. Ratajczak AE, Szymczak-Tomczak A, Skrzypczak-Zielinska M, et al. Vitamin C Deficiency and the Risk of Osteoporosis in Patients with an Inflammatory Bowel Disease. Nutrients. 2020;12(8).

82. Jo H, Lee D, Go C, et al. Preventive Effect of Vitamin C on Dextran Sulfate Sodium (DSS)-Induced Colitis via the Regulation of IL-22 and IL-6 Production in Gulo(-/-) Mice. Int J Mol Sci. 2022;23(18).

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Frontiers in Endoscopy, Series #93

EUS-Guided Ablation Techniques for Pancreatic Lesions: A Review of Current Practices and Future Directions

February 2025 • Volume XLIX, Issue 2
Kanika Garg,Neal A. Mehta,Douglas G. Adler

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INTRODUCTION

Endoscopic ultrasound (EUS) has undergone a significant transformation, from a primarily diagnostic tool to an increasingly therapeutic one, in the evaluation and management of many benign and malignant conditions, most notably pancreaticobiliary diseases. EUS-guided ablation procedures, including chemoablation and radiofrequency ablation (RFA), are novel minimally invasive techniques that are emerging as potential therapeutic modalities in the management of focal pancreatic lesions. 

Both solid and cystic pancreatic lesions present significant clinical challenges due to their potential for malignancy and the complexities involved in their management, often requiring a multidisciplinary and multimodal approach. In pancreatic adenocarcinoma, for instance, long term 5-year survival rates remain dismal at only 13%, despite neoadjuvant chemotherapy, as many patients are not candidates for curative surgery.1 EUS-guided radiofrequency ablation provides a promising therapeutic option that, although not yet included in standard treatment paradigms, may potentially enhance outcomes while introducing minimal risk.  

EUS-guided chemoablation involves the injection of destructive/cytotoxic agents using a fine needle aspiration (FNA) needle directly into a focal lesion. EUS-guided RFA involves delivering thermal energy directly into a target lesion via a monopolar electrode to induce cell death.2,3 

Although the adoption of EUS-guided chemoablation and radiofrequency ablation in clinical practice is variable, primarily used in tertiary care centers with multidisciplinary expertise, there continues to be a growing amount of evidence evaluating these exploratory techniques. This review aims to summarize current practices and future directions of EUS-guided ablation for both pancreatic cysts and tumors.

Radiofrequency Ablation
Technology and Safety

RFA Technology

RFA delivery systems are designed to induce necrosis on the target lesion in contact with a radiofrequency energy delivery probe. A specialized catheter with a distal electrode is used and an alternating current of 400-500 kHz is passed from the electrode to the target tissue.4,5 Radiofrequency waves cause vibration of water molecules adjacent to the probe, generating heat that is transferred to the target tissue.6 Ideally, the target tissue is heated to at least 50 degrees Celsius, leading to irreversible cell damage and death, through coagulative necrosis and protein denaturation.2,3,7 In the United States, the only EUS-RFA device currently approved for pancreatic use by the Food and Drug Administration is the EUSRA™ RF Electrode (TaeWoong Medical, Gimpso-si, South Korea). This needle connects to their VIVA RF generator (STARmed, Koyang, Korea), which cools the electrode tip by circulating saline to reduce tissue charring.8

EUS-RFA Technique

With EUS-guided RFA, a 19- or 22- gauge FNA needle is introduced into the target lesion under direct endosonographic guidance. The stylet is then removed and the RFA catheter is advanced within the needle. Finally, the FNA needle is gradually withdrawn, exposing the electrode tip [Figure 1]. Radiofrequency energy is then applied for 90 to 120 seconds, until complete ablation is achieved at the impedance value of 800 ohms with the electrosurgical generator set at 10 W.9 The power output automatically cuts off once this impedance level is reached to prevent further tissue damage.8

EUS-RFA Safety

The most common adverse events (AEs), specifically for pancreatic EUS-guided RFA, include development of post-procedural pain and pancreatitis.10-15 Less frequently, RFA also runs the risk of thermal damage to surrounding vessels, which may result in pseudoaneurysm formation.16  A French study evaluating 100 patients undergoing 116 EUS-RFA sessions reported no procedure-related mortality but the authors noted an AE rate of 19%. Of these AEs, all but one were pancreatic in nature (abdominal pain, pancreatitis, or main pancreatic duct leak). The majority (86%) of the AEs required no interventions. The proximity of pancreatic neoplasms to the main pancreatic duct (≤1mm) was identified as an independent risk factor for AEs.11 In a study of 377 EUS-RFA sessions performed in 252 patients, Khoury et al. found rates of mild, moderate, and severe AEs, were 10.1%, 4.2% and 0.5%, respectively.14

EUS-guided Chemoablation

Choice of Agents

The most common agents used in EUS-guided chemoablation of pancreatic lesions include ethanol, gemcitabine, and paclitaxel. Ethanol, most commonly used at 80% and 99% concentrations, was the first solution used as a chemoablative agent for pancreatic lesions.17 Ethanol induces cell death by causing cell membrane lysis, protein denaturation, and vascular occlusion.18 Paclitaxel is a chemotherapy agent that inhibits cell replication by binding to microtubules.19,20  Paclitaxel is a highly viscous agent requiring a specialized infusion apparatus, such as a syringe strapped to a high-pressure “gun” or a specialized infusion device, to efficiently infuse the admixture through an FNA needle.21 Gemcitabine, another chemotherapeutic agent, is an antimetabolite that works by interfering with DNA synthesis.22 Ethanol is often used when treating pancreatic cysts and pancreatic neuroendocrine tumors, either alone or in combination with these other chemotherapeutic agents.18,19 More recently, alcohol-free protocols have shown promise in treating both cysts and neuroendocrine tumors.23

Chemoablation Technique

For pancreatic cysts, a 19- or 22- gauge FNA needle is used, depending on the size of the cyst. First, a transgastric or transduodenal puncture of the cyst is performed under EUS guidance.17 Fluid is then aspirated from the cyst, leaving just a small rim of fluid around the needle tip to ensure the needle is not introduced into surrounding pancreatic parenchyma. Next, the selected agent is infused [Figure 2]. The total volume infused generally equals the volume that was just aspirated from the cyst cavity.24 The ablation procedure differs slightly based on which agent is being used. When using ethanol, the cyst cavity is lavaged, where the agent is aspirated and reinjected for 3 to 5 minutes, in order to maximize the ablative effect on the cyst epithelium, improve distribution, and remove obstructive debris or dilute viscous cyst fluid.17,25-27 Chemotherapeutic agents on the other hand, are generally injected and left in the cyst cavity permanently to potentiate their cytotoxic effect.28

For solid pancreatic tumors, generally a 22- or 25- gauge FNA needle is advanced into the lesion under direct EUS-visualization.29 The needle tip is placed 0.5 to 1.0 cm from the distal tumor edge and the agent of choice is incrementally injected at the same site until a hyperechoic blush is visibly expanding within the tumor. Further injections at one site are discontinued when the hyperechoic blush extends up to the tumor margin.30 For larger lesions, additional injections are given in the same path as the needle is retracted towards the proximal tumor border.31 Additional passes can be made avoiding the same needle track, if needed, based on tumor size and pattern of spread after initial injection.30 The goal is to inject just enough ethanol to permeate the tumor and terminate the injection as the injectate appears to extravasate outside the lesion.30

Chemoablation Safety

The most common AEs for EUS-guided chemoablation therapy includes abdominal pain and pancreatitis.32,33 In a study of 207 patients undergoing pancreatic cyst ablation with ethanol, 21.2% experienced AEs, including abdominal pain, fever, pancreatitis, and intracystic bleeding. When looking at 347 patients who underwent cyst ablation with paclitaxel-based regimens (with or without ethanol), 15% of patients experienced AEs, the majority of which were pancreatitis and abdominal pain.34 For solid pancreatic tumors, AE rates of chemoablation have also been reported as high as 21.2%.33

Pancreatic Cysts

Pancreatic cysts, largely incidentally identified on cross-sectional imaging performed for unrelated purposes, have increasing incidence with age.35-37 Pancreatic cystic lesions (PCLs) include various entities with differing malignant potential. Types of PCLs include intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), serous cystadenomas (SCAs), pseudocysts, and solid pseudopapillary neoplasms (SPNs).38-41 Of these types, IPMNs and MCNs are categorized as mucinous pancreatic cysts, and have the greatest risk for malignant transformation. Certain characteristics for IPMNs, such as size greater than 3 centimeters, the presence of mural nodules, as well as communication with and/or dilation of the main pancreatic duct, increase their malignant potential.42-44 The reported risk of malignancy for patients with main duct IMPN ranges from 38-68%, whereas the risk of malignancy for MCNs ranges from 10-17%.40 EUS-guided ablation is generally only considered in non-surgical patients with either an enlarging/symptomatic MCN or IPMN, with cyst diameter of at least 1 cm and high-risk features.17

RFA of Pancreatic Cysts

The use of EUS-guided RFA for management of PCLs was first described in a pilot prospective study in 2015 by Pai et al. Of the six patients reported, two achieved complete response, defined as at least 95% reduction in cyst size. 45 A recent review pooling this pilot study with three others, 2 prospective and one retrospective, demonstrated that EUS-guided RFA for PCLs resulted in at least partial, if not complete, radiologic resolution in only 36.8% of cases at a follow up of 10.2 months. The total number of patients in this pooled review, however, was only 44, highlighting the paucity of data on this topic.14

Chemoablation of Pancreatic Cysts

EUS-guided chemoablation for pancreatic cysts has been studied for the last two decades. In that time, although the technique has not substantially changed, the agents used have evolved significantly. Initially, chemoablation of pancreatic cysts started with ethanol in 2005.46 Soon after, paclitaxel injection was combined with ethanol lavage therapy.20 A review by Papaefthymiou et al. evaluating 15 studies found that ethanol alone resulted in cyst resolution in 32% of cases, while the combination of ethanol and paclitaxel yielded complete cyst resolution in 70% of cases.47

To address safety concerns, newer protocols have explored alcohol-free chemoablation regimens. 

The CHARM trial demonstrated that in patients with mucinous-type pancreatic cysts, 67% of those who underwent alcohol-free chemoablation with saline lavage and infusion of an admixture of paclitaxel and gemcitabine had complete ablation of their cysts at 12 months which was comparable to 61% of patients in the ethanol lavage group.48 Recent long-term follow up of the same patient population found that 87% of those who had complete response at 12 months maintained resolution at a mean follow up of 36.5 months, demonstrating durability of EUS-guided chemoablation of pancreatic cysts.23 Higher efficacy has been observed with chemoablation of cysts which are unilocular and less than 35 mm in size.49,50 Despite this data, chemoablation of pancreatic cysts has still not been widely adopted. This is likely due to the paucity of long term/guideline-driven data, difficulty in ordering chemoablative medications outside of the oncologic space, and ultimately endoscopist reluctance to inject these cytotoxic medications into cysts without a defined treatment paradigm.

Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (pNETs) represent 1-2% of pancreatic cancers and can be classified as nonfunctioning or functioning.51 Nonfunctioning pNETs typically present as advanced disease or as localized disease found incidentally on cross-sectional imaging, whereas functioning pNETs often present earlier due to hormone-related symptoms.52-55

pNETs are further categorized by differentiation and grade; Well-differentiated pNETs are graded 0 to 3 based on mitotic count and Ki67 index, while poorly differentiated neuroendocrine carcinomas are classified as grade 3 and tend to be more aggressive.56,57 EUS-RFA is not usually employed for poorly differentiated cases, as these generally necessitate more aggressive treatment approaches such as systemic chemotherapy.58

RFA of Pancreatic Neuroendocrine Tumors

For pNETs that require treatment, surgery is considered the gold standard. However, patients who are at high risk for surgery due to severe comorbidities or an unfavorable tumor location may require alternative treatment options. Additionally, there is a need for minimally invasive palliative options for symptomatic unresectable or recurrent pNETs.7 EUS-RFA has been evaluated for both functional and nonfunctional pNETS. Data has shown that EUS-RFA is particularly useful for patients with small (< 2 cm) and localized tumors, offering a viable option for non-surgical candidates who require treatment due to advanced WHO grade or symptoms. A recent review of eleven studies involving 292 patients found a pooled complete radiologic response of 87.1% and pooled technical success rate of 99.2%. Of these, 134 patients had functional pNETs, for which the pooled clinical response rate was 94.9%.59 Another review of 61 patients found the overall effectiveness of EUS-RFA to be 96% without differences between functional vs. non-functional pNETs. While tumor location was not predictive of response to EUS-RFA, a pNET size cut-off value of ≤18 mm was associated with better treatment response, with a sensitivity of 80 % and specificity of 78.6%.60 Of note, several studies and case series have described rapid hypoglycemia relief within the same day for patients with insulinomas after EUS-RFA.61-64  However, since most insulinomas are typical treated surgically, EUS-RFA is only considered an alternative option for select patients.

Chemoablation of Pancreatic
Neuroendocrine Tumors

In patients with low-grade pNETs < 2 cm in size who are not surgical candidates, EUS-guided ablation with ethanol (EUS-EA) may be considered as another alternative treatment option. EUS-guided ablation of an insulinoma was first described in 2006, with rapid improvement in symptoms after EUS-EA in a patient who could not undergo surgical resection due to comorbidities.65 Another study found that of 5/9 patients (55.5%) with insulinomas who initially experienced symptom relief after EUS-EA later relapsed, with symptoms returning after a median of 128 days following the first ablation.66 A propensity score-matching study by So et al. comparing EUS-guided ethanol ablation to surgery for management of nonfunctioning small pNETs found comparable 10-year overall (OS) and disease-specific survival (DSS) rates. Of the EUS-EA cohort, 65% showed complete ablation, but 46% had local recurrence after a median follow-up of 34.5 months.67 A recent study evaluating the efficacy of EUS-guided ethanol injection of pNETs found that 88% (22/25) of patients achieved complete ablation at 1 and 6 months.68 While EUS-EA may offer potential alternative for a select group of patients who are not suitable for surgical resection and are treated at expert centers, its application remains limited, and careful monitoring is essential due to the relatively high rates of recurrence. 

RFA of Pancreatic Adenocarcinoma

Given the aggressive nature of pancreatic ductal adenocarcinoma (PDAC) and the low percentage of patients that present with resectable disease, there has always been interest in exploring additional therapeutic options to treat this malignancy.69-72 EUS-RFA is being studied as a potential palliative option for non-surgical candidates. Technical feasibility was first demonstrated in 2012 by Arcidiacono et al., though they used an experimental combination RFA and cryogenic cooling probe that is no longer on the market.73 In 2016 Songet al. also demonstrated that EUS-RFA could be performed successfully in a pilot study of six patients with unresectable PDAC with minimal adverse events.74

Furthermore, several small, non-randomized, single-center studies have suggested that EUS-RFA may offer some benefit in terms of tumor reduction or survival in select patients with locally advanced or unresectable disease, though results remain mixed and generally modest [Figure 3]. Scopelliti et al. reported successful EUS-RFA in 10 patients and observed a reduction in tumor size in 50% on follow-up imaging.75 In another small cohort of 10 patients with unresectable disease, Thosaniet al. reported a median survival of 20.5 months for patients receiving 1-4 EUS-RFA sessions in combination with chemotherapy, compared to published averages of 9-12 months for those treated with chemotherapy alone.12 In this cohort, tumor regression was observed in 7 out of 10 patients, with >50% reduction in size in 3 of those 12.12 However, these results should be interpreted with caution, given the small sample size and lack of control groups. In another observational prospective study by Ohet al., 22 patients with both locally advanced and metastatic disease, who underwent a median of five EUS-RFA sessions and subsequent chemotherapy, had a median overall survival of 24 months, but this was not directly compared to outcomes in patients receiving chemotherapy alone.76 A more recent study with 15 patients with locally advanced PDAC and 11 with metastatic disease demonstrated only a 42.3% overall survival of six months post EUS-RFA, but did show improvements in performance status and reduction in tumor size.77  Notably, a post-treatment hypodense necrotic area was observed in the 11 patients who were still alive at the 6-month follow-up, suggesting effective tumor ablation.

While this technology, which is still in early stages of development, has generated interest, data have been obtained from very small, carefully selected groups of patients. Further large scale, controlled studies are essential to determine the long-term survival benefits, identify optimal treatment protocols, and fully assess the role of EUS-RFA in multimodal therapy for pancreatic cancer. Currently, there are two clinical trials underway that are exploring the combination of EUS-RFA and chemotherapy in patients with PDAC (NCT 05723107 and NCT 04990609). However, it is important to note that both are single arm studies, and the evidence from these trials is still limited in terms of establishing clear survival benefits and treatment efficacy. 

Chemoablation of Pancreatic Adenocarcinoma

EUS-guided chemoablation of pancreatic adenocarcinoma has not been thoroughly studied, is rarely performed, and remains experimental. Only one study to date has investigated the feasibility of EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer.31 This approach involves delivering chemotherapy directly to the tumor, potentially improving local drug concentrations while minimizing systemic side effects. In the study by Levy et al., the technique was found to be feasible and safe, with minimal adverse effects. Further studies are required to assess its clinical benefits.

Conclusion

EUS-guided ablation techniques, including RFA and chemoablation, offer a minimally invasive option for managing pancreatic lesions, particularly for patients who are not candidates for surgical resection. While the available data suggest that these approaches may improve local control and quality of life, they have not yet become mainstream therapies incorporated into the management of pancreatic disease and must be considered exploratory at this time. One of the key limitations to the widespread adoption of EUS-guided ablation is the lack of large, randomized controlled trials that clearly establish long-term survival benefits, particularly in the neoadjuvant setting. Most studies to date have been small, single-center, and non-randomized, limiting data analysis and making it difficult to draw definitive conclusions about their effectiveness. Additionally, these techniques are not included in current treatment paradigms, further limiting their use in clinical practice.

Despite these challenges, the potential of EUS-guided ablation therapies remains optimistic, and ongoing studies will be crucial in addressing these gaps. Until larger trials are completed, it is unlikely that these techniques will gain widespread adoption, but they may become a valuable tool for a select group of patients, particularly those with advanced or unresectable pancreatic lesions who lack other therapeutic options. 

References

References

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13. Armellini E, Facciorusso A, Crinò SF. Efficacy and Safety of Endoscopic Ultrasound-Guided Radiofrequency Ablation for Pancreatic Neuroendocrine Tumors: A Systematic Review and Metanalysis. Medicina (Kaunas). Feb 14 2023;59(2)doi:10.3390/medicina59020359

14. Khoury T, Sbeit W, Napoléon B. Endoscopic ultrasound guided radiofrequency ablation for pancreatic tumors: A critical review focusing on safety, efficacy and controversies. World J Gastroenterol. Jan 07 2023;29(1):157-170. doi:10.3748/wjg.v29.i1.157

15. Fahmawi Y, Mehta A, Abdalhadi H, Merritt L, Mizrahi M. Efficacy and safety of endoscopic ultrasound-guided radiofrequency ablation for management of pancreatic lesions: a systematic review and meta-analysis. Transl Gastroenterol Hepatol. 2022;7:30. doi:10.21037/tgh-20-84

16. Fegrachi S, Walma MS, de Vries JJJ, et al. Safety of radiofrequency ablation in patients with locally advanced, unresectable pancreatic cancer: A phase II study. Eur J Surg Oncol. Nov 2019;45(11):2166-2172. doi:10.1016/j.ejso.2019.06.008

17. Du C, Chai NL, Linghu EQ, Li HK, Feng XX. Endoscopic ultrasound-guided injective ablative treatment of pancreatic cystic neoplasms. World J Gastroenterol. Jun 21 2020;26(23):3213-3224. doi:10.3748/wjg.v26.i23.3213

18. Zhang WY, Li ZS, Jin ZD. Endoscopic ultrasound-guided ethanol ablation therapy for tumors. World J Gastroenterol. Jun 14 2013;19(22):3397-403. doi:10.3748/wjg.v19.i22.3397

19. Koehler B, Ryoo DY, Krishna SG. A Review of Endoscopic Ultrasound-Guided Chemoablative Techniques for Pancreatic Cystic Lesions. Diagnostics (Basel). Jan 17 2023;13(3)doi:10.3390/diagnostics13030344

20. Oh HC, Seo DW, Lee TY, et al. New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection. Gastrointest Endosc. Apr 2008;67(4):636-42. doi:10.1016/j.gie.2007.09.038

21. Moyer MT, Maranki JL, DeWitt JM. EUS-Guided Pancreatic Cyst Ablation: a Clinical and Technical Review. Curr Gastroenterol Rep. Apr 23 2019;21(5):19. doi:10.1007/s11894-019-0686-5

22. Bergman A, Peters G. Gemcitabine. In: Peters G, ed. Deoxynucleoside Analogs In Cancer Therapy Cancer Drug Discovery and Development. Humana Press; 2006: 225-251.

23. Lester C, Walsh L, Hartz KM, et al. The Durability of EUS-Guided Chemoablation of Mucinous Pancreatic Cysts: A Long-Term Follow-Up of the CHARM trial. Clin Gastroenterol Hepatol. Feb 2022;20(2):e326-e329. doi:10.1016/j.cgh.2021.03.041

24. Moyer MT. Top tips for EUS-guided pancreatic cyst chemoablation (with video). Gastrointest Endosc. Jul 2024;100(1):116-121. doi:10.1016/j.gie.2024.02.009

25. DeWitt J, McGreevy K, Schmidt CM, Brugge WR. EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc. Oct 2009;70(4):710-23. doi:10.1016/j.gie.2009.03.1173

26. DiMaio CJ, DeWitt JM, Brugge WR. Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions. Pancreas. Jul 2011;40(5):664-8. doi:10.1097/MPA.0b013e3182128d06

27. Oh HC, Seo DW, Song TJ, et al. Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. Gastroenterology. Jan 2011;140(1):172-9. doi:10.1053/j.gastro.2010.10.001

28. Oh HC, Seo DW, Kim SH, Min B, Kim J. Systemic effect of endoscopic ultrasonography-guided pancreatic cyst ablation with ethanol and paclitaxel. Dig Dis Sci. Jul 2014;59(7):1573-7. doi:10.1007/s10620-014-3037-2

29. Levy MJ, Thompson GB, Topazian MD, Callstrom MR, Grant CS, Vella A. US-guided ethanol ablation of insulinomas: a new treatment option. Gastrointest Endosc. Jan 2012;75(1):200-6. doi:10.1016/j.gie.2011.09.019

30. Lakhtakia S. Therapy of Pancreatic Neuroendocrine Tumors: Fine Needle Intervention including Ethanol and Radiofrequency Ablation. Clin Endosc. Nov 2017;50(6):546-551. doi:10.5946/ce.2017.167

31. Levy MJ, Alberts SR, Bamlet WR, et al. EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer. Gastrointest Endosc. Jul 2017;86(1):161-169. doi:10.1016/j.gie.2016.11.014

32. Garg R, Mohammed A, Singh A, et al. EUS-guided radiofrequency and ethanol ablation for pancreatic neuroendocrine tumors: A systematic review and meta-analysis. Endosc Ultrasound. 2022;11(3):170-185. doi:10.4103/EUS-D-21-00044

33. Zhang L, Tan S, Huang S, et al. The safety and efficacy of endoscopic ultrasound-guided ablation therapy for solid pancreatic tumors: a systematic review. Scand J Gastroenterol. Sep 2020;55(9):1121-1131. doi:10.1080/00365521.2020.1797870

34. Attila T, Adsay V, Faigel DO. The efficacy and safety of endoscopic ultrasound-guided ablation of pancreatic cysts with alcohol and paclitaxel: a systematic review. Eur J Gastroenterol Hepatol. Jan 2019;31(1):1-9. doi:10.1097/MEG.0000000000001297

35. de Jong K, Nio CY, Hermans JJ, et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clin Gastroenterol Hepatol. Sep 2010;8(9):806-11. doi:10.1016/j.cgh.2010.05.017

36. Romutis S, Brand R. Burden of New Pancreatic Cyst Diagnosis. Gastrointest Endosc Clin N Am. Jul 2023;33(3):487-495. doi:10.1016/j.giec.2023.03.001

37. Chang YR, Park JK, Jang JY, Kwon W, Yoon JH, Kim SW. Incidental pancreatic cystic neoplasms in an asymptomatic healthy population of 21,745 individuals: Large-scale, single-center cohort study. Medicine (Baltimore). Dec 2016;95(51):e5535. doi:10.1097/MD.0000000000005535

38. Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL. Cystic neoplasms of the pancreas. N Engl J Med. Sep 16 2004;351(12):1218-26. doi:10.1056/NEJMra031623

39. Karoumpalis I, Christodoulou DK. Cystic lesions of the pancreas. Ann Gastroenterol. 2016;29(2):155-61. doi:10.20524/aog.2016.0007

40. Stark A, Donahue TR, Reber HA, Hines OJ. Pancreatic Cyst Disease: A Review. JAMA. May 03 2016;315(17):1882-93. doi:10.1001/jama.2016.4690

41. Abdelkader A, Hunt B, Hartley CP, Panarelli NC, Giorgadze T. Cystic Lesions of the Pancreas: Differential Diagnosis and Cytologic-Histologic Correlation. Arch Pathol Lab Med. Jan 2020;144(1):47-61. doi:10.5858/arpa.2019-0308-RA

42. Choi SH, Park SH, Kim KW, Lee JY, Lee SS. Progression of Unresected Intraductal Papillary Mucinous Neoplasms of the Pancreas to Cancer: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. Oct 2017;15(10):1509-1520.e4. doi:10.1016/j.cgh.2017.03.020

43. Servin-Rojas M, Fong ZV, Fernandez-Del Castillo C, et al. Identification of high-risk features in mucinous cystic neoplasms of the pancreas. Surgery. May 2023;173(5):1270-1274. doi:10.1016/j.surg.2023.01.011

44. Youssef FF, Liu L, Lin W, et al. Pancreatic cyst features predict future development of pancreatic cancer: results of a nested case-control study. Gastrointest Endosc. Feb 2024;99(2):262.e1-262.e9. doi:10.1016/j.gie.2023.10.038

45. Pai M, Habib N, Senturk H, et al. Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors. World J Gastrointest Surg. Apr 27 2015;7(4):52-9. doi:10.4240/wjgs.v7.i4.52

46. Gan SI, Thompson CC, Lauwers GY, Bounds BC, Brugge WR. Ethanol lavage of pancreatic cystic lesions: initial pilot study. Gastrointest Endosc. May 2005;61(6):746-52. doi:10.1016/s0016-5107(05)00320-2

47. Papaefthymiou A, Johnson GJ, Maida M, et al. Performance and Safety of EUS Ablation Techniques for Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis. Cancers (Basel). May 05 2023;15(9)doi:10.3390/cancers15092627

48. Moyer MT, Sharzehi S, Mathew A, et al. The Safety and Efficacy of an Alcohol-Free Pancreatic Cyst Ablation Protocol. Gastroenterology. Nov 2017;153(5):1295-1303. doi:10.1053/j.gastro.2017.08.009

49. Cho SH, Seo DW, Oh D, Song TJ, Lee SK. Long-Term Outcomes of Endoscopic Ultrasound-Guided Ablation vs. Surgery for Pancreatic Cystic Tumors. Clin Gastroenterol Hepatol. Aug 2024;22(8):1628-1636.e4. doi:10.1016/j.cgh.2024.03.021

50. Muthusamy VR, Chandrasekhara V, Acosta RD, et al. The role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms. Gastrointest Endosc. Jul 2016;84(1):1-9. doi:10.1016/j.gie.2016.04.014

51. Society AC. Cancer Facts and Figures 2024. Atlanta: American Cancer Society; 2024.

52. Alshareefy Y, Cummins S, Mazzoleni A, et al. A review of functional pancreatic neuroendocrine tumors: Exploring the molecular pathogenesis, diagnosis and treatment. Medicine (Baltimore). Nov 17 2023;102(46):e36094. doi:10.1097/MD.0000000000036094

53. Eloubeidi MA, Decker GA, Chandrasekhara V, et al. The role of endoscopy in the evaluation and management of patients with solid pancreatic neoplasia. Gastrointest Endosc. Jan 2016;83(1):17-28. doi:10.1016/j.gie.2015.09.009

54. Khanna L, Prasad SR, Sunnapwar A, et al. Pancreatic Neuroendocrine Neoplasms: 2020 Update on Pathologic and Imaging Findings and Classification. Radiographics. 2020;40(5):1240-1262. doi:10.1148/rg.2020200025

55. Grozinsky-Glasberg S, Mazeh H, Gross DJ. Clinical features of pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. Aug 2015;22(8):578-85. doi:10.1002/jhbp.226

56. McCall CM, Shi C, Cornish TC, et al. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol. Nov 2013;37(11):1671-7. doi:10.1097/PAS.0000000000000089

57. Kloppel G, Couvelard R, Hruban  R, et al. Who classification of tumours of endocrine organs. Lyon, France: World Health Organization; 2017.

58. Akirov A, Larouche V, Alshehri S, Asa SL, Ezzat S. Treatment Options for Pancreatic Neuroendocrine Tumors. Cancers (Basel). Jun 14 2019;11(6)doi:10.3390/cancers11060828

59. Khoury T, Sbeit W, Fusaroli P, et al. Safety and efficacy of endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine neoplasms: Systematic review and meta-analysis. Dig Endosc. Apr 2024;36(4):395-405. doi:10.1111/den.14681

60. Imperatore N, de Nucci G, Mandelli ED, et al. Endoscopic ultrasound-guided radiofrequency ablation of pancreatic neuroendocrine tumors: a systematic review of the literature. Endosc Int Open. Dec 2020;8(12):E1759-E1764. doi:10.1055/a-1261-9605

61. Lakhtakia S, Ramchandani M, Galasso D, et al. EUS-guided radiofrequency ablation for management of pancreatic insulinoma by using a novel needle electrode (with videos). Gastrointest Endosc. Jan 2016;83(1):234-9. doi:10.1016/j.gie.2015.08.085

62. Oleinikov K, Dancour A, Epshtein J, et al. Endoscopic Ultrasound-Guided Radiofrequency Ablation: A New Therapeutic Approach for Pancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab. Jul 01 2019;104(7):2637-2647. doi:10.1210/jc.2019-00282

63. Marx M, Trosic-Ivanisevic T, Caillol F, et al. EUS-guided radiofrequency ablation for pancreatic insulinoma: experience in 2 tertiary centers. Gastrointest Endosc. Jun 2022;95(6):1256-1263. doi:10.1016/j.gie.2021.11.045

64. Borrelli de Andreis F, Boškoski I, Mascagni P, et al. Safety and efficacy of endoscopic ultrasound-guided radiofrequency ablation for pancreatic insulinoma: A single-center experience. Pancreatology. Aug 2023;23(5):543-549. doi:10.1016/j.pan.2023.05.004

65. Jürgensen C, Schuppan D, Neser F, Ernstberger J, Junghans U, Stölzel U. EUS-guided alcohol ablation of an insulinoma. Gastrointest Endosc. Jun 2006;63(7):1059-62. doi:10.1016/j.gie.2005.10.034

66. Yan Z, Zhu C, Wu X, et al. A single-center experience on endoscopic ultrasonography-guided ethanol ablation of insulinomas. Pancreatology. Jan 2023;23(1):98-104. doi:10.1016/j.pan.2022.12.007

67. So H, Ko SW, Shin SH, et al. Comparison of EUS-guided ablation and surgical resection for nonfunctioning small pancreatic neuroendocrine tumors: a propensity score-matching study. Gastrointest Endosc. Apr 2023;97(4):741-751.e1. doi:10.1016/j.gie.2022.11.004

68. Matsumoto K, Kato H, Itoi T, et al. Efficacy and Safety of Endoscopic Ultrasonography-Guided Ethanol Injections of Small Pancreatic Neuroendocrine Neoplasms: a prospective, multicenter study. Endoscopy. Oct 25 2024;doi:10.1055/a-2452-4607

69. Blackford AL, Canto MI, Dbouk M, et al. Pancreatic Cancer Surveillance and Survival of High-Risk Individuals. JAMA Oncol. Aug 01 2024;10(8):1087-1096. doi:10.1001/jamaoncol.2024.1930

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71. Conroy T, Castan F, Lopez A, et al. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial. JAMA Oncol. Nov 01 2022;8(11):1571-1578. doi:10.1001/jamaoncol.2022.3829

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73. Arcidiacono PG, Carrara S, Reni M, et al. Feasibility and safety of EUS-guided cryothermal ablation in patients with locally advanced pancreatic cancer. Gastrointest Endosc. Dec 2012;76(6):1142-51. doi:10.1016/j.gie.2012.08.006

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BOOK REVIEWS

Mind Your Gut: The Science-Based, Whole-Body Guide to Living Well with IBS 

January 2025 • Volume XLIX, Issue 1

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Kate Scarlata MPH, RDN and Megan 
ISBNs:978-0-306-83233-8 
Pages: 370 pages (hardcover) 
Hatchette Book Group, 
New York, New York 

 “Mind Your Gut” written by Kate Scarlata MPH, RDN and Megan Riehl PsyD is a book produced for patients who deal with irritable bowel syndrome (IBS). The two authors have extensive experience in managing clinical issues involving the “brain-gut axis” especially in the realm of dietary and behavioral interventions. 

The book is divided into 10 chapters, 2 appendices, and a resource page. The book starts with explaining theories of the brain-gut axis in the setting of IBS followed by a description of the “FODMAP” (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet. The section explaining food allergies is well written and has the potential to prevent patients with IBS from assuming that many or all gastrointestinal (GI) symptoms are due to some type of allergy. 

The book proceeds with a wonderful description of cognitive behavioral therapy with easy-to-do exercises to help patients with IBS have reduction of their GI symptoms. After this section, further chapters describe the FODMAP diet in detail including how to do appropriate menu-planning in the setting of IBS and how to make “sane food choices.” The chapters that describe the risks of avoidant/restrictive food intake disorder, orthorexia, as well as other food intake disorders are very well written and will help patients with IBS to be aware of and to prevent such conditions from occurring. The section on the benefits and disadvantages of proceeding with diets that promote a “healthy microbiome” are helpful and do point out that the American College of Gastroenterology does not recommend using probiotics for IBS. Of note, the American Gastroenterological Association has parallel recommendations. Although probiotics and prebiotics may be beneficial in the setting of IBS in some patients, the authors are extremely clear that such interventions may make GI symptoms worse. 

The book then goes into detail about GI conditions that can overlap or be confused with IBS. Such conditions include celiac disease, disaccharidase deficiencies, small intestinal bacterial overgrowth and many other disorders. The GI disease descriptions are written well enough to be potentially used as patient handouts in a GI clinic. 

Finally, the book ends with extensive recipes to prevent IBS symptoms (Appendix I), coping resources while preparing for a colonoscopy (Appendix II), and a wonderful resource section for further information. 

I would recommend this book highly as a resource for patients with IBS who need further appropriate educational resources. This book stands out as an asset for correct information in a world filled with frequent medical falsehoods and pseudo-science, especially in the setting of IBS. The book also is a great educational resource for gastroenterology fellows, dietician students, and psychology students wanting to learn more about non-pharmacologic treatments of IBS. 

John F. Pohl MD, Professor of Pediatrics 

Division of Pediatric Gastroenterology 

Primary Children’s Hospital 

University of Utah 

Salt Lake City, Utah 

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FROM THE PEDIATRIC LITERATURE

Population Screening for Biliary Atresia

January 2025 • Volume XLIX, Issue 1

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Biliary atresia (BA) is a progressive, obstructive cholangiopathy which is the leading cause of liver transplantation in children. Early detection of BA is essential as a Kasai hepatoportoenterostomy (“Kasai procedure”) can slow progression of hepatic fibrosis associated with BA which potentially allows a patient to be older when liver transplantation is needed. The Kasai procedure is most beneficial when performed before 45 days of age. Thus, it should be of utmost importance to develop accurate population screening methods allowing for the early diagnosis of BA. The authors of this study evaluated the feasibility of a BA screening program at a large United States Intermountain West healthcare system.

The authors utilized data from 4 of the 33 included healthcare system hospitals over a 15-month period. Newborns born 35 weeks or older and who were admitted to the newborn nursery were included, and all infants admitted to the newborn intensive care unit (NICU) were excluded. Infants who were supposed to undergo total bilirubin level serum testing had their orders modified to include a fractionated bilirubin level which included a direct bilirubin level. Any infant with an elevated direct bilirubin level was identified, and the parents or the child’s primary care provider subsequently was contacted so that consent could be obtained to check a second fractionated bilirubin level. All infants with a second elevation of the direct bilirubin level were then referred to the pediatric hepatology clinic at the tertiary children’s hospital involved in this study. A direct bilirubin level was considered elevated if it was ≥ 0.6 mg/dL.

In total, 12,276 newborns were eligible for this study, and 98.2% of these infants (12,055) underwent direct bilirubin testing. An elevated direct bilirubin level was identified in 100 infants for which 6 were excluded due to either underlying medical or social issues. Another 4 infants were lost to follow up. The remaining 90 infants were available to be screened with a second fractionated bilirubin level. The families of 70 infants could not be contacted or declined study participation. The primary care physicians of these infants were contacted so that follow-up fractionation of the total bilirubin level could be recommended. Only 20 infants underwent actual second screening of their direct bilirubin level for which an elevated direct bilirubin level was still present in 15 infants. Those 15 infants were evaluated by pediatric hepatology, and no BA cases were identified.

There was no statistically significant difference in sex or birthweight between infants with normal and elevated direct bilirubin levels although infants with an estimated gestational age greater than 39 weeks were significantly more likely to have an elevated direct bilirubin level. The authors note that during the study period, two newborns born at participating study hospitals were eventually diagnosed with BA. However, both infants had been admitted to the NICU and initially were excluded from study participation.

Although this feasibility study did not identify any newborn infants with BA, it did demonstrate the potential for BA screening in a large healthcare system. The study process used to screen for BA has the potential to be applied in other healthcare systems as well as with state newborn screening.

Guthery S, Jensen M, Esplin M, O＊Brien E, Krong J, Srivastava R.  Feasibility of biliary atresia newborn screening in an integrated health network.  Journal of Pediatric Gastroenterology and Nutrition 2024; 79: 954-961.

Long-Term Outcomes in Pediatric Ulcerative Proctitis

Ulcerative proctitis in children is a variant of ulcerative colitis, but unlike the adult population, treatment guidelines for pediatric ulcerative proctitis are not clear. The authors of this study performed a retrospective study to determine the disease course and treatment outcomes for pediatric patients with ulcerative proctitis.

Data from this study came from 10 pediatric treatment centers throughout Japan during the period between 2013 and 2022. All included patients were under 18 years of age and had a diagnosis of ulcerative colitis. Patients with inflammatory bowel disease (IBD) unclassified, monogenic IBD, and no IBD follow up were excluded. Patient demographics, clinical course, laboratory testing, and treatments for ulcerative proctitis were determined. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and the partial Mayo Endoscopic Score were utilized to assess disease. Ulcerative colitis was diagnosed per the Revised Porto Criteria, and ulcerative proctitis was defined as inflammation present from the rectosigmoid region extending to the anorectal junction.

A total of 54 patients were included in the study.  The median age at diagnosis was 12 years, and 44% of patients were male. Median PUCAI at time of diagnosis was 20 (remission score was considered less than 10) with 62% of patients having a partial Mayo Endoscopic Score of 2 at diagnosis. The authors noted that C-reactive protein and albumin levels were typically normal at time of ulcerative proctitis diagnosis. The most common treatment after initial diagnosis was 5-aminosalicylic acid therapy (5-ASA) given as a suppository (40%). Oral 5-ASA therapy was used in 20% of patients while a combination of oral 5-ASA and topical 5-ASA therapy (suppository or enema) was used in 25% of patients. Long-term disease remission occurred in 95% of patients (62% during initial therapy) although 93% of patients required modification of therapy. Nonadherence to therapy occurred in 39% of patients.

Control of ulcerative proctitis symptoms using 5-ASA therapy monotherapy occurred in 63% of cases while 30% of patients had disease remission followed by symptom breakthrough requiring immunosuppression therapy. No initial disease remission with a subsequent need for immunosuppression occurred in 7% of cases. Patients requiring immunosuppression were statistically more likely to require more colonoscopies, have inflammation extending above the peritoneal reflection or rectosigmoid region, or have inflammation eventually extending past the left side of the colon compared to patients who responded to 5-ASA monotherapy. Patients who were unable to achieve disease remission after 3 months were more likely to require biologic therapy.

This study demonstrates that 5-ASA therapy appears to control ulcerative proctitis in most pediatric patients. However, disease extension, need for frequent diagnostic colonoscopies, and prolonged time to disease remission appear to be risk factors for requiring a step up in medical therapy. This study occurred in Japan, and similar studies are needed in other countries to see if similar outcomes to therapy exist in pediatric patients with ulcerative proctitis internationally.

Miyazawa A, Nambu R, Shimizu H, Kudo T, Nishizawa T, Kumagai H, Hagiwara S, Kaji E, Mizuochi T, Kurasawa S, Kakuta F, Ishige T, Shimizu T, Iwama I, Arai K. Long-term course and prognostic factors in pediatric ulcerative proctitis: a multicenter cohort study. Inflammatory Bowel Disease 2024; izae266.doi: 10.1093/ibd/izae266. Online ahead of print.


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