Nutrition Reviews in Gastroenterology, SERIES #21

Exploring the Role of Vitamin C in Gastrointestinal Function and Disorders

February 2025 • Volume XLIX, Issue 2
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).

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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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12. Thosani N, Cen P, Rowe J, et al. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) for advanced pancreatic and periampullary adenocarcinoma. Sci Rep. Oct 03 2022;12(1):16516. doi:10.1038/s41598-022-20316-2

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

70. Park W, Chawla A, O’Reilly EM. Pancreatic Cancer: A Review. JAMA. Sep 07 2021;326(9):851-862. doi:10.1001/jama.2021.13027

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

72. Słodkowski M, Wroński M, Karkocha D, Kraj L, Śmigielska K, Jachnis A. Current Approaches for the Curative-Intent Surgical Treatment of Pancreatic Ductal Adenocarcinoma. Cancers (Basel). Apr 30 2023;15(9)doi:10.3390/cancers15092584

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

74. Song TJ, Seo DW, Lakhtakia S, et al. Initial experience of EUS-guided radiofrequency ablation of unresectable pancreatic cancer. Gastrointest Endosc. Feb 2016;83(2):440-3. doi:10.1016/j.gie.2015.08.048

75. Scopelliti F, Pea A, Conigliaro R, et al. Technique, safety, and feasibility of EUS-guided radiofrequency ablation in unresectable pancreatic cancer. Surg Endosc. Sep 2018;32(9):4022-4028. doi:10.1007/s00464-018-6217-x

76. Oh D, Seo DW, Song TJ, Park DH, Lee SK, Kim MH. Clinical outcomes of EUS-guided radiofrequency ablation for unresectable pancreatic cancer: A prospective observational study. Endosc Ultrasound. 2022;11(1):68-74. doi:10.4103/EUS-D-21-00049

77. Robles-Medranda C, Del Valle R, Puga-Tejada M, et al. Assessing EUS-guided radiofrequency ablation in unresectable pancreatic ductal adenocarcinoma: a single-center historic cohort study. Gastrointest Endosc. Aug 2024;100(2):250-258. doi:10.1016/j.gie.2024.03.023

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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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Nutrition Reviews in Gastroenterology

Thank You to the 2024 Peer Reviewers of the Nutrition Reviews in Gastroenterology Series

January 2025 • Volume XLIX, Issue 1
Neha D. Shah,Elizabeth Wall

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We extend our sincere appreciation to the reviewers of the 2024 Nutrition Reviews in Gastroenterology series for their thoughtful and scholarly critique of manuscripts.

Their expertise, time and thoughtful contributions are vital to the scientific publication process.

We thank:

Jami Baltz, MS, RD-AP, CNSC
Amanda Bode, RDN, LDN
Stacey Collins, MA, RDN/LD
Amanda Dixon, RD
Shanti L. Eswaran, MD
Carol Ireton-Jones, PhD, RDN,
CNSC, FASPEN, FAND 
Nancee Jaffe, MS, RD
Kian Keyashian, MD 
Vanessa Kumpf, PharmD, BCNSP
Amanda Leonard, MPH, RD, LD, CDE
Mary Marian, DCN, RDN, CSO, FAND
Dejan Micic, MD
Christianna Moran, MS, RDN
Stacy Pelekhaty, MS, RD
Maitreyi Raman, MD, MSc,
FRCPC, CAGF
Brittany Roman-Green, MS, RD, CPT
Naureen Sajwani, MS, RD, CNSC 
Pooja Singhal, MD
Irene Sonu, MD
Adam Stein, MD
Shelby Yaceczko, DCN, RDN-AP, CNSC
Coka Yip, DNP

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SPECIAL ARTICLE

The Sphinx and Sphincters of the Gastrointestinal Tract: A Clinical Review

January 2025 • Volume XLIX, Issue 1
Theja V. Channapragada,C.S. Pitchumoni

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The term ‘sphincter’ likely  has its origin in the legendary Sphinx (or sphynx), a prominent mythological figure in Egyptian and Greek mythology, a creature with the body of a lion and the head of a human that terrorized the people by demanding the trespassers to answer a riddle. Unlike the mythological Sphinx, which has a negative connotation, the sphincters in the human body are physiologically beneficial and needed to prevent several disorders. Of the sphincters in the gastrointestinal tract, several are made up of smooth muscle (lower esophageal, pyloric, sphincter of Oddi, ileocecal and internal), and striated muscle (upper esophageal and external anal sphincters). Sphincteric structure (striated or smooth muscle) and functions vary depending on the location. The individual dysfunctions are the pathophysiological basis of several common gastrointestinal disorders, such as transfer and transit/oropharyngeal dysphagia, gastroesophageal reflux disease (GERD), gastroparesis, pancreaticobiliary functional pain syndromes (sphincter of Oddi dysfunctions), small intestinal bacterial overgrowth (SIBO) and frequent constipation syndromes.

Introduction

Galen, the esteemed Greek physician of 129 CE, is credited with the first use of the term “sphincter,” meaning “band” or “lace.” A sphincter is a ring-like muscle that surrounds a lumen, regulating the flow of liquids, solids, or gases, which can contract or relax, shorten, or lengthen the lumen. Sphincters are classified as anatomical or functional, composed of smooth or striated muscle, voluntarily or involuntarily in regulation and they play a critical role in compartmentalization and directional movement in the gastrointestinal tract. The upper esophageal sphincter (UES), lower esophageal sphincter (LES), pyloric sphincter (PS), ileocecal sphincter (IS), the sphincter of Oddi (SO), and the external and internal anal (EAS & IAS) are the main sphincters of the gastrointestinal tract. The present review of the gastrointestinal tract sphincters (GIS) meant for clinicians summarizes the available data on the structure, function, and disorders. While discussing the individual sphincters, the role of the surrounding structures cannot be ignored.

Upper Esophageal Sphincter (UES) 

Structure

The UES is a tonically active sphincter made up of several striated muscles, including the cricopharyngeus (CP), inferior pharyngeal constrictor (IPC), and the longitudinal fibers of the cervical esophagus. The CP comprises the majority of the posterior and lateral portions of the lower third UES. The Killian’s Triangle is located between the transverse fibers of the CP and the oblique fibers of the lower inferior constrictors. The glossopharyngeal (CN IX), vagus nerve (CN X), and its branches are the predominant nerves that supply the region. Acetylcholine is the neurotransmitter involved in the efferent pathway.1,2

Physiology

The UES is involved in various actions, such as swallowing, belching, retching, vomiting, and changes in respiration.1,2 The physiology of swallowing is a complex process that involves the coordinated efforts of various muscles in the oropharynx and the esophagus, including the sphincter regions of the UES and LES, to move food from the mouth into the stomach. When food is being swallowed, the nuclei of the brainstem that control the UES are inhibited, leading to a decrease in UES pressure. As a result, the UES opens to allow the passage of food. During belching, rumination, vomiting, and regurgitation, the UES permits a retrograde transportation of food, fluid, or air. To open the UES during swallowing, the CP relaxes, and the suprahyoid muscle contract, allowing for efficient opening.1 The stylopharyngeus muscle also shortens, widening the transverse diameter of the UES, while the infrahyoid muscle pulls the anterior wall forward for protection against aspiration. After the food passes through, the CP muscle returns to a contracted state and closes the UES. In the process of swallowing, in addition to the vagus and glossopharyngeal nerves, trigeminal (CN V), facial (VII), and hypoglossal nerves (XII) are involved. The factors influencing the resting UES pressure are tabulated in Table 1. 

The UES pressure is impacted by its unique anatomy and physiology, which makes analyzing pressure difficult using traditional manometric systems. The recently available high-resolution manometry (HRM) that replaced the fluid-filled channels of traditional manometer has solid-state circumferential sensors which are closely spaced and can capture UES contractile and relaxation states more accurately.9 The pressure varies from 35 to 200 mm Hg in HRM studies. HRM is being utilized for a variety of UES disorders which include cricopharyngeal (CP) dysphagia, Zenker diverticulum, and globus. Few studies have evaluated UES function after stroke/neurological disorders with HRM.9

Clinical Disorder(s): Pathogenesis, Diagnosis, and Management

Globus pharynegeus (GP) is a recurrent sensation of a lump or tightness in the throat unrelated to swallowing or pain. Per Rome IV criteria, the sensation must occur between meals, and there must be no evidence of dysphagia or odynophagia, gastric inlet patch, gastroesophageal reflux, or eosinophilic esophagitis. The symptoms must have been present for at least three months, with symptom onset at least six months prior to diagnosis with a frequency of at least once a week.10 Additionally, major esophageal motor disorders such as achalasia/EGJ outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, and absent peristalsis must be absent.11

Temporary relief may be achieved by swallowing several times. The etiology is unclear. The risk factors considered in GP are stress factors, dysfunctional UES pressure, laryngopharyngeal reflux (LPR), conditions causing irritation or inflammation of the pharynx, and hypertrophy of the base of the tongue. 

Globus is a possible esophageal disorder associated with GERD symptoms, but the role of GERD in causing globus is unclear. Previous studies have shown mixed results, with some finding GERD as a major cause of globus symptoms and others not finding a significant association.11 This may contradict the new guidelines observed in Rome IV. Globus symptoms may be associated with dysfunctional UES findings. Diagnostic methods such as neck ultrasound, video fluorography, and endoscopy are not useful in diagnosis or management. The utility of HRM is limited. There is not a specific treatment for Globus, but when warranted, an ENT examination to rule out neoplasm may be appropriate. Cognitive behavioral therapy and speech-language therapy may also assist with managing symptoms.

Cricopharyngeal dysphagia (CD), also referred to as transfer dysphagia or oropharyngeal dysphagia can lead to various symptoms such as globus sensation, coughing or choking while attempting to swallow solid or liquids, aspiration, odynophagia, regurgitation, fear of eating, avoiding social dining situations, and recurrent aspiration pneumonia. CD can occur due to either neuromuscular disorders or mechanical impairment of the UES. The underlying pathophysiology involves the failure of the cricopharyngeus muscle to relax and open during the initiation of swallowing, leading to difficulties in transferring the food bolus. Cerebrovascular accidents involving cranial nerves and associated brainstem nuclei V, VII, IX, X, and XII lead to impairment of muscle UES function, further leading to CD.12,13

During a videofluoroscopic examination, a cricopharyngeal bar or cricopharyngeal achalasia can be observed as a posterior impression on the esophagus, typically located at the C5 or C6 level. A CP bar refers to the enlargement or hypertrophy of the cricopharyngeal muscle. This bar-like structure may partially obstruct the UES passage.14 CP bar is a radiographic discovery found in around 5% to 19% of elderly individuals who undergo a barium upper gastrointestinal series.14  Among these patients, approximately 13% may experience dysphagia.14 

In older adults, there may be a decline in the relaxation and flexibility of the UES, making swallowing more challenging and aspiration frequent. There might be a delay in initiating the swallowing process in the throat, a shorter duration of the swallowing action, and a reduced opening time of the CP.15,16 Age-related changes can lead to prolonged clearance times and potential exposure of the larynx, particularly in elderly patients with dysfunctional UES or swallowing mechanisms.16,17 

Factors that Increase UES PressureFactors that Decrease UES Pressure
Awaking
Phonation
Posture
Esophageal secondary peristalsis
Increase in intraabdominal pressure
Stress
Gastroesophageal reflux (GERD)		Sleeping
Swallowing
Belching
Vomiting
Exhalation
Elderly
Table 1. Factors Contributing to UES Pressure3–8

Multiple treatment options are available for CD. One of these options is botulinum toxin injection, which is a popular and preferred option for treatment due to its low-risk and cost-effective profile compared to surgery.12 The success rates of botulinum toxin injection are slightly lower (69%) compared to myotomy (78%).18 Treatment of CP dysphagia secondary to stroke does not focus on managing the UES dysfunction alone but using functional therapy to assist in triggering the components of the swallowing reflex. 

Zenker’s (pharyngoesophageal) diverticulum (ZD), named after the German Pathologist Friedrich Albert Von Zenker (1825-1898) in 1877, is the herniation of hypopharyngeal mucosa into the anatomical muscular weakness of the Killian’s Triangle due to the dysregulated contraction of pharyngeal muscles. The prevalence of ZD is 1.8-2.3% of patients with dysphagia who have a radiographic examination, highest in elderly populations in the seventh and eighth decades. Patients may have a sensation of a lump in the throat with mucous build-up. The associated symptoms include dysphagia to liquids and eventually solids, halitosis, aspiration episodes, cough, food regurgitation, or rarely weight loss.19 Modified barium swallow assists with the definitive diagnosis. HRM can reveal elevated residual UES pressures.20 In symptomatic patients, surgical options include diverticulectomy, diverticulotopexy, and myotomy. Endoscopic cricopharyngeal myotomy is becoming increasingly available in tertiary care centers.19 

Lower Esophageal Sphincter

Structure

The primary function of the LES is to prevent the regurgitation of gastric contents back into the esophagus and allow the coordinated passage of food or fluid into the stomach. In addition, the LES allows for the venting of gas after meals, permitting belching.21 The LES spans 3-4 cm in length and is composed of intrinsic and extrinsic muscles. The LES should be considered in the context of the gastroesophageal junction (GEJ), an anatomically complex anti-reflux barrier. As a result of recent studies, it has been noted that the LES is only a part of the mechanism of GEJ, with several participants.22 The GEJ is the anatomical region, and the LES refers to the structures contributing to barrier function.22  The GEJ is defined by the Z line, which demarcates the termination of the esophageal mucosa (squamous) and the beginning of the gastric mucosa (columnar). The distal margin of the LES is situated about 2 cm below the Z line. Consideration of the components of the GEJ in the process of swallowing and the prevention of reflux is important rather than attributing all the functions solely to LES, as was done in the past. 

The components of the GEJ involve 1) the sphincter itself, 2) the subdiaphragmatic segment of the esophagus, 3) the phrenoesophageal ligament, and 4) the acute angle of His (the angle of entry of the esophagus into the stomach).22,23 The diaphragm is critical to maintaining the GEJ competence; the hiatus in the diaphragm is formed by a loop of muscle, the right crus. The hiatus allows for the passage of the esophagus, vagal trunks, and blood vessels. The phrenoesophageal ligament is a circumferential connecting ligament that creates a union with the right crus to the structures passing through the hiatus. The ligament connects with the GEJ, causing brief shortening of the esophagus and superior displacement of the GEJ during swallowing. The phrenoesophageal ligament aids in keeping the LES intraabdominal. During inspiration, the right crus of the diaphragm contracts causing pressure to be applied to the esophagus proximal to the GEJ, leading to contraction of the intrinsic muscles. During periods of high abdominal pressure, the barrier function of the GEJ is maintained through this mechanism. The right portion of the GEJ is created by the angle of his. The angle of His is a union between the gastric cardia and distal esophagus which functions as a pinchcock to inhibit gastric reflux into the esophagus. 

The LES receives innervation from the autonomic nervous system, specifically through parasympathetic (vagus) and sympathetic (splanchnic) inputs. Sensory signals from the LES are transmitted to the NTS through vagal sensory afferents, while vagal motor efferents originating from the preganglionic fibers of the dorsal motor nucleus project back down to the LES.24

Physiology

The components of GEJ participate in maintaining the tone of the LES. Resting tone in normal individuals ranges from 10 to 30 mm Hg compared to intragastric pressure, with the greatest pressure readings at night.23 This tone is achieved through a combination of transmitted intra-abdominal/thoracic pressures, passive muscle recoil, and active tone.21,23 During a swallow, the LES contracts to prevent reflux, and this contraction persists for a short period of time after swallowing due to the inhibitory pathway of the vagus nerve and postganglionic myenteric neurons that release nitric oxide. 

Frequent transient LES relaxations (TLESR) are often mentioned as the predominant factor in promoting reflux contents and symptoms of GERD. TLSESRs are spontaneous and independent relaxation of the LES and diaphragm that lasts anywhere from 10-60 seconds and are vagally mediated.21,23 TLESRs occur without an associated pharyngeal contraction or esophageal peristalsis and are triggered by gastric distention, particularly of the cardia. TLESRs are responsible for most reflux events in healthy individuals. TLSERs occur without pharyngeal contraction or esophageal peristalsis and can last longer than LES relaxations induced by swallowing. However, not all TLESRs cause reflux. They play a significant role in belching and can be increased by gastric distention. 

There is evidence for a myogenic basis of LES tone. Asoh and Goyal observed that the sphincter muscle shows a continuous electrical spike activity distinct from the esophageal body.24 The vagus nerve provides major inhibitory and excitatory innervation to the LES, with the sympathetic nerve minimally influencing LES tonic contraction and relaxation.25 The preganglionic fibers of the vagus nerve communicate with excitatory and inhibitory postganglionic myenteric neurons to innervate the LES smooth muscle. The preganglionic fibers release acetylcholine to the postganglionic fibers of the myenteric neurons. The postganglionic excitatory neurons release acetylcholine and substance P to cause constriction of the sphincter. The postganglionic inhibitory neurons release NO and lead to the relaxation of the LES, with neuronal nitric oxide synthase as a source of NO in the nerves. These inhibitory and excitatory nerves influence the myogenic tone of the LES. The lack of inhibitory innervation may lead to achalasia. Overactivity of the excitatory input can lead to hypertensive contraction of the LES at resting states.24

Several neurotransmitters and hormones influence the tone of the LES. LES tone is decreased by including nitric oxide (NO), vasoactive intestinal peptide (VIP), beta-adrenergic agonists, dopamine, possibly cholecystokinin (CCK), and secretin.23 On the other hand, substances like gastrin, alpha-adrenergic agonists, and muscarinic receptor agonists can increase LES tone. Other factors, such as peptides and hormones, may influence LES pressure, but the role in humans is not clear. Intraabdominal pressure and gastric distention also influence LES pressure. 

Clinical Disorder(s): Pathogenesis, Diagnosis, and Management

Gastrointestinal Esophageal Reflux Disease (GERD) GERD has been extensively discussed in numerous publications by several experts (Katz, Goyal, Spechler, Yadlapati, and others). This topic is summarized substantially to limit the size of this article. The underlying cause of GERD involves the malfunction of one or more components of the GEJ. Other factors which complement the pathogenesis of GERD include excessive TLESR, hiatal hernia, hyposalivation, and dysmotility, including defects in secondary peristalsis involved in acid clearing. Studies have investigated the mechanism of TLESRs and the increased prevalence of reflux events in GERD patients, highlighting differences in the compliance or gradients of the GEJ and the localization of the acid pocket on top of the meal.25–27 Acid pocket, defined by Kahrilas et al., is a relatively new term in the concept of the pathogenesis of GERD.28 Acid pocket is an area of accumulated unbuffered gastric acid in the proximal stomach after meals and serves as a reservoir of acid in GERD patients. From the acid pocket, there is upward migration of acid film that contributes to mucosal injury in the squamocolumnar junction. 

The role of several individual food items on LES is controversial in relation to GERD. In several studies, citrus and spicy food had little to no effect on LES pressure, although they are noted to exacerbate symptoms when esophagitis is present.29,30 The effect of caffeine on LES is variable. Alcohol, tobacco smoking, peppermint, high-fat foods, and chocolate influence the pathogenesis of GERD; in laboratory studies, these food items reduce LES tone. However, larger clinical trials are needed to investigate the association. 

GERD symptoms include heartburn which is substernal burning from the epigastrium toward the neck. Heartburn and regurgitation are the main symptoms of GERD, but symptoms of GERD are non-specific and can overlap with those of other disorders of the LES sphincter, such as achalasia.31

The management of GERD is well discussed in a recent practice guideline article by the ACG, which primarily involves controlling gastric acid secretion but is not directed toward the pathophysiology of the GEJ.31 There are no medications available to increase LES pressure or prevent frequent TLESR contractions. Prokinetic therapy with propusid, a 5-HT4 receptor agonist, increases LES sphincter pressure and promotes esophageal peristalsis while decreasing the pyloric sphincter.32 The medication is unpopular in the US due to its cardiac side effects but is used in several countries as a supplementary option to PPI in the management of GERD. Other prokinetics, such as metoclopramide, are shown to increase LES pressure in addition to enhanced peristalsis of the esophagus and improved gastric emptying. Baclofen is a GABAb agonist that can reduce TLESR, enabling reflux episodes, decreasing postprandial acid and non-acid reflux events, and belching episodes. 

Achalasia

The term achalasia was first used by Sir Arthur Hurst in 1927, derived from a Greek term meaning “lack of relaxation.” Primary achalasia is characterized by impaired relaxation of LES in response to swallowing and aperistalsis of the esophagus smooth muscle.33,34 The pathogenesis of primary achalasia involves the dysfunctional interplay of inhibitory neurotransmitters such as NO and VIP and excitatory neurotransmitters such as acetylcholine in the myenteric plexus, leading to increased LES pressure. Symptoms include progressive dysphagia from solids and liquid, and weight loss may be modest or non-existent.35,36

Secondary achalasia is characterized by the same symptoms but often of shorter duration, usually secondary to cardio-esophageal junctional cancer. Significant weight loss is a feature. Chagas disease, frequently seen in several parts of Central America, is due to infection by the parasite Trypanosoma cruzi. In Chagas disease, there is damage to the myenteric esophageal plexus leading to partial or absent LES relaxation accompanied by aperistalsis. As a result, there is the development of megaesophagus and megacolon in the gastrointestinal tract.37

To establish the diagnosis of achalasia, the standard procedures are barium esophagram, esophageal manometry, and endoscopy.33 The results are complementary and barium studies show a dilated esophagus with a classic bird beak sign. The main function of endoscopy is to exclude cardio esophageal junctional cancer by retroversion of the scope. Diagnosis of achalasia by HRM is the current standard gold test. Characterizing achalasia using Chicago classification subtypes is useful for the management of the patient.38 In all three subtypes, there is impaired GEJ relaxation with distinct esophageal pressurization and contraction. In types I and II, there is 100% failed peristalsis. Type I is characterized by the absence of pan esophageal pressurization to > 30 mm Hg. Achalasia type II is characterized by 100% failed peristalsis (aperistalsis) with pan-esophageal pressurization to > 30 mm Hg. Achalasia type III is characterized by spastic contractions because of abnormal lumen obliterating contractions with or without periods of pan-esophageal pressurization. Type I and II are associated with a good response to myotomy. Type III may require extensive myotomy. 

The goal of the treatment of achalasia is to reduce the hypertonicity of the LES, which can improve esophageal emptying. Treatment options include pharmacologic, endoscopic, and surgical.

Botulinum toxin blocks the excessive unopposed cholinergic stimulation of the LES and only affects the neurogenic component of the sphincter with no influence on the myogenic tone. The treatment results only in a 50% reduction of basal LES pressure with short-acting benefits.33  Botulinum toxin injection, however, is a therapy of choice for patients unfit for definitive surgical therapy such as pneumatic dilation or laparoscopic Heller myotomy (LHM).33 Pneumatic dilation (PD) uses a balloon dilator which opens the muscularis propria of LES, leading to symptomatic relief. Surgical myotomy involves the division of the muscle fibers of the LES, circular layer, without disruption of the mucosal layer.33 The recently available laparoscopic myotomy has decreased morbidity and faster recovery.

Hiatal Hernia (HH)

In the sliding type of HH, the LES is above the diaphragm reducing the function of the GEJ. In HH, there is a separation between the LES and crural diaphragm that can diminish the basal pressure of the GEJ and lead to a greater pressure gradient during relaxation, influencing the pathogenesis of GERD.23

Pyloric Sphincter

Structure

An excellent review by Ramkumar and Schulze provides clinically useful information on pyloric sphincter (PS).39 The gateway connecting the antrum of the stomach to the duodenum is known as the pyloric sphincter. The term “pylorus” comes from the Greek word “pylon,” which translates to “gatekeeper.” Essentially, the PS promotes forward flow from mechanical and chemical digestion (stomach) areas to the site of absorption of nutrients (duodenum and small intestine). The PS is a narrow zone 1cm wide, defined by thickened circular smooth muscle loops. 

The PS connects the antrum to the duodenum through the proximal pyloric loop (PPL) and distal pyloric loop (DPL), respectively.39 DPL is rich in connective tissue that influences resting PS diameter and resistance. PPL is located 2-3 cm above the pyloric opening near the greater curvature of the stomach. The DPL and PPL join at the lesser curvature of the stomach, forming a connective tissue and layer of fat known as the pyloric torus.39 The contraction of the DPL and the PPL controls the pyloric diameter. The distal corpus and pyloric antrum serve as peristaltic pumps. The entire segment contracts as a unit with the distal antrum.40 See Figure 3. 

Functionally the PS can be viewed in the context of other gastric segments. The fundus generates the tone, while the corpus and antrum process the food before emptying. The PS regulates the gastric emptying rate.41,42

The PS is under the influence of the autonomic nervous system. The vagus nerve supplies afferent and efferent signals from and to the pylorus. The afferents contain sensory nerve fibers, primarily stretch receptors, that respond to lower levels of a stretch compared to the antrum and proximal stomach. The parasympathetic nervous system, through CN X, causes the relaxation of the PS Motor fibers of vagal efferents and releases inhibitory responses through VIP and NO, leading to the relaxation of the sphincter. Several of these nerve fibers contain nitric oxide synthase (nNOS).43-45

The pylorus has an abundance of sympathetic nerve fibers. Through the greater and lesser splanchnic nerves from the celiac ganglion, the sympathetic nervous system causes constriction of the pylorus and the sphincter. Constriction of the pylorus is mediated by vagal efferent excitatory fibers that release acetylcholine. In addition, the pylorus has intrinsic innervation from the stomach’s myenteric plexus that extends through the pylorus into the duodenum, deeply integrating into the sphincter muscles and influencing contraction and relaxation.40 

One must review the gastric motor functions to understand the pyloric sphincter function since they share integrated processes. Smooth muscle cells (SMC) of the stomach, with connective tissue interspersed between, play a significant role in the trituration of food and gastric emptying.42 SMC are coupled by gap junctions and transmit electrical impulses to neighboring cells leading to the synchronicity of contractions.42 SMCs are coupled with the Interstitial Cells of Cajal (ICC) by gap junctions, which help regulate the stomach’s motor patterns. 

Physiology

The PS plays a vital role within the stomach’s migrating motor complex (MMC), a cyclical motor process that aims to eliminate undigested particles.40 The MMC encompasses four distinct phases. Phase 1, lasting 45-60 minutes, is characterized by slow waves independent of contraction. In Phase 2, slow waves occur with frequent phasic contractions. Phase 3, mediated by neural signals, involves contractions that persist for 5-15 minutes and move towards the pyloric sphincter, independent of slow waves. Throughout this process, the pylorus and duodenum remain relaxed and open, facilitating the movement of food remnants out of the stomach during phase III. In Phase 4, contractile activity is inhibited, merging with the subsequent phase of the digestive cycle. The absence of pyloric relaxation can result in gastric outlet obstruction. During the inter-digestive period, certain hormones such as motilin and ghrelin play a role in regulating the activity of gastric pumps and inhibition of PS contraction.40

Gastric emptying is a complex process that involves coordination from several intricate neuro-hormonal processes, from the smooth muscle cells, ICC, and parasympathetic and sympathetic nervous systems. The PS and duodenum function in a synchronized manner. Prior to gastric emptying, the terminal antrum and PS serve as grinders and filters, respectively.40 

During the digestive phase, the fundus of the stomach can hold large volumes of food without an increase in pressure, known as accommodation.40 In this filling phase, gastric smooth muscles are not contracted. Liquids leave the stomach much faster than solids. Solids that remain in the stomach then move to the antrum and become triturated into chyme of particles less than 2mm in size and leave 2-3 hours after a meal.46 Following the filling phase, a pumping phase is present with contraction of the fundus and increased peristaltic contractions in the antrum. Through this process, undigested food is mixed with gastric acid and pepsin, and the antrum is filled to a threshold prior to food entering the duodenum.40

The pylorus plays a major role in preventing the regurgitation of duodenal contents while regulating the emptying of chyme.39,40 Following stimulation from the pacemaker and activation of ICC, gastric motility begins. The peristaltic contraction from the fundus propels digested food and chyme from the proximal to the distal antrum, where the PS is relaxed. A small portion of chyme moves into a relaxed pylorus into the duodenum, with some chyme moving back into the proximal antrum. The peristaltic contraction becomes more vigorous and faster and reaches the terminal antrum, constricting the pylorus and restricting emptying. These contents are retropulsed back into the stomach leading to shearing forces that break down food particles into smaller pieces. The PS continues to be contracted and provides a sieve/filter function to reduce food particles to less than 2mm before emptying occurs. The contractions in the pylorus lead to an anterograde flow of chyme into the duodenum and a retrograde flow of food that escapes grinding.39,40,42 During the digestive period, PS can influence gastric emptying. Failure of the antral contractions or pyloric relaxation can decrease gastric emptying.42 

The soluble fiber in the diet influences gastric motility, creating a gel formation with liquid in the stomach, resulting in a substantial delay in gastric emptying.47 Slower gastric emptying is associated with lower postprandial blood glucose levels.47

Clinical Disorder(s): Pathogenesis, Diagnosis, and Management

Gastroparesis & the Pyloric Sphincter

Gastroparesis is a functional disorder defined by delayed gastric emptying without mechanical obstruction associated with nausea, vomiting, early satiety, bloating, and abdominal pain.48 While idiopathic gastroparesis is seen in 30% of cases, several etiologies contribute to symptoms ranging from neuromuscular diseases affecting the non-sphincter gastric muscles to post-surgical complications and pyloric dysfunction. Patients with gastroparesis may also have pyloric dysfunction. Pyloric dysfunction can consist of pylorospasm or intermittent contractions that cause increased baseline tone at the pylorus and sphincter. Diabetes contributes to the significant pathogenesis of gastroparesis. Patients with gastroparesis are found to have abnormal interstitial cells of Cajal and neuropathy of the myenteric plexus, leading to loss of gastric pacemaker activity. 

Diabetic gastroparesis patients are shown to have lower PS distensibility and higher pyloric sphincter pressures.48 Distensibility refers to an elastic tissue’s ability to stretch and expand in response to applied pressure.49 The term applies to ring-shaped sphincters compared to similar terms such as compliance, which refers to a hollow organ. PS distensibility is inversely correlated to gastric emptying, and studies have shown that pyloric distensibility was altered in 30-50% of patients with gastroparesis.48 

ModalityEffectComments
Prokinetic Agents: Erythromycin Metoclopramide *
Other medications in development include:
felcistetag (5-HT4 agonist)
tradipitant (NK1 antagonist)
relamorelin (ghrelin agonist)
trazpiroben
(dopamine D2/D3 receptor agonist)42		Erythromycin is a commonly used antibiotic that accelerates gastric emptying through activation of the MMC42 Metoclopramide, a peripheral cholinergic and antidopaminergic agent, peripherally improves gastric emptying and central action resulting in an anti-emetic effect54Erythromycin prokinetic effects are limited by tachyphylaxis42 Metoclopramide has serious central nervous system adverse effects, partially irreversible tardive dyskinesia54
Diet modificationAppropriate glycemic control, especially for patients with diabetes36  Avoidance of alcohol and tobacco Low fat, low soluble fiber diet of small portionsIncreased blood glucose can slow gastric emptying, especially in diabetics Alcohol and tobacco can modify gastric emptying Fat, soluble fiber, and large volume can slow gastric emptying 
Intrapyloric botulinum toxinNeurotoxic protein that leads to relief of pylorospasm & improvement of gastric emptying53No current systematic evidence  evaluating its effectiveness55
Surgical pyloroplastySurgery that widens the pylorus to promote short-term gastric emptying53No current randomized trials evaluating its effectiveness for gastroparesis53
Endoscopy pyloromyotomy
(G-Poem)		Division of the pylorus from the mucosal surface with incision of the circular muscular layer to improve gastric emptying56 More studies are needed to evaluate its effectiveness 
Gastric electrical stimulationDirect stimulation of the pacemaker to improve gastric emptying36No current systematic evidence evaluating its effectiveness36
Table 2. Treatment Modalities for Gastroparesis

Gastric emptying study using scintigraphy is an available test in many institutions and is considered to be the gold standard for diagnosing gastroparesis.50,51 Radioactive tracers, such as technetium-99 m, are added to liquid and solid foods. Other tests to diagnose gastric emptying include a breath test with carbon 13-octanoic acid or acetic acid.52 However, these are more time-consuming compared to scintigraphy. Intraduodenal/pyloric manometry and Functional Luminal Imaging Probe (FLIP) can help to assess the PS but are available only in tertiary care centers and at this time of limited clinical interest. 

The role of the PS in gastroparesis and management has been discussed and reviewed in the following articles.42,53 A summary is shown in Table 2.

Hypertrophic Pyloric Stenosis

Hypertrophic pyloric stenosis (HPS) involves a thickening of the pyloric lumen to greater than 1-3mm, associated with rigid and overlapping mucosal folds that create a point of obstruction. HPS is seen in young infants 1 to 2 months after birth. Ultrasound is the preferred diagnostic test choice due to its ease of use with no contrast or no radiation exposure.40 Laparoscopic pyloromyotomy, involving the hypertrophied pyloric muscle incision, is the treatment of choice.39,57

Ileo-Cecal Sphincter

Structure

The junctional region between the ileum and colon, the Illeo-colonic junction (ICJ), has been dubbed the ‘apothecary barrier’ due to its role in reinforcing water absorption in the colon.58 This segment, also known as the ileocecocolonic segment, consists of the ileocecal sphincter (ICS) and cecum and behaves similarly to the LES region discussed earlier. The ICS has an episodic and intermittent propagating motor activity and functions to transfer digestive contents and residue from the ileum to the cecum, leading to the early concept of the ICS as an intestinal stomach.58  

The ICS exhibits several features of other sphincters. Anatomically the site is marked by considerable thickening of the circular muscle coat.59 The terminal ileum and cecum join at an acute angle. The ileum’s muscular components merge with the layers of the cecum and colon, creating an ileal papilla, further supported by ligamentous connections between all three structures. The smooth muscle in the distal portion of the ileum wall thickens to create a sphincter. This intricate relationship between the structures of this region may play a role in the ICS’s competency.59,60 The vagus and splanchnic nerves innervate the ICS. The vagal efferent stimulation reduces the sphincteric pressure and increases motor activity of the ileum.

Physiology

ICS maintains a sustained isometric tone of myogenic origin.59,59,61 Manometry studies have been unable to assess the position of the manometric pressures of the ICS.62

The ICS controls forward and backward flow through integration with the distal ileum and proximal colon motility. The gastro-ileal and ileocolonic reflexes involving the ICS affect the sphincter’s overall motility. The ICS tone increases immediately after a meal and lessens during the inter-digestive phase.58 

The ileocolonic reflex involves colonic distension, which is followed by ICS contraction.63 Higher distending pressures cause higher excitatory responses. Ileal distension can have variable responses of the ICS; distention closer to the ICS causes excitatory and inhibitory responses likely due to descending excitatory and inhibitory pathways.58 

The distal ileum synthesizes several hormones that influence digestive motility, including peptide YY (PYY), glucagon-like peptides, and neurotensin.Neurotensin is a hormone and neurotransmitter that functions as a hormone in the distal ileum.64 We are not discussing in depth the absorptive features of the terminal ileum; however, the terminal ileum plays a significant role in B12 absorption and entero-hepatic circulation of bile acids. 

Clinical Disorder(s): Pathogenesis, Diagnosis, and Management

Small Intestinal Bacterial Overgrowth Syndrome (SIBO)

Clinically the role of the ICS in preventing small intestinal bacterial overgrowth syndrome (SIBO) has been discussed previously.65 The ICS separates the small and large bowel, which have distinct physiological properties, especially in bacterial content. The ICS limits colo-ileal reflux, which can prevent the colonization of the ileum by colonic microflora. Surgical removal of the ICS may enhance the development of SIBO due to retrograde bacterial migration from the large to the small bowel. 

The Sphincter of Oddi

Structure 

The sphincter of Oddi (SO) consists of three layers of smooth muscle surrounding the common bile duct, main pancreatic duct, and ampulla of Vater. 

Function

The SO plays a role in preventing duodenal reflux, regulating bile and pancreatic flow, and facilitating retrograde gallbladder filling. The SO has a basal pressure of 10mm Hg in humans, and pressure gradients dictate the flow.

Functional Biliary Sphincter of Oddi Dysfunction Functional Pancreatic Sphincter of Oddi Dysfunction
1. Criteria for biliary pain include:  Pain located in the epigastrium and/or right upper quadrant and all of the following: Builds up to a steady level and lasts 30 minutes or longer Occurring at different intervals (not daily) Severe enough to interrupt daily activities or lead to an emergency department visit Not significantly related to bowel movements Not significantly relieved by postural change or acid suppression
2. Elevated liver enzymes or dilated bile duct,
but not both
3. Absence of bile duct stones or other structural abnormalities Additional Supportive Criteria: 
1. Normal amylase/lipase
2. Abnormal sphincter of Oddi manometry
3. Hepatobiliary scintigraphy		1. Documented recurrent episodes of pancreatitis (typical pain with amylase or lipase >3 times normal and/or imaging evidence of acute pancreatitis)
2. Other etiologies of pancreatitis excluded
3. Negative endoscopic ultrasound
4. Abnormal sphincter manometry Diagnostic criteria must include all of the above
Table 3. SOD Classification, Biliary and Pancreatic(Adapted from Rome IV Criteria)10,68,69

Anterograde phasic contractions at the SO propel bile and pancreatic secretions into the duodenum. This is followed by a relaxation phase allowing the passive filling of bile into the SO. Increasing basal pressure leads to resistance to flow into the duodenum, allowing the gallbladder to fill. Bile and pancreatic juices flow into the duodenum when basal pressure decreases below CBD and PD pressure.

The filling of the SO triggers varying phasic contractions during different digestive phases. A meal stimulates the release of CCK, causing gallbladder contraction and relaxation of the SO. CCK also directly stimulates SO smooth muscle. Somatostatin, released from endocrine cells throughout the digestive tract, causes gallbladder contraction and SO relaxation.66

Clinical Disorder(s): Pathogenesis, Diagnosis, and Management

Sphincter of Oddi dysfunction (SOD)

Sphincter of Oddi dysfunction (SOD) is commonly present in females ages 20-50, with a general population prevalence of 1.5%. The biliary or pancreatic sphincter may become stenotic, causing blockage of bile and pancreatic juice flow. Furthermore, the sphincter’s smooth muscle may have an inappropriate response to neuronal or hormonal stimuli that normally cause contraction.66,67

The disease presentation and clinical findings are on a spectrum, and the ROME IV criteria can assist in describing the clinical features.10,68,69 The diagnostic criteria for SOD dysfunction are tabulated. 

Patients with idiopathic recurrent pancreatitis (IARP) may have a prevalence of SOD as high as 72%.70 Toouli et al. observed 57% of patients with IARP had elevated SO pressures in a study with 28 patients with IARP.71 In the pathogenesis of acute pancreatitis, however, it is well-recognized that a stone at the ampulla can initiate pancreatic injury.  

Once, the most widely used Milwaukee classification for SOD was carefully re-evaluated in Rome IV criteria, and as a result, type III SOD was eliminated to avoid unnecessary or unwanted sphincterotomy as the diagnosis was based solely on patient history. Thus, SOD is divided into two types using a structural perspective based on symptoms, radiographic findings, and laboratory abnormalities. Type I SOD has abnormal chemistries and dilated biliary or pancreatic duct imaging. Type II SOD has abnormal biochemical markers or abnormal imaging.72

Risk factors for SOD include patients who underwent cholecystectomy, irritable bowel syndrome (IBS), and use of exogenous agents such as opiates. As mentioned previously, CCK relaxes the SO in patients with intact gallbladders. In patients six months after cholecystectomy, CCK can fail to relax the SO. Patients with postcholecystectomy may have elevated basal SO pressures with increased retrograde SO phasic contractions. The gallbladder may act to prevent sudden increases in retrograde intraductal pressures from ductal obstruction. The incidence of SOD after cholecystectomy is variable, with approximately 1.5% of patients developing the disorder.73

Patients with IBS may have an association with SOD. Patients with IBS who undergo cholecystectomy may exhibit a diminished response to CCK compared with postcholecystectomy patients without IBS, leading to the pathogenesis of SOD. Opiates are known to alter flow through the SO, with morphine increasing the amplitude and frequency of the phasic wave through the mu receptor.66 

Manometry is the gold standard for diagnosing SOD, especially diagnosing SOD type I. The therapy is only offered at select tertiary care centers due to its time-consuming nature, technical expertise requirements, and potential complications such as post-ERCP pancreatitis.66,74

Certain exogenous agents reduce the pressure and resistance of the SO, leading to the relaxation of the sphincter. These agents include calcium-channel blockers, botulinum toxin, and glyceryl trinitrate, showing some evidence of symptomatic relief.75–77 There currently is a lack of large, randomized, and controlled trials to demonstrate the efficacy of these pharmacological agents for the treatment of SOD.

For both types of SOD, endoscopic sphincterotomy is the best treatment option with significant pain reduction. Roughly 90% of patients with type I biliary SOD and 60–94% of SOD type II patients have had improvement in pain following a biliary sphincterotomy.66 ,67

Anal Sphincter 

Structure

Internal Anal Sphincter (IAS) 

The IAS and EAS are the two sphincters of the anal canal. The IAS, an extension of the circular ring of the involuntary smooth muscle of the rectum, terminates 10mm above the anal verge and is 2.5cm long, 2-5mm thick in size, and is comprised of both circular and longitudinal muscle separated by connective tissue. The IAS is surrounded superiorly by the levator ani muscle and is encased by the EAS, comprised of skeletal muscle, and is under voluntary control.78,79

The IAS is under dual innervation from the autonomic and enteric nervous systems. The sympathetic nerve fibers arise from the lower thoracolumbar ganglion to form the superior hypogastric plexus.80 Parasympathetic fibers arising from spinal cord levels S2-S4 form the inferior hypogastric plexus giving rise to the superior, middle, and inferior rectal nerves that supply the anal canal.80 The parasympathetic input is primarily inhibitory in nature, prompting relaxation mainly through muscarinic receptor stimulation. The sympathetic nervous system is shown to have both an inhibitory and excitatory influence, dependent on receptor activation. Alpha and beta adrenoreceptors are present in the IAS, with stimulation of alpha adrenoreceptors leading to excitation and stimulation of the beta receptors leading to an inhibitory effect.81–83 Anal pressure and tone are primarily influenced through the parasympathetic nervous system. 

Pathology Associated with Low Resting IAS Pressure Comment
Obstetric anal sphincter injury during childbirthA significant correlation between IAS injury is observed during childbirth and fecal incontinence
Anorectal surgical procedures: anal dilatation fistula surgery low anterior resection hemorrhoidectomyAdvances in surgical techniques have decreased iatrogenic injuries
Rectal prolapsePathogenesis is not clearly understood but may involve IAS dilation and altered RAIR mechanisms
Radiation toxicityFollowing radiotherapy significant reduction in RAP and physiological sphincter length in patients, indicating IAS dysfunction
SclerodermaAffects the anorectal region  Low IAP 
Pathology Associated with
Low Resting IAS Pressure 



Comment
Anal fissure 
Elevated resting pressure in the anal canal greater than 90mm Hg leads to ischemia of the anal lining
Internal sphincter achalasiaA rare and multifactorial disorder 
Table 4.
IAS Pathology and IAS Pressure
Adapted from Kumar & Emmanuel et al.78

The enteric nervous system affects the IAS through neurotransmitters, mainly NO. The circular muscle layer is embedded with inhibitory neurons that release NO, leading to relaxation. VIP is also shown to influence inhibitory responses in the IAS.84  

Due to the specialized cell properties of the smooth muscle, the basal tone is myogenic, with tone and phasic contractile activity being independent of nervous system input.85

External Anal Sphincter (EAS) 

The EAS is composed of striated muscles, voluntary, and encompasses the IAS, extending to the anal verge. The subcutaneous and superficial muscle bundles make up the EAS. The nervous system innervation comes from the perianal branch of S4 and the inferior rectal branch of the internal pudendal nerve, while sensation comes from the inferior rectal nerve, a branch of the pudendal nerve.80 The EAS is under conscious input from higher cortical centers.

Physiology

The anal sphincter play an important role in maintaining continence, controlling defecation, and passing flatus. The complex process is accomplished through the integrated motor functions of the anal sphincter muscles, rectum, pelvic floor muscles, the sensory visceral somatic components of the pelvic nerves, and higher cortical centers.85 

Low Pressure 
Modality Effect
Lifestyle Modification Promotion of improved stool consistency and stable bowel movements through dietary modification and reflex mechanisms
MedicationAnti-diarrheal medications 
Surgical Repair Direct repair 
Augmentation Techniques Unclear mechanism 
Artificial anal sphincters
BiofeedbackRectal sensitivity training involving the patient to squeeze EAS on activation
of RAIR reflex
NeuromodulationSacral nerve stimulation (SNS) Percutaneous Tibial Nerve Stimulation (PTNS)
High Pressure 
Modality Effect 
Topical Therapy  (nitroglycerin, diltiazem)Relaxation of IAS smooth muscle through activation
of NO or blockade of calcium channels 
Botulinum ToxinNeurotoxin causes a reduction in resting anal pressure and an increase
in blood flow. 
Lateral Sphincterotomy Division of IAS
to reduce RAP
Table 5.
Treatment Options for Low and High
Resting Anal Pressure States of the IASAdapted from Kumar & Emmanuel et al.78

The IAS is a complex muscle responsible for maintaining continence and is divided into upper and lower portions. The lower portion contributes significantly to the basal anal resting tone, responsible for 50-85% of the resting anal pressure (RAP).85 The control of the IAS involves intrinsic and extrinsic neurons and myogenic neurons. The lower IAS has a high resting pressure to prevent leakage of fecal contents or flatus and is coordinated with the contraction of the EAS to maintain continence. The upper IAS relaxes reflexively during rectal filling/distention, a process known as recto anal inhibitory reflex (RAIR) plays a critical role in maintaining continence. The RAIR permits the passage of feces from the rectum to the upper anal canal, allowing the anal sensory epithelium to “sample” and distinguish luminal contents of solid, liquid, and gaseous origin. The volume of distension/filling can affect RAIR, with larger volumes contributing to prolonged relaxation periods of the IAS. Relaxation of the IAS occurs during the RAIR, which is a direct evaluation of IAS function. The contraction of IAS is mediated by sympathetic nerves through alpha adrenoreceptors and relaxation through Beta receptors. 

Unlike the IAS, the EAS only contributes to a small portion of the anal resting tone. EAS is unique compared to other striated muscles as it has continuous tonic activity even at rest. However, changes in posture and increased intra-abdominal pressure can trigger an anal reflex, increasing the resting tone of the EAS. The second sacral spinal segment enables the EAS to have integrated activity, resulting in voluntary contraction that can last between 40-60 seconds. This contraction is vital for deferring defecation and facilitating rectal accommodation. Additionally, higher cortical signals can also transmit inhibiting signals that can cause relaxation of the EAS, allowing for the fecal bolus to pass.86,87

Clinical Disorder(s): Pathogenesis, Diagnosis, and Management

An excellent and exhaustive review by Kumar and Emmanuel highlights the IAS pathology in the context of anal pressure.78 Insufficient IAS pressure at rest can result in different degrees of fecal incontinence, often accompanied by diarrhea. High-pressure states generated in the IAS can cause the inability to defecate. Understanding these causes is crucial for the appropriate diagnosis and treatment of individuals with low and high internal anal sphincter pressure. Due to space limitations, the following important topics are summarized in Table 4. 

Anal rectal manometry (ARM) is the gold standard for assessing sphincter and anorectal function. ARM involves evaluating resting and squeeze pressures of the anal sphincter, RAIR, rectal sensation, changes in anal and rectal pressures during attempted defecation, rectal compliance, and a balloon expulsion test. However, there is currently no standardized protocol for interpreting or performing the test, and variations exist in manometry probes and study populations. High-resolution manometry (HRM) can be utilized to measure circumferential pressures, providing additional information in the evaluation of anal rectal function.78 

Dyssynergic defecation (DD) is a condition characterized by a lack of coordination of muscle contractions of the anorectal region, specifically puborectalis, and EAS, leading to difficulties in evacuating stool. Diagnosing DD involves ruling out underlying abnormalities and considering factors such as inadequate fiber and liquid intake, immobility, medications, and metabolic, neurological, or structural disorders. The balloon expulsion test (BET) and anorectal manometry ARM help to evaluate the pressure activity in the rectoanal region and aid in the diagnosis of DD.88

Conclusion 

The gastrointestinal sphincters are gatekeepers that regulate the flow of solids, liquids, and gases in the digestive system. They are made up of both striated and smooth muscles and are influenced by nerves and hormones. These essential sphincters permit unidirectional or bidirectional flow. However, apart from the LES and anal sphincters, technical difficulties have prevented a thorough examination of the UES, PS, SO, and Ileocecal sphincters, resulting in gaps in our knowledge regarding their neuro-motility and disease prevention roles. Recent advances in technology and increased interest in their study offer hope for a better understanding of their structure, function, and impact on clinical disorders. With current advances in neuro-motility physiology and the technical feasibility of studying previously inaccessible sphincters, we can gain a better understanding of their roles in physiology and disease. 

Acknowledgment: The authors acknowledge Shree Swapna Kalapatapu for her contribution to the anatomical diagrams included in this article. 

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76. Pasricha PJ, Miskovsky EP, Kalloo AN. Intrasphincteric injection of botulinum toxin for suspected sphincter of Oddi dysfunction. Gut. 1994;35(9):1319-1321. doi:10.1136/gut.35.9.1319

77. Staritz M, Poralla T, Ewe K, Meyer zum Büschenfelde KH. Effect of glyceryl trinitrate on the sphincter of Oddi motility and baseline pressure. Gut. 1985;26(2):194-197. doi:10.1136/gut.26.2.194

78. Kumar L, Emmanuel A. Internal anal sphincter: Clinical perspective. Surg J R Coll Surg Edinb Irel. 2017;15(4):211-226. doi:10.1016/j.surge.2016.10.003

79. Barleben A, Mills S. Anorectal anatomy and physiology. Surg Clin North Am. 2010;90(1):1-15, Table of Contents. doi:10.1016/j.suc.2009.09.001

80. Raizada V, Mittal RK. Pelvic floor anatomy and applied physiology. Gastroenterol Clin North Am. 2008;37(3):493-509, vii. doi:10.1016/j.gtc.2008.06.003

81. Rattan S. Sympathetic (adrenergic) innervation modulates but does not generate basal tone in the internal anal sphincter smooth muscle. Gastroenterology. 2008;134(7):2179-2181; author reply 2181-2182. doi:10.1053/j.gastro.2008.05.017

82. Parks AG, Fishlock DJ, Cameron JD, May H. Preiminary investigation of the pharmacology of the human internal anal sphincter. Gut. 1969;10(8):674-677. doi:10.1136/gut.10.8.674

83. Ballester C, Sarriá B, García-Granero E, et al. Relaxation by beta 3-adrenoceptor agonists of the isolated human internal anal sphincter. Life Sci. 2010;86(9-10):358-364. doi:10.1016/j.lfs.2010.01.005

84. Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9(5):286-294. doi:10.1038/nrgastro.2012.32

85. Bajwa A, Emmanuel A. The physiology of continence and evacuation. Best Pract Res Clin Gastroenterol. 2009;23(4):477-485. doi:10.1016/j.bpg.2009.06.002

86. Kumar D, Waldron D, Williams NS, Browning C, Hutton MR, Wingate DL. Prolonged anorectal manometry and external anal sphincter electromyography in ambulant human subjects. Dig Dis Sci. 1990;35(5):641-648. doi:10.1007/BF01540414

87. Varma KK, Stephens D. Neuromuscular reflexes of rectal continence. Aust N Z J Surg. 1972;41(3):263-272.

88. Rao SSC, Patcharatrakul T. Diagnosis and Treatment of Dyssynergic Defecation. J Neurogastroenterol Motil. 2016;22(3):423-435. doi:10.5056/jnm16060

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Dispatches from the GUILD Conference, Series #65

Diagnosis and Management of Irritable Bowel Syndrome

December 2024 • Volume XLVIII, Issue 12
Satish S.C. Rao,Abeer Aziz,Delaram Asadi

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INTRODUCTION

Irritable bowel syndrome (IBS) often presents with recurring abdominal pain, bloating, diarrhea, or constipation with an estimated pooled prevalence of 4.1% to 10.1%,1,2 respectively. In the western world IBS is twice more common in females than males.1,2

IBS has a substantial impact on healthcare burden, both to patients and society, in terms of daily symptoms, quality of life (QoL), work productivity, and healthcare costs.3-5 Many patients experience chronic, disruptive symptoms for many years prior to seeking health care, and typically report lengthy and complex treatment histories.4,6,7 Results from the IBS in America survey indicate that most patients with constipation-predominant IBS (IBS-C) experience symptoms at least 4 to 6 days per week,7 while another survey found that over half of patients with diarrhea-predominant IBS (IBS-D) reported experiencing fecal urgency most of the time.6 Abdominal pain is an important symptom and a key driver of health care seeking behavior.4 The main QoL domains affected by IBS includes general health, social functioning, and mental health.8,9

IBS may be caused by multiple pathophysiological mechanisms, including disordered gut-brain interactions, abnormalities in gastrointestinal (GI) motility, visceral hypersensitivity (a cardinal dysfunction), altered intestinal permeability, immune dysfunction, and gut dysbiosis.9-13 Genetic polymorphisms and environmental factors, including dietary and enteric, also play a role.12 Acute viral or bacterial gastroenteritis remains a strong risk factor for IBS, with 10% of patients reporting IBS after acute infections (i.e., post-infectious IBS).12 Whether IBS symptoms arise because of abnormal stress response to infectious and/or inflammatory gut responses, or from gut dysbiosis causing release of inflammatory mediators that affect the gut-brain axis merits further studies.12 The diagnostic approach and management of IBS, under the three main subcategories of IBS-D and IBS-C, and bloating, will be discussed. An overlap between these categories and other forms of IBS including IBS-M (mixed IBS with diarrhea and constipation) and IBS-U (undifferentiated IBS) may also exist.9,10

Clinical Approach to IBS-D

Diagnostic tests

IBS-D can usually be diagnosed with the help of Rome diagnostic criteria (Table 1, 2) without performing an array of diagnostic tests, although selected testing is appropriate in some patients to distinguish organic diseases from lower gastrointestinal motility disorders.9,10 (Figure 1) Key organic conditions  that should be excluded in patients with suspected IBS-D include inflammatory bowel disease (IBD), hormonal disturbances, enteric infections, colorectal cancer, and disorders associated with malabsorption such as celiac disease, bile acid diarrhea, or carbohydrate maldigestion.9,10,13 A complete blood count is recommended to identify elevated white blood cell count, or anemia, while measures of systemic inflammation such as C-reactive protein (CRP) or fecal calprotectin can help discriminate between IBS and IBD.9,14 Given its low yield in this setting,15 routine colonoscopy is not recommended in the absence of alarm features.9 A small proportion of patients with suspected IBS-D may have microscopic colitis.14,15 Hence, colonoscopy with random colon biopsies is recommended.14 

Hydrogen and methane breath tests can be useful in diagnosing various food intolerance syndromes, small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO), which are commonly associated with IBS-like symptoms.16,17 Despite significant heterogeneity in test performance, preparations, and indications, a recent consensus of experts and the American College of Gastroenterology (ACG) clinical practice guidelines concluded that breath hydrogen and methane testing can be useful in diagnosing not only carbohydrate maldigestion and SIBO, but also in assessing patients with bloating and methane-associated constipation.16,17 Since 25% of patients with IBS-D have evidence of bile acid diarrhea, regardless of cholecystectomy,18 tests such as 23-seleno-25-homotaurocholic acid retention test (75SeHCAT) or testing for 7-C4, a bile acid precursor, may be useful, especially to identify patients who may benefit from bile acid binding resins. 

The value of celiac screening remains unclear. Current ACG guidelines recommend screening patients with tissue transglutaminase antibody (TtG) test,19 which is supported by a recent meta-analysis demonstrating a significantly higher prevalence of biopsy-proven celiac disease among all subtypes of IBS compared with controls.20 Likewise on a case-by-case basis, for example recent foreign travel, or antibiotic use, appropriate consideration should be given for stool evaluation of ova, parasites, culture and C. difficile toxin evaluation.

Management of IBS-D

A diet low in fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs) has become popular and has been evaluated.10,21,22 Meta-analysis of 7 RCTs found a significant effect of a low FODMAP diet in improving overall symptoms of IBS,10 with overall improvement in about half to two-thirds of patients.22 The most likely symptoms to respond include bloating and abdominal pain, and diarrhea is more likely to improve than constipation.22 A two-to-four-week trial is usually sufficient to assess response, with many patients responding within the first two weeks of FODMAP restriction. A recent network meta-analysis showed that low FODMAP diet was as superior to BDA/NICE diet for bloating and distension, and it is better than habitual diet for global gas symptom, although here was a higher risk of bias.23

Further, the long-term efficacy of this diet is unknown. A low FODMAP diet is not intended to be a long-term treatment strategy, but rather a tool for identifying patients who are sensitive to FODMAPs so that some of these foods can be systematically reintroduced to determine which foods are triggers and individualize diets accordingly.22,23 This process is best guided by a dietitian with expertise in caring for patients with GI disorders. An alternative approach is to perform fructose, lactose, fructan or sucrose breath tests,24,25 and/or disaccharidase mucosal enzyme assay26  to precisely determine the underlying etiology with one or more enzyme deficiency or food intolerance(s), and then provide tailored nutrition advice.25

Antidiarrheals and antispasmodics: Loperamide, a peripheral µ-opioid receptor agonist, is often recommended for patients with IBS-D.27 Although an effective antidiarrheal, there is no evidence supporting its efficacy in relieving abdominal pain, bloating, or global IBS symptoms.10 (Table 3) Similarly, despite being used for decades to treat abdominal pain associated with IBS, the evidence supporting the use of antispasmodics is modest.9,27 However, these agents do appear to provide some short-term benefit in IBS, but their use can be limited by dose-dependent anticholinergic adverse effects (e.g., constipation, fatigue, dry mouth, dizziness, blurred vision).27 Peppermint oil, which causes smooth muscle relaxation by blocking calcium channels, has been found to improve IBS symptoms in a small number of trials.10 In particular, an enteric-coated, sustained-release formulation of peppermint oil, IB Gard®, improved symptom scores in an RCT involving 72 patients with IBS-D/M, with significant improvement compared to placebo, and within 24 hours 28. Overall, the AGA guidelines gave this class a conditional and either low or very low evidence. (Table 3D) 

Recurrent abdominal pain, on average, ≥1 day per week in the last 3 months, associated with ≥2 of the following criteria:
1. Related to defecation 2. Associated with a change in frequency of stool 3. Associated with a change in form (appearance) of stool
Criteria fulfilled for the last 3 months with symptom onset ≥6 months
Table 1. Rome IV Diagnostic Criteria for IBS9 

Antidepressants: Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are useful in relieving pain and overall symptoms in IBS.27 These medications work centrally and peripherally via pain perception, visceral hypersensitivity, and GI motility. Although the efficacy of antidepressants according to predominant stool pattern has not been well studied, TCAs may be most appropriate in IBS-D given their ability to slow colonic motility and their mildly constipating effects.27 The serotonin and norepinephrine reuptake inhibitors (SNRIs) have not been studied adequately in this population. Given the diarrhea-predominant symptoms, a trial of low-dose TCA would be an appropriate option as these neuromodulators are very effective for treatment of pain. The AGA guidelines gave a conditional, low evidence recommendations for these agents. (Table B) A recent large community based RCT showed that a titrating dose of amitriptyline (10-30 mg/day) for 6 months, was superior to placebo in improving IBS symptoms.29

Management of bloating: Bloating is intricately linked and often associated with IBS.10,17,30 To that end, restriction of dietary FODMAPs has been found in studies of varying design to decrease bloating in a large proportion (50-82%) of patients.10,30 Another strategy is the use of probiotics, which are defined as attenuated bacteria or bacterial products that are beneficial to the host. Based on data from 37 RCTs involving 4403 patients, the ACG Task Force on IBS determined that probiotics have low quality of evidence and therefore gave a weak recommendation for treatment of IBS, with possible benefit on bloating and flatulence, rather than on bowel urgency or function.10 However, due to the poor quality and heterogeneity of the evidence, recommendations regarding the use of particular strains or species, or the subtype of IBS most likely to respond, could not be made.10 Also, a recent study cautioned against indiscriminate probiotic use as it may lead to colonization of probiotic organisms in the small bowel causing small intestinal bacterial overgrowth (SIBO), D-lactic acidosis, bloating and brain fog.31

Recent change in bowel habit (< 3 months)
Age ≥50 years, no previous colon cancer screening, and presence of symptoms
Unintentional weight loss
Evidence of overt GI bleeding(i.e., melena or hematochezia)
Nocturnal pain or passage of stools
Family history of colorectal cancer, celiac disease or IBD
Palpable abdominal mass or lymphadenopathy
Evidence of iron-deficiency anemia
Positive test for fecal occult blood
Table 2. Alarm Features39 
GI: gastrointestinal; IBD: inflammatory bowel disease.

Rifaximin, an oral, non-absorbable, broad-spectrum antibiotic, has been extensively evaluated in IBS and found to improve bloating.10,32 Based on data from 6 RCTs involving 2441 non-constipated IBS patients, the ACG Task Force recommends rifaximin for improvement of global IBS symptoms as well as bloating.10 Although the precise mechanism for its benefit in IBS remains unclear, rifaximin appears to have beneficial effects on GI symptoms of diarrhea, pain and bloating, mucosal inflammation, and stabilization of the gut microbiota. Further, preclinical evidence suggests that the effects of rifaximin in IBS may involve mechanisms beyond the gut microbiota, including the modulation of proinflammatory cytokines and intestinal permeability.32

Rifaximin is approved in a 14-day regimen for the treatment of IBS-D and up to two retreatments in those who experience recurrence. Rifaximin is well tolerated, with a safety profile similar to that of placebo.32 The potential for an increased risk for Clostridium difficile infection and/or the emergence of microbial resistance has been reassuring.10,32  The AGA guidelines gave Rifaximin a conditional, moderate evidence recommendation.27 (Table 3D)

Specific therapies for IBS-D: Alosetron is a selective serotonin 5-HT3 receptor antagonist that improves global IBS symptoms and abdominal pain.10,27 Recently, a network meta-analysis of 18 RCTs involving various therapies (alosetron, ramosetron, rifaximin, eluxadolione) ranked alosetron first in efficacy for achieving the composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms, and effect on stool consistency in patients with IBS-D/M.27,33 However, it’s use has been limited by the small risk of ischemic colitis (1.03 cases per 1000 patient-years) and serious complications of constipation (0.25 cases per 1000 patient-years),34 leading to the restriction of its use to women with severe IBS-D who have not responded to conventional therapies.34 Although marketed under a Risk Evaluation and Mitigation Strategy program, requirements for the program have been updated to make it less onerous for prescribers than when it was first initiated.27 Alosetron was afforded a conditional recommendation with moderate certainty in evidence by the AGA.27 (Table 3B)

Eluxadoline is an oral, locally acting, mixed μ- and κ-opioid agonist/δ-opioid receptor antagonist approved for use in adults with IBS-D.35,36 Unlike pure µ-opioid receptor agonists, this agent reduces visceral hypersensitivity without completely disrupting intestinal motility, theoretically decreasing the potential for medication-related constipation.35,36 Meta-analysis of data from three large RCTs demonstrated significant benefits of eluxadoline on stool consistency and overall symptom improvement IBS-D patients but failed to demonstrate a clear effect on abdominal pain.10 However, subsequent analysis of the pivotal trials37 and a phase 4 study36 found eluxadoline to be effective in improving abdominal and stool consistency in IBS-D patients reporting inadequate symptom response to loperamide. Eluxadoline has been relatively well tolerated in clinical trials, with the most common adverse effects being constipation, nausea, and vomiting.10,36,38 However, due to the risk of pancreatitis, this agent is contraindicated in patients without a gallbladder, known or suspected biliary duct obstruction or sphincter of Oddi disease/dysfunction, alcohol use, history of pancreatitis, severe hepatic impairment, and severe constipation or its sequelae.38 The AGA assessment gave eluxadoline a conditional recommendation with moderate certainty.27,35 (Table 3B)

DrugClassNDoseSide EffectsEfficacy (Drug vs. Placebo)
EluxadolineMixed μ/κ Agonist & Antagonist1617 (2 RCT)75/100 mg qdConstipation, nausea, pain27.2 vs 16.7 %, RR 0.87 (0.8-0.9)
RifaximinNonabsorbable Broad Spectrum antibiotic1258 (3 RCT)550 MG TIDNausea, URI, UTIRR 0.85%
(0.8-0.9)
RifaximinGCC agonist2438/636 (1 RCT – 2 PHASES)550 mg/tidNausea, URI, UTI N. Pharyngitis38% vs 31%; RR 0.9 (0.8-1)
Alosetron5 HT3 antagonist4227 (8 RCT)0.5-1 mg bidIschemic Colitis, constipationRR 0.6 (0.5-0.67)
Loperamideμ agonist 2883 (2 RCT) 2 or 6 mg bidHeadache, nausea, diarrheaRR 0.4 (0.2-0.8) 
Amitriptyline Desipramine ImipramineTricyclic Antidepressant523 (8 RCT)Variable
Constipation/sleep/High Withdrawal rateRR 0.67 (0.5-0.8)
Fluoxetine ParoxetineSSRI7 RCTVariableWeight gain, dreamsRR 0.74 (0.5-1.06
12 drugs (Cochrane)Antispasmodics2983 (22 RCT)VariableDry mouth, Dizziness, visionRR 0.74 (0.59-0.9)
Table 3A. Efficacy and Safety of Drug Treatments for IBS-D Based on AGA Guidelines AGA Guidelines for IBS-D35
5 HT3 = 5 Hydroxy Tryptamine 3; SSRI = Selective Serotonin receptor inhibit.
RCT = Randomized controlled trial; qd = once/day; Bid = twice a day; TID = three times/day.
UTI = Urinary tract infection; RR = Relative risk ratio

Clinical Approach to IBS-C

Diagnostic Tests for IBS-C: A first step is to obtain a detailed clinical history, and perform a digital rectal exam,40 and physical examination, combined with selected tests to exclude organic disease. (Figure 1). Further, evaluation of the pathophysiology of constipation may prove useful.9,41 It is important to characterize what a patient means by the term constipation; is it altered stool frequency or is it difficulty with defecation or both. Assessment of incomplete evacuation and stool consistency using a Bristol stool scale is important as well as associated features, such as degree of straining during defecation and use of digital maneuvers to assist defecation.9 It is essential to perform a digital rectal exam,40 which can help identify fecal impaction, anal stricture, rectal mass, and/or dyssynergia.9,39,42 Patients with paradoxical anal contraction on straining or inadequate push effort or anal/puborectalis relaxation should be referred for anorectal physiologic testing.39,42

Again, the presence of key alarm symptoms (e.g., unintentional weight loss, rectal bleeding) and whether patient has undergone recent screening colonoscopy per national recommendations are important. Assessment for hypothyroidism or hypercalcemia with a serum TSH and serum calcium may be useful.9 Although IBS-C and CIC are among the most common overlapping disorders associated with chronic constipation, it is important to exclude secondary causes of constipation such as drugs, metabolic disorder, neurological disorders and others.42

Once alarm features and secondary causes for a constipation have been excluded, the Rome IV criteria can be useful to diagnose IBS-C.9 (Tables 2,3)

General Management and Diet

Patient should be educated about IBS and advised to increase fluid intake, and maintain a fiber-rich diet, and regular exercise and reduce daily stressors. Poorly fermentable, soluble fiber (e.g., psyllium) is a recommended, evidence-based treatment for IBS-C.9,41 In contrast, insoluble fiber (e.g., bran) has no significant effect on IBS symptoms and on the contrary, may increase pain and bloating.10,41 Although an appropriate first-line treatment, fiber supplementation should be introduced gradually, starting with low doses and titrating slowly as tolerated to minimize unwanted GI effects (bloating, flatulence, and abdominal discomfort).10,44 Patients should also be educated that, unlike stimulant laxatives, response to fiber may take several weeks.42

New or Updated Recommendations Strength of RecommendationCertainty in Evidence
 1.
In patients with IBS-D, the AGA suggests using eluxadoline
Implementation remark; eluxadoline is contraindicated in patients without a gallbladder, or those who drink more than 3 alcoholic beverages per day		ConditionalModerate
2a. In patients with IBS-D, the AGA suggests using rifaximinConditionalModerate
2b.
In patients with IBS-D with initial response retreatment with rifaximin recurrent symptoms, the AGA suggests retreatment with rifaximin		ConditionalModerate
3. In patients with IBS-D, the AGA suggests using alosetronConditionalModerate
4. In patients with IBS-D, the AGA suggests using loperamideConditionalModerate
5. In patients with IBS, the AGA suggests using TCAsConditionalModerate
6. In patients with IBS, the AGA suggests against using SSRIsConditionalModerate
7. In patients with IBS, the AGA suggest using antispasmodicsConditionalModerate
Table 3B. AGA Guidelines for IBS-D
*For all recommendation statements, the comparator was no drug treatment.

Laxatives and fruits: Stimulant laxatives (senna, bisacodyl, castor oil, cascara, and aloe) help to produce bowel movements by decreasing water absorption and stimulating intestinal motility, either directly or indirectly through release of prostaglandins.42,44 These agents are often used on a rescue basis, such as in patients who have not defecated in several days, or more regularly if required.45 Based on data from 2 RCTs, the AGA considers sodium picosulfate and bisacodyl to be effective for CIC,46 although their use can be limited by poor tolerability, particularly regarding diarrhea and abdominal cramping. There is insufficient evidence to recommend the use of other stimulant laxatives for CIC, and similarly, there are no RCTs of stimulant laxatives in IBS-C.41

Polyethylene glycol (PEG) is an osmotic laxative that extracts fluid into the intestinal lumen to soften stools and accelerate colon transit. 47 The short- and long-term efficacy of PEG has been well-established in patients with CIC,47 with efficacy and safety established up to 6 months in an RCT47 and 24 months in a retrospective trial. Its efficacy in IBS-C, however, is less clear. (Table 4A) Data from two small RCTs found that PEG improved stool frequency in patients with IBS-C, but not pain or other IBS-related symptoms.10,48 Based on these data, the ACG recommends against the use of PEG for overall symptom improvement in IBS patients.10 Recently Kiwi fruit has been shown to be useful in improving IBS symptoms in an RCT.49

Antidepressants: Both TCAs and SSRIs are effective in relieving pain and overall symptoms in IBS.46 Given their prokinetic and anxiolytic effects, an SSRI is more appropriate option for constipation-related symptoms. These agents should be initiated at low doses and takes 4 to 8 weeks to achieve therapeutic response.46 (Table 4A)

Specific Therapies for IBS-C: Several specific therapies, (lubiprostone, linaclotide, plecanatide, and tenapanor) have been FDA approved over the last decade for the treatment of IBS-C.46,50-56 These therapies include secretagogues that act on intestinal enterocytes to stimulate net efflux of ions and water into the intestinal lumen, accelerate intestinal transit, and facilitate ease of defecation. These agents significantly improve bowel and abdominal symptoms in IBS-C,46 and are approved for this use.46,50-56 These agents were afforded a conditional recommendation with moderate certainty by the AGA guidelines. (Table 4B)

Lubiprostone was the first compound approved in 2006. It is a prostaglandin E1 derivative that acts on type 2 chloride channels (ClC2) of small intestinal enterocytes to increase secretion of chloride and fluid into the intestinal lumen.10 This agent is approved at dosages of 8 µg twice daily. The most common adverse effect with lubiprostone is dose-related nausea, occurring in 8% of patients receiving 8 µg and 24 µg twice daily, in pivotal trials of IBS-C and CIC compared with 4% and 3% of patients receiving placebo.50 Lubiprostone should be taken with food and water to minimize nausea and treatment can be initiated at lower doses and titrated upward as needed.46

Linaclotide and plecanatide are guanylate cyclase (GC)-C agonists that produce cyclic GMP intracellularly leading to activation of chloride ion secretion through the cystic fibrosis transmembrane regulator (CFTR), increasing fluid secretion into the GI tract and accelerating intestinal transit.51,52 Additionally, because GC-C pathways are involved in modulating pain fiber activity,53 these agents have effects on the abdominal pain and sensory symptoms of patients with IBS-C.54,55 In clinical trials, however, improvement in stool frequency tends to occur earlier (i.e., within a week of treatment initiation) with linaclotide compared with improvement in abdominal pain and bloating, which make take up to 8 to 12 weeks.51 A recent placebo controlled RCT study showed that linaclotide improves abdominal pain in patients IBS-C by improving rectal hypersensitivity and attenuating the signals from the rectum to the brain.55

DrugClassNDoseSide EffectsEfficacy (Drug vs. Placebo)
TenapanorNHE3 channel Inhibitor1372 (3 RCT)50 mg bidDiarrhea34 vs. 27%,
RR, 0.84
(0.79-0.94)
PlecanatideGuanylate Cyclase C (GCC) agonist1632 (3RCT)3 mg dailyDiarrhea, bloatingRR, 0.87
(0.83-0.92)
LinaclotideGCC agonist2443 (3 RCT)290 mcg/dayDiarrhea, bloatingRR, 0.81
(0.77-0.85)
LubiprostoneCCI2  activator1154 (3 RCT)8 mcg bidNausea, diarrheaRR, 0.88
(0.79-0.96)
Tegaserod5 HT4 agonist2883 (4 RCT) 2 or 6 mg bidHeadache, nausea, diarrhea35 vs. 24%, RR, 0.87 (0.81-0.93) 
PEGOsmotic139 (1 RCT)30 g dailyBloating, diarrheaRR, 0.9 (0.66-1.2)
Amitriptyline Nortriptyline Imipramine Desipramine SimipramineTCA523 (8 RCT)VariableConstipation, sleepRR, 0.67
(0.54-0.82)
Paroxetine CitalopramSSRI7 RCTVariableWeight gain, dreamsRR, 0.74
(0.52-1.06)
12 drugs (Cochrane)Antispasmodics2983 (22 RCT)VariableDry mouthRR, 0.67 (0.55-0.80)
Table 4A. AGA Guidelines for IBS-C46

Both linaclotide and plecanatide are approved at once-daily doses for use in IBS-C and CIC.46 (Table 9) Diarrhea is the most common adverse effect, which is usually mild and leads to few treatment discontinuations. Diarrhea can be managed by administering linaclotide 30 to 60 minutes before breakfast,46 or by starting with a low dose (72 µg/day) and titrating up to 290 mg/day.

New or Updated Recommendations Strength of RecommendationCertainty in Evidence
1. In patients with IBS-C, the AGA suggests using tenapanorConditionalModerate
2. In patients with IBS-C, the AGA suggest using plecanatide ConditionalModerate
3. In patients with IBS-C, the AGA recommends using linaclotideStrongHigh
4.
In patients with IBS-C, the AGA suggests using tegaserod
Implementation remark: Tegaserod was reapproved for women under the age of 65 years without a history of cardiovascular ischemic events
(such as myocardial infarction, stroke, TIA, or angina)		ConditionalModerate
5. In patients with IIBS-C, the AGA suggests using lubiprostone ConditionalLow
6. In patients with IIBS-C, the AGA suggests using PEG laxativesConditionalLow
7. In patients with IBS, the AGA suggests using TCAsConditionalLow
8. In patients with IBS, the AGA suggest against using SSRIs ConditionalLow
9. In patients with IBS, the AGA suggests using antispasmodicsConditionalLow
Table 4B. AGA Guidelines for IBS-C
*For all recommendation statements, the comparator was no drug treatment.
TIA: Transient ischemic Attack; PEG: Polyethylene Glycol; TCA: Tricyclic Antidepressants; SSRI: Selective Serotonin Receptor Reuptake Inhibitor.

Tenapanor is a new class of drug and is a sodium hydrogen exchanger 3 blocker that inhibits sodium absorption in the intestinal lumen.46,56 In 2 large clinical trials, tenapanor 50 mg BID was superior to placebo in improving IBS-C symptoms. It has been approved for IBS-C.46,56 Its main side effect is diarrhea.

CONCLUSIONS

IBS is a common disorder that imposes considerable health care burden. Dissatisfaction with current therapies remained but progress has been made on several fronts. Advances in understanding of the pathogenesis of these disorders have paved the way for new treatments. Recent evidence on the role of certain foods causing symptoms, and carefully planned dietary intervention, particularly the low-FODMAP diet, as a therapeutic strategy may be useful for many IBS patients. The best clinical trial evidence for IBS-D supports the use of alosetron, TCAs, peppermint oil, rifaximin, and eluxadoline. Although the predominance of abdominal pain differentiates IBS-C from chronic constipation, significant overlap exists, and treatment options are largely similar. First-line treatment of IBS-C/chronic constipation typically consists of diet and lifestyle modifications, along with nonprescription laxatives (soluble fiber, PEG). High-quality evidence supports the efficacy of prosecretory agents (lubiprostone, linaclotide, plecanatide), and NHE3 blocker tenapanor for the treatment of IBS-C. Cognitive behavioral therapy, especially using home-based APPs is gaining popularity and its wider availability will improve access to this therapy along with the stress-reduction therapies such as yoga and meditation, but these interventions need more evidence. 

References

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4. Heidelbaugh JJ, Stelwagon M, Miller SA, Shea EP, Chey WD. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol 2015;110(4):580-7. doi:10.1038/ajg.2015.67

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6. Sayuk GS, Wolf R, Chang L. Comparison of Symptoms, Healthcare Utilization, and Treatment in Diagnosed and Undiagnosed Individuals With Diarrhea-Predominant Irritable Bowel Syndrome. Am J Gastroenterol. 2017;112(6):892-899. doi:10.1038/ajg.2016.574

7. Ballou S, McmahonC, Lee HN, et. al. Effects of irritable bowel syndrome on daily activities vary among subtypes based on results from the IBS in America survey. Clin Gastro Hepatol 2019; 17:2471-78.

8. Taylor DCA, Abel JL, Doshi JA, et al. The Impact of Stool Consistency on Bowel Movement Satisfaction in Patients With IBS-C or CIC Treated With Linaclotide or Other Medications: Real-World Evidence From the CONTOR Study. J Clin Gastroenterol. 2019;53(10):737-743. doi:10.1097/mcg.0000000000001245

9. Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology. 2016;150(6):1393-1407.e5. doi:10.1053/j.gastro.2016.02.031

10. Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1-18. doi:10.1038/s41395-018-0084-x

11. Pimentel M, Lembo A. Microbiome and Its Role in Irritable Bowel Syndrome. Dig Dis Sci. 2020;65(3):829-839. doi:10.1007/s10620-020-06109-5

12. Barbara G, Grover M, Bercik P, et al. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology. 2019;156(1):46-58.e7. doi:10.1053/j.gastro.2018.07.011

13. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 Suppl 1:S1-35. doi:10.1038/ajg.2008.122

14. Banerjee A, Srinivas M, Eyre R, et al. Faecal calprotectin for differentiating between irritable bowel syndrome and inflammatory bowel disease: a useful screen in daily gastroenterology practice. Frontline Gastroenterol. 2015;6(1):20-26. doi:10.1136/flgastro-2013-100429

15. Chey WD, Nojkov B, Rubenstein JH, Dobhan RR, Greenson JK, Cash BD. The yield of colonoscopy in patients with non-constipated irritable bowel syndrome: results from a prospective, controlled US trial. Am J Gastroenterol. 2010;105(4):859-65. doi:10.1038/ajg.2010.55

16. Rezaie A, Buresi M, Lembo A, et al. Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus. Am J Gastroenterol. 2017;112(5):775-784. doi:10.1038/ajg.2017.46

17. Pimentel M, Saad RJ, Long MD, Rao SSC. ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol. 2020;115(2):165-178. doi:10.14309/ajg.0000000000000501

18. Slattery SA, Niaz O, Aziz Q, Ford AC, Farmer AD. Systematic review with meta-analysis: the prevalence of bile acid malabsorption in the irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther. 2015;42(1):3-11. doi:10.1111/apt.13227

19. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-76; quiz 677. doi:10.1038/ajg.2013.79

20. Irvine AJ, Chey WD, Ford AC. Screening for Celiac Disease in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-analysis. Am J Gastroenterol. 2017;112(1):65-76. doi:10.1038/ajg.2016.466

21. van Lanen AS, de Bree A, Greyling A.  Efficacy of a low-FODMAP diet in adult irritable bowel syndrome: a systematic review and meta-analysis. European Journal of Nutrition 2021: 60; 3505-3522.

22. Chey WD. Food: The Main Course to Wellness and Illness in Patients With Irritable Bowel Syndrome. Am J Gastroentero. 2016;111(3):366-371. doi:10.1038/ajg.2016.12

23. Black CJ, Staudacher HM, Ford AC. Efficacy of a low FODMAP diet in irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2022;71(6):1117-1126. doi:10.1136/gutjnl-2021-325214

24. Amieva-Balmori M, Coss-Adame E, Rao NS, Dávalos-Pantoja BM, Rao SSC. Diagnostic Utility of Carbohydrate Breath Tests for SIBO, Fructose, and Lactose Intolerance. Dig Dis Sci. 2020;65(5):1405-1413. doi:10.1007/s10620-019-05889-9

25. Rao SS, Yu S, Fedewa A. Systematic review: dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome. Aliment Pharmacol Ther. 2015;41(12):1256-70. doi:10.1111/apt.13167

26. Viswanathan L, Rao SSC, Kennedy K, Sharma A, Yan Y, Jimenez E. Prevalence of Disaccharidase Deficiency in Adults With Unexplained Gastrointestinal Symptoms. J Neurogastroenterol Motil. 30 2020;26(3):384-390. doi:10.5056/jnm19167

27. Lembo A, Sultan S, Chang L, Heidelbaugh JJ, Smalley W, Verne GN. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea. Gastroenterology. 2022;163(1):137-151. doi:10.1053/j.gastro.2022.04.017

28. Cash BD, Epstein MS, Shah SM. A Novel delivery System of Peppermint Oil Is an Effective Therapy for Irritable Bowel Syndrome Symptoms. Dig Dis Sci. 2016;61(2):560-71. doi:10.1007/s10620-015-3858-7

29. Ford AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023;402(10414):1773-1785. doi:10.1016/S0140-6736(23)01523-4

30. Foley A, Burgell R, Barrett JS, Gibson PR. Management Strategies for Abdominal Bloating and Distension. Gastroenterol Hepatol (N Y). 2014;10(9):561-71. 

31. Rao SSC, Yu S, Tetangco EP, Yan Y. Probiotics can Cause D-Lactic Acidosis and Brain Fogginess: Reply to Quigley et al. Clin Transl Gastroenterol. 2018;9(11):207. doi:10.1038/s41424-018-0077-5

32. Schoenfeld P, Pimentel M, Chang L, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39(10):1161-8. doi:10.1111/apt.12735

33. Black CJ, Burr NE, Camilleri M, et al. Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis. Gut. 2020;69(1):74-82. doi:10.1136/gutjnl-2018-318160

34. Tong K, Nicandro JP, Shringarpure R, Chuang E, Chang L. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program. Therap Adv Gastroenterol. 2013;6(5):344-57. doi:10.1177/1756283×13491798

35. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. N Engl J Med. 21 2016;374(3):242-53. doi:10.1056/NEJMoa1505180

36. Brenner DM, Sayuk GS, Gutman CR, et al. Efficacy and Safety of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea Who Report Inadequate Symptom Control With Loperamide: RELIEF Phase 4 Study. Am J Gastroenterol. 2019;114(9):1502-1511. doi:10.14309/ajg.0000000000000327

37. Lacy BE, Chey WD, Cash BD, Lembo AJ, Dove LS, Covington PS. Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use. Am J Gastroenterol. 2017;112(6):924-932. doi:10.1038/ajg.2017.72

38. Viberzi (eluxadoline)[prescribing information]. Allergan USA IM, NJ; 2020. 

39. Ford AC, Lacy BE, Talley NJ. Irritable Bowel Syndrome. N Engl J Med. 2017;376(26):2566-2578. doi:10.1056/NEJMra1607547

40. Rao SSC. Rectal Exam: Yes, it can and should be done in a busy practice! Am J Gastroenterol.  2018;113(5):635-638. doi:10.1038/s41395-018-0006-y

41. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109 Suppl 1:S2-26; quiz S27. doi:10.1038/ajg.2014.187

42. Rao SS, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults. Nat Rev Gastroenterol Hepatol. 2016;13(5):295-305. doi:10.1038/nrgastro.2016.53

43. Ramkumar D, Rao SS. Efficacy and safety of traditional medical therapies for chronic constipation: systematic review. Am J Gastroenterol. 2005;100(4):936-71. doi:10.1111/j.1572-0241.2005.40925.x

44. Rao SSC, Brenner DM. Efficacy and Safety of Over-the-Counter Therapies for Chronic Constipation: An Updated Systematic Review. Am J Gastroenterol. 2021;116(6):1156-1181. doi:10.14309/ajg.0000000000001222

45. Bharucha AE, Pemberton JH, Locke GR, 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology. 2013;144(1):218-38. doi:10.1053/j.gastro.2012.10.028

46. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation. Gastroenterology.l 2022;163(1):118-136. doi:10.1053/j.gastro.2022.04.016

47. Dipalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol. 2007;102(7):1436-41. doi:10.1111/j.1572-0241.2007.01199.x

48. Chapman RW, Stanghellini V, Geraint M, Halphen M. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol.  2013;108(9):1508-15. doi:10.1038/ajg.2013.197

49. Gearry R, Fukudo S, Barbara G, et al. Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort—Results of an International Multicenter Randomized Controlled Trial. Official journal of the Am J Gastroenterol. 2023;118(6):1058-1068. doi:10.14309/ajg.0000000000002124

50. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome–results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther.  2009;29(3):329-41. doi:10.1111/j.1365-2036.2008.03881.x

51. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107(11):1714-24; quiz p.1725. doi:10.1038/ajg.2012.255

52. Rao SSC. Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol. 2018;11:1756284818777945. doi:10.1177/1756284818777945

53. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3′,5′-monophosphate. Gastroenterology. 2013;145(6):1334-46.e1-11. doi:10.1053/j.gastro.2013.08.017

54. Rao SS, Quigley EM, Shiff SJ, et al. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol. 2014;12(4):616-23. doi:10.1016/j.cgh.2013.09.022

55. Rao SSC, Xiang X, Yan Y, et al. Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis. Aliment Pharmacol Ther. 2020;51(12):1332-1341. doi:10.1111/apt.15772

56. Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. doi:10.14309/ajg.0000000000000516

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LIVER DISORDERS, SERIES #17

Drug-Induced Liver Injury (DILI): A Practical Review

December 2024 • Volume XLVIII, Issue 12
Ramiro De La Guerra,Tyrell Daniel,Oluwakemi Adewuyi,Michael Babich

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Drug-induced liver injury (DILI) is a common cause of acute liver injury and is the most common cause of acute liver failure in the United States1. DILI can be caused by a wide variety of compounds, including antibiotics, anticonvulsants, antidepressants, and herbal supplements. The risk of DILI is increased in patients with underlying liver disease, alcohol use, and certain genetic polymorphisms.

The diagnosis of DILI is based on a history of drug exposure, liver enzymes, and, less commonly, liver biopsy. Clinical and histologic presentation can mimic other causes of liver injury, which can make diagnosis challenging. The treatment of DILI, however, is supportive and includes stopping the offending drug and treating any complications. The prognosis of DILI is variable, but most cases are mild and resolve with discontinuation of the offending drug. Accurate diagnosis is paramount to prevent further unnecessary testing, therapies, complications, and lengthy hospital stays. 

Background

Drug-induced liver injury (DILI) is a common cause of acute liver injury and is the most common cause of acute liver failure in the United States.1 It is estimated that DILI occurs in 1-6% of hospitalized patients and liver injury may occur 10-15% of patients taking new medications. A study by Chalasani et al. conducted in a large academic medical center in the US found that DILI accounted for 13% of cases of acute liver injury in hospitalized patients between 1994 and 2006.18 Additionally, DILI remains the leading reason for the post-market withdrawal of medications by the Federal Drug Administration (FDA) in the United States.2,16 Compounds commonly implicated in DILI include antimicrobials, antidepressants, anticonvulsants, analgesics, and herbal and dietary supplements. In Western countries, acetaminophen remains the leading cause of DILI.3

The incidence of DILI ranges between 2.4 in 100,000 to 19 in 100,000 persons per year globally24,7 according to population studies in the UK, France, and Sweden. A recent study by Björnsson et al. encompassing the population of Iceland utilizing a national healthcare database revealed an incidence of non-acetaminophen DILI of 19 in 100,000 per year8 in that population. The true incidence of DILI, however, is difficult to accurately determine. Liver injury is a significant consideration during drug development given the vast number of medications metabolized in the liver. Adverse effects of medications, including DILI, often can be discovered in clinical trials prior to regulatory approval and drug marketing. These clinical trials, however, are generally comprised of a limited number of subjects. Given the low incidence of DILI, the majority of cases are only discovered after regulatory approval and increased use of a medication in the general population. In a prospective survey to physicians in France performed over a 3-year period, the incidence of symptomatic DILI was found to be 14 in 100,000 patients per year.7 Notably, this number was 16 times greater than adverse hepatic events reported to the French regulatory authority.7 Similarly, in the United States, the post-market Adverse Events Reporting System established by the FDA is voluntary, may be incomplete, and may skew attribution of causality, ultimately underestimating true incidence of DILI25 in the general population.  

Pathophysiology

The pathophysiology of DILI is complex and not fully understood. However, it is thought to involve a combination of genetic, environmental, and drug-related factors. Liver injury related to drugs or herbal and dietary supplements can generally be subdivided into two types of DILI—intrinsic or idiosyncratic. 

Intrinsic DILI is defined as a direct, dose-dependent, and predictable hepatotoxicity. These compounds are generally thought to cause predictable liver injury in patients regardless of risk factors in a mainly dose-dependent fashion. Injury commonly arises from the drug itself or an active metabolite. This results in a series of events resulting in cell death. Mechanisms include production of free radicals, reactive oxygen species, interfering with native cellular components and cellular functions.36 This can subsequently lead to entities such as acute hepatitis or sinusoidal obstruction syndrome. Many intrinsically hepatotoxic compounds are identified in pharmaceutical trials or removed by regulatory agencies after post-market reporting.37 Some compounds, however, normally limited to therapeutic doses, are known to cause intrinsic hepatotoxicity in higher doses. The most common and well-studied example is acetaminophen (APAP), which is the leading cause of drug-induced liver failure in the US. In supratherapeutic doses, the accumulation of the hepatotoxic APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) causes direct oxidative cellular injury.3 Other compounds implicated with intrinsic liver injury in high doses include niacin and iron sulfate as well as those naturally occurring in some mushrooms such as Amanita phalloides. 

Idiosyncratic DILI, however, is unpredictable and liver injury may not be dose dependent. The difficulty in identifying idiosyncratic DILI arises from its variable presentation and unpredictability. The incidence of idiosyncratic reactions to medications is low and, as a result, often escapes identification in preclinical and clinical pharmaceutical trials.36,38 Idiosyncratic DILI is thought to affect a predisposed population based on risk factors that are not well understood. 

Risk Factors

Several risk factors for DILI have been proposed in the medical literature, however there is no clear evidence to suggest that they represent major risk factors for the development of all-cause DILI independent of a specific compound.40

Certain risk factors, however, may predispose an individual to injury with specific medications. Children are thought to be at higher risk of developing DILI with certain medications such as anticonvulsant and antimicrobial medications whereas older adults are more likely to develop liver injury with amoxicillin-clavulanate, nitrofurantoin, and isoniazid.39,40 Females may have an increased risk with minocycline, methyldopa, diclofenac, nitrofurantoin, and nevirapine. Risk for DILI in pregnancy may be increased with methyldopa, hydralazine, and antiretrovirals.42

Risk FactorMedications
Age
 ChildrenAnticonvulsants Antimicrobials
 Older AdultsNitrofurantoin Amoxicillin-clavulanate Isoniazid
Female SexMinocycline Methyldopa Diclofenac Nitrofurantoin Nevirapine
PregnancyTetracycline Methyldopa Hydralazine Antiretrovirals
Diabetes MellitusMethotrexate Antituberculosis medications
Alcohol ConsumptionAcetaminophen (chronic alcohol use) Methotrexate Isoniazid Anabolic steroids
Drug-drug InteractionsAntituberculosis medications Anticonvulsants
Table 1.
Risk Factor Associated with DILI
Related to Particular Compounds

Other chronic comorbidities have been seen associated with higher risk of liver injury in combination with specific agents. In particular, diabetes mellitus may be related to a higher risk of DILI with methotrexate and antituberculosis medications as seen in a publication by the US DILI Network (DILIN).9

Environmental risk factors such as chronic alcohol use may be an additional risk factor for DILI, particularly with methotrexate and isoniazid41. Chronic alcohol use also increases the risk of liver injury from acetaminophen overdose. Interestingly, acute coingestion of alcohol with an acetaminophen overdose has been seen to confer a lower risk of DILI due to suspected substrate competition for metabolism of both compounds.43 

Drug-drug interactions, particularly with antituberculosis medications and anticonvulsants, may potentially increase the risk for DILI.41

R ratio =ALT ÷ ALT ULN _________________ Alk Phos ÷ Alk Phos ULN
Table 2. Calculation of R Ratio47
ALT: alanine aminotransferase, ULN: upper limit of normal of resulting laboratory, Alk Phos: alkaline phosphatase

Gender may also be associated with different outcomes following acute liver injury. Notably, acute liver injury in females was more likely to progress to acute liver failure as seen in several DILI registries.4,18,29

Other risk factors have been proposed which may increase the risk of DILI, such as other underlying liver disease, smoking, obesity, and malnutrition, however there is no clear evidence to suggest that these are major independent risk factors.41

Another risk factor proposed in the medical literature is race, however there remains no convincing evidence to suggest this as an independent risk factor due to confounding socioeconomic variables. Data from the US DILIN cohort saw that DILI in African-Americans was noted to occur in a younger age group and was associated more frequently with chronic symptoms when compared to Caucasians despite no significant difference in patterns of injury and recovery time. African Americans in that cohort, when compared to Caucasians, were seen to be twice as likely to develop severe liver injury leading to worse outcomes.19 Reasons for these outcomes are unclear, but may be related to unaccounted-for disparities in access to healthcare and reporting of adverse effects as well as other socioeconomic biases.51

Clinical presentation

The clinical presentation of DILI is variable and depends on the severity of the injury. Patients with mild DILI may have no symptoms or only mild symptoms, such as fatigue, nausea, and vomiting. With increasing severity of DILI, patients may exhibit jaundice, abdominal pain, and ascites. In very severe cases, DILI can present with coagulopathy and encephalopathy (signifying acute liver failure) and can subsequently lead to death.8

Clinically, DILI can be subcategorized based on the pattern of injury to the liver—hepatocellular, cholestatic, or mixed hepatocellular and cholestatic injury.44 Hepatocellular injury can be identified by a disproportionate increase in serum aminotransferases when compared to alkaline phosphatase. Cholestatic injury is identified by a disproportionate increase in alkaline phosphatase when compared to aminotransferases. In both cases, serum bilirubin may be elevated and synthetic function of the liver may be affected. These patterns can typically be differentiated by the calculation of the R ratio (Table 2) which compares the values of ALT and alkaline phosphatase. Typically, certain medications have been found to be more commonly associated with a specific pattern of hepatic injury (Table 3). 

Pattern of Liver InjuryCompounds Associated with DILI
Hepatocellular   R ratio ≥5Fluoroquinolones Isoniazid Macrolides Nitrofurantoin Minocycline Phenytoin Lamotrigine Valproate NSAIDs Diclofenac  INF-beta INF-alphaAnti-TNF agents Immune-checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab) Allopurinol Azathioprine Amiodarone Inhaled anesthetics Sulfasalazine
Cholestatic   R ratio ≤2Amoxicillin-clavulanate Androgen-containing steroids Trimethoprim/Sulfamethoxazole AzathioprineFluoroquinolones Phenytoin Sulfasalazine
Mixed   R ratio = 2 to 5Allopurinol  Immune-checkpoint inhibitors (early) FluoroquinolonesPhenytoin Sulfasalazine
Table 3. Pattern of Liver Injury Associated with Common Culprits of DILI
*Note: some compounds can produce multiple patterns of injury or can initially cause one pattern and later cause another pattern. These compounds are listed several times in this table

A poorly understood mechanism of injury, however, is immune-mediated DILI. This pattern of injury, thought to be related to an immune-mediated attack of the liver as a result of a specific metabolite, can often be associated with symptoms of hypersensitivity such as fever, rash, joint pains, lymphadenopathy, and eosinophilia.45 This symptomatic presentation may also resemble infectious mononucleosis. This pattern of injury has been associated with amoxicillin-clavulanate, diclofenac, phenytoin, and allopurinol.46

Another specific pattern includes drug-induced autoimmune hepatitis (DI-AIH). This presents with features of autoimmune hepatitis (AIH) such as elevated gamma-globulins, antibodies against smooth muscle, and/or antinuclear antibodies.46 Interestingly, this entity is responsive to treatment with corticosteroids and, as such, it is important to differentiate this entity from other injury patterns of DILI, where steroids may be less efficacious. Particularly, minocycline use in children can be seen to have a delayed pattern of injury resembling AIH. 

Globally, the most common medications implicated in DILI are antibiotics, with the most common culprit in Western countries being amoxicillin-clavulanate (Table 4).8,19,48 More recently, however, with the increased use of herbal/dietary supplements (HDS), incidence of liver injury attributed to these agents has also been increasing.59,60 The most common cause of injury among HDS are bodybuilding supplements.60 Clinically, this can present with prolonged jaundice in otherwise healthy young men. Liver injury related to non-bodybuilding supplements is more commonly seen in females, usually presents with a hepatocellular pattern of injury and is associated with worse outcomes and higher rates of transplantation.60 

Diagnosis 

Despite its low incidence, DILI should always be included in a differential diagnosis of liver injury. Diagnosis of DILI poses significant difficulty to the clinician given the variability of objective markers of liver injury and the difficulty to assign causality to a certain medication. One of the earliest definitions of DILI, specifically that with an hepatocellular pattern of injury, was developed by Dr. Hyman Zimmerman based on observations published in 1968 and again in 1999, suggesting that elevation of aspartate transaminase (AST) or alanine transaminase (ALT) more than three times the upper limit of normal (ULN) along with an elevation of total bilirubin more than two times the ULN in the absence of cholestasis (elevation of alkaline phosphatase < 2x the ULN) is a predictor of severe liver injury and poor outcomes (with a mortality of 10-50%, in pre-transplant days).26,27 Later dubbed Hy’s law, these parameters, in the absence of other etiologies of liver injury, signaled the potential for a drug to cause liver injury and have comprised part of the recommendations by the FDA for pharmaceutical trials. 

Spanish Registry (n = 843)48DILIN (n = 899)19Icelandic Study (n = 96)8
Amoxicillin-clavulanate (22%)Amoxicillin-clavulanate (10%)Amoxicillin-clavulanate (22%)
Anti-tuberculosis (4.5%)Isoniazid (5.3%)Diclofenac (6.3%)
Ibuprofen (3%)Nitrofurantoin (4.7%)Nitrofurantoin (4%)
Flutamide (2.6%)Sulfam-trimeth (3.4%)Azathioprine (4%)
Atorvastatin (1.9%)Minocycline (3.1%)Infliximab (4%)
Diclofenac (1.8%)Cefazolin (2.2%)Isotretinoin (3%)
Ticopidine (1.4%)Azithromycin (2%)Atorvastatin (2%)
Azathioprine (1.3%)Ciprofloxacin (1.8%)Doxycyline (2%)
Fluvastatin (1.3%)Levofloxacin (1.4%)Imatinib (1%)
Simvastatin (1.3%)Diclofenac (1.3%)Isoniazid (1%)
HDS (3.4%)HDS (16.1%)HDS (16%)
Table 4. The Most Common Implicated Agents Causing DILI in Three Prospective Studies on DILI
Abbreviations: DILI, drug-induced liver injury; HDS, herbal and dietary supplements; Sulfam-trimeth, sulfamethoxazole-trimethoprim
Reproduced from: Björnsson ES. Clinical management of patients with drug-induced liver injury (DILI). UEG Journal. 2021 Sep;9(7):781-6.

In an effort to further delineate causality based on objective measurements, the Roussel Uclaf Causality Assessment Method (RUCAM) system was developed in 1993 as an assessment score reflecting the likelihood that liver injury can be attributed to a specific compound.30 This system was validated on findings of a consensus meeting of experts (including Drs. Benhamou, Bircher, Dana, Maddrey, Neuberger, Orlani, Tygstrup and Zimmerman) and uses a combination of serologic, clinical, and radiologic features of liver injury assigned to a point system. This study found that scores usually agreed among the experts, with only 16% of scores being more than 1 point divergent.30,47

History

DILI should be considered amongst a wider differential diagnosis of more common causes of liver injury, as it largely remains a diagnosis of exclusion. Obtaining an accurate and thorough history is paramount to making a diagnosis of DILI. This should particularly involve a comprehensive review of medications with respect to the timing of their initial dosing, onset and chronicity of symptoms, and liver chemistry abnormalities. Additionally, care should be taken to inquire about the use of herbal and dietary supplements as these are increasingly more common causes of DILI.13 

Figure 1. A diagnostic workflow for assessing cases of suspected DILI 49. Reproduced from Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017 Jun 1;66(6):1154-64: Figure 3. Used with permission from BMJ Publishing Group Ltd.

A particularly useful tool for clinicians developed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) along with the National Library of Medicine is LiverTox (https://www.ncbi.nlm.nih.gov/books/NBK547852). This is a publicly available and easily accessible online textbook which maintains continuously up-to-date information on the likelihood and pattern of hepatotoxicity of over 1200 compounds.50 The aim of the LiverTox resource is to consolidate information that is not readily available and is dispersed throughout multiple publications in multiple disciplines throughout the world. This repository is constantly updated as new medications are introduced and their hepatotoxic side effects are brought to light through more frequent use. 

Laboratory Investigations

After a thorough history is obtained, liver chemistry abnormalities should be analyzed for their pattern of injury. This can be objectively accomplished by calculating an R ratio (Table 2). This in turn will help differentiate between hepatocellular injury, cholestatic injury, or a mixed injury. The pattern of injury can then guide further workup. 

For a hepatocellular pattern of injury (R ratio ≥5), causes of acute hepatitis should be further investigated. Preliminary testing should include serologies for acute viral hepatitis (including HCV RNA), serologies for autoimmune hepatitis, as well as imaging studies of the liver such as ultrasonography. If first-line testing is unrevealing, a hepatocellular pattern of injury should be further explored with ceruloplasmin and serologies for less common etiologies of viral hepatitis such as CMV, EBV (quickly assessed with monospot testing), and COVID, and possibly liver biopsy. 

For a cholestatic pattern of injury (R ratio ≤2), primary testing should involve imaging studies, such as abdominal ultrasound. If unrevealing, further testing by cholangiography, serologies for primary biliary cholangiopathy (PBC), and liver biopsy can be considered. 

A mixed pattern of liver injury (R ratio 2-5) should primarily involve workup for acute viral hepatitis (as detailed above), serologies for autoimmune hepatitis, as well as imaging studies of the liver with ultrasonography. If this is unrevealing, further testing for ceruloplasmin levels, serologies for less common causes of viral hepatitis, and liver biopsy can also be considered. 

If thorough testing and history can reasonably exclude a non-DILI etiology of liver injury, a literature review utilizing the LiverTox database should be performed to reexamine the likelihood of liver injury by reported medications and/or dietary or herbal supplements. 

Ultimately the final diagnosis of DILI is based on clinical judgment and clinical suspicion. Consultation with an expert should be sought if there remains a doubt about the diagnosis or if specialized assistance is needed for further workup such as with endoscopic cholangiography. 

Liver Biopsy

The diagnosis of DILI typically does not require a liver biopsy. Biopsy findings may be supportive of DILI but are rarely diagnostic. Nearly every type of histologic abnormality can be mimicked by certain drugs, although each individual drug is typically associated with a histologic pattern characteristic to that drug. Review of every drug’s histologic pattern is beyond the scope of this article. Histologic evaluation may be useful, however, to exclude an alternate etiology of liver injury, particularly if there is no initial resolution of liver injury (i.e., persistently abnormal liver chemistries) following withdrawal of a suspect agent (dechallenge). 

Acute liver failure

Clinical symptoms should be closely evaluated during presentations with acute liver injury. Particular care should be taken to monitor for progression to ALF based on diagnostic indicators, namely an INR >1.5 and signs of hepatic encephalopathy (altered mental status/asterixis). A timely diagnosis of ALF should prompt immediate referral to a liver transplant center in order to begin evaluation for liver transplantation, particularly in the setting of DILI, due to the high associate mortality rate. 

Treatment

Once the diagnosis of DILI has been established, the mainstay of treatment is the removal of the offending compound/medication. Dechallenging results in a complete resolution of liver injury without the need for additional treatment in a vast majority (>90%) of cases.52,53 Furthermore, a successful dechallenge suggests the potential causality of a medication to liver injury and care should be taken to avoid re-exposure. Although care for DILI is mainly supportive, there are certain directed therapies which have shown to improve outcomes in liver injury by specific agents. 

Although treatment of liver injury related to acetaminophen with N-acetylcysteine (NAC) has been well-established, evidence has suggested that treatment of non-acetaminophen liver injury with NAC should be considered in patients presenting with ALF related to idiosyncratic DILI. A randomized trial by the US ALF study group revealed a two-fold increase in transplant-free survival in patients who received NAC vs a placebo infusion.54

Treatment of DILI related to terbinafine and leflunomide with a bile-acid binder has been shown to facilitate clearance of these compounds.52,55 Valproic acid hepatotoxicity can be treated with carnitine, which regulates fatty acid uptake and mitochondrial beta-oxidation.52,56 In patients undergoing myeloablative hemopoietic stem cell transplant (HSCT), ursodiol has shown good results as prophylaxis against sinusoidal obstruction syndrome (SOS, formerly veno-occlusive disease). Similarly, defibrotide can be considered not only as a treatment for severe SOS but also as prophylaxis for those at high risk.57

The use of corticosteroids in idiosyncratic DILI remains controversial, and corticosteroids are mainly reserved for use in the setting of drug-induced AIH, severe hepatitis related to immunotherapy, or in hypersensitivity. In patients with severe liver injury, lower survival was seen in patients treated with corticosteroids.58 Close monitoring is essential during treatment with corticosteroids. In the absence of a response to treatment, corticosteroid treatment should be discontinued in order to prevent steroid-related adverse effects, and an alternate diagnosis should be considered.51 In the event of response to corticosteroid treatment, steroids should be withdrawn in a gradual manner. This should be paired with close follow up and monitoring of liver chemistries for the reappearance of liver injury in order to detect an AIH component, which would require ongoing treatment.  

Conclusion

Drug-induced liver injury (DILI) is a serious condition that can lead to severe liver injury, acute liver failure, and even death. Although the incidence of DILI is relatively low, it is important for clinicians to be aware of DILI and its general workup in order to recognize and manage this condition early. Diagnosis is mostly clinical, with the assistance of resources such as LiverTox. The approach to suspected DILI involves recognizing general signs and symptoms, careful history taking, excluding alternative causes of liver injury, assessing severity, identifying and discontinuing the offending drug. It is similarly important to monitor for ALF in order to provide a timely referral to a liver transplant center. 

The most common cause of DILI in the US remains acetaminophen and the use of NAC is well-established in its treatment, but NAC should be considered in use for idiosyncratic DILI given data on improved outcomes in non-acetaminophen related DILI. In most cases, removal of the offending medication results in resolution.

The best way to prevent DILI, however, is to avoid agents that are known to cause liver injury, particularly in those individuals who are susceptible. Providers should be aware of the increased use of herbal and dietary supplements and the increasing incidence of liver injury related to their use. 

Aftermarket reporting of DILI remains extremely important in providing ongoing data regarding the hepatotoxicity of medications. Providers should strongly consider reporting hepatotoxic effects of medications to regulatory agencies. In the US, reports to the FDA Adverse Events Reporting System (FAERS) database can be submitted by anyone, including healthcare professionals, patients, and consumers. 

In some cases, it may be necessary to rechallenge a patient with the suspected drug if it is the only effective treatment for a particular condition, however this should only be done after careful consultation with a hepatologist. 

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Nutrition Reviews in Gastroenterology, SERIES #20

Patient-Centered Plant-Based Approach to Diets for Gastrointestinal Disorders

December 2024 • Volume XLVIII, Issue 12
Anh Trinh Doan,Anna Simons,Ian Fladie,Alexis Bejcek,Vani Paleti

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Over the past decade, whole food plant-based diets (WFPBDs) have gained popularity as evidence has emerged regarding their association with improved morbidity and mortality for many patient populations, including those with gastrointestinal diseases. Multiple factors contribute to the benefits of a WFPBD, including the impact of fiber on the gut microbiome, reduction of the additives found in processed foods such as emulsifiers and stabilizers, and the anti-inflammatory properties of plant-based foods compared to animal-based foods. This review discusses general components and benefits related to WFPBDs, with an evidence-based focus on their role in managing and preventing gastrointestinal disorders. In addition, we offer practical guidance and tools for healthcare providers to help their patients adopt and sustain a WFPBD.  

Introduction

Whole food plant-based diets (WFPBDs) emphasize maximizing the intake of plant-based foods while minimizing highly processed and animal-based foods. Over the last decade, WFPBDs have been emerging with strong evidence regarding their impact on morbidity and mortality in various diseases.1 Current evidence has highlighted the positive effect of WFPBDs on not only gastrointestinal (GI) diseases but also metabolic syndrome, cardiovascular diseases, cognitive function, and overall mortality risk.1-3 WFPBDs encourage a high-fiber intake to influence the diversity and composition of the gut microbiome, a key connection between diet and metabolic health.4 Ultra-processed foods may play a role as a significant contributor to the development of GI disorders such as inflammatory bowel disease (IBD), colorectal cancer, and metabolic dysfunction-associated steatotic liver disease (MASLD).2,5,6 WFPBDs aim to address and mitigate the underlying factors that may contribute to these disorders.1-3,5,6

Despite the increasing popularity of WFPBDs, there are still inconsistencies in its definition, leading to confusion about its composition among patients and healthcare providers. This review explores the core principle of WFPBDs and their multifaceted connections to various GI disorders. We will also outline a patient-centric approach for providers to help patients adopt new dietary habits while addressing the potential challenges of WFPBDs.

What is a Whole Food Plant-based Diet?

The WFPBD focuses on the consumption of vegetables, fruits, whole grains, and legumes in their most natural form while reducing or eliminating animal products.7 This emphasis on whole foods inherently decreases the intake of emulsifiers and stabilizers, which are standard components of ultra-processed foods. Emulsifiers, often used to improve texture and shelf life, have been associated with increased inflammation and detrimental changes to the microbiome composition.8 Similarly, stabilizers, such as maltodextrins, have been linked to intestinal protective mucus layer damage and the subtle development of intestinal inflammation.8

WFPBD can be tailored to fit individual preferences, offering flexibility in food choice while maintaining its core principle of whole, minimally processed plant-based diet. Patients may adopt various forms of WFPBD, such as vegan, lacto-ovo-vegetarian, pescatarian, or Mediterranean diets (MD).7 (See Table 1) With guidance from registered dietitians and healthcare providers with expertise in WFPBD, patients can choose a dietary pattern that best matches their health goals and cultural preferences, all while supporting long-term health benefits and managing their GI diagnosis.

Fiber and the Gut Microbiome

Fiber is traditionally defined as the non-digestible components that make up the plant cell wall.9 It remains a critical part of the diet today, with plants serving as the primary source. Dietary fiber has various properties – solubility, fermentability, and viscosity – that influences its health benefits within the GI tract.10 Solubility refers to the ability of the fiber to dissolve in water. Fermentability indicates the ability of the gut bacteria to digest fiber. Viscosity refers to fiber’s capacity to hold water and form a thick, gel-like substance.4 As such, fiber can be categorized into many types: soluble/fermentable/viscous (e.g., pectin, galactomannans, beta-glucans), soluble/fermentable/non-viscous (e.g., inulin, oligofructose, fructo-oligosaccharides), and insoluble/non-fermentable/non-viscous (e.g., lignin, cellulose).10,11 (See Table 2)

Types Definition
Whole food plant-based dietWhole food ingredients comprised primarily of vegetables, minimally processed fruits, whole grains, legumes, nuts, or seeds. Covers a wide range of other diets including vegan, lacto-ovo-vegetarian, pescatarian, and Mediterranean diet.
Vegan dietStrictly excludes meat, poultry, eggs, dairy, and any food that contains them.
Lacto-ovo-vegetarian dietInclude eggs and dairy. Excludes meat, poultry, and fish.
Pescatarian dietIncludes seafood but excludes meat and poultry. May or may not include eggs and dairy.
Mediterranean dietPrimarily fruits, vegetables, whole grains, and fish. Poultry, eggs, and dairy are eaten in moderation. Meat and added sugars are consumed infrequently.
Table 1. Definitions of Whole Food Plant-Based Diets7

Gut microbiota is a community of microorganisms, including bacteria, archaea, fungi, and viruses, that reside within the GI tract, shaping our gut immune system by regulating the expression of colonic regulatory T cells.12 Soluble, non-viscous, and fermentable fibers, once fermented by colonic bacteria, help generate short-chain fatty acids (SCFAs) such as butyrate and acetate, which are the preferred energy sources for colonic mucosa cells.13 SCFAs also promote the growth of beneficial gut bacteria, such as Bifidobacteria and Lactobacilli. Subsequently, they increase the immune reactive myenteric neurons and inhibit the signaling pathway for colonic inflammation.4 In contrast, a low-fiber diet can disrupt this process, resulting in dysbiosis, a harmful imbalance in the gut microbiota characterized by reduced bacterial diversity and an overgrowth of harmful microorganisms.14,15

Properties BenefitsTypesFood Sources
SolubleViscous/ fermentable–
Moderate pre-biotics potential –
Produce SCFAs to stimulate immune system		Beta-glucan, pectin, guar gumGuar beans, oats, barley, fruits, cereal brans, berries
Non-viscous/ fermentable–
Strong pre-biotics potential –
Produce SCFAs to stimulate immune system		Inulin, fructo-oligosaccharides, oligofructose, galacto-oligosaccharidesChicory root, asparagus, garlic, onion, artichoke
Insoluble/ non-fermentable/ non-viscous -Alleviate constipation Cellulose, ligninSkins of fruits, leafy greens, wheat bran,
green beans, quinoa, nuts, flaxseed
Table 2. Roles and Types of Fiber4,9-11

Meanwhile, insoluble/poorly fermentable fiber irritates gut mucosa, stimulates mucous, and water secretion. An osmotic load is then formed to improve absorption and decrease gastrointestinal transit time, alleviating chronic constipation.11 

Polyphenols and the Gut Microbiome

Polyphenols are natural metabolites synthesized exclusively by plants. Most polyphenols come from fruits, vegetables, grains, spices, herbs, and teas. Extensive studies on these compounds have highlighted their beneficial roles in promoting antioxidant, anti-inflammatory properties and healthy gut microbiome.16 Upon consumption, only a small fraction of polyphenols is absorbed in the small intestine.17 The remaining polyphenols are metabolized by the colon and undergo a transformative process facilitated by gut microbes. This process promotes a shift in the composition of the gut microbiota from harmful species, such as Clostridium spp. and Bacteroides spp., to beneficial bacteria, including Lactobacillus spp. and Bifidobacterium spp.18,19 These beneficial species produce butyrate and promote anti-inflammation through a reduction in C-reactive protein.18

Other studies have noted the ability of polyphenols to interact and cause apoptosis of harmful cell membranes via hydrogen bonding with lipid bilayers.20 This antimicrobial property allows polyphenols to inhibit the growth of pathogenic bacteria such as Escherichia coli and Klebsiella pneumoniae while providing protective effects against tumor cells.17,20 Moreover, the antioxidant and anti-inflammatory effects of polyphenols are likely related to their ability to inhibit pro-inflammatory cytokines such as TNF-alpha and IL-6 and suppress free radical generation by activated neutrophils in the GI lumen.21 One of the most well-known polyphenols is curcumin, a natural compound found in turmeric. It has shown potential benefit for IBD patients. One study has demonstrated that daily intake of 2 grams of curcumin, combined with sulfasalazine or mesalamine, was more effective in preventing clinical relapse in patients with ulcerative colitis compared to treatment with sulfasalazine or mesalamine and placebo compound.22

GI Disorders DietsWFPBD Foods 
Inflammatory bowel disease–
Mediterranean diet –
Lacto-ovo-vegetarian diet –
For strictures or active flares: foods in small particle size 		–
Fruit. If stricturing: soft fruits (banana, berries, avocado), fruits in small particle size, no peels –
Vegetables. If stricturing: small particle size for cooked vegetables, no peels –
Protein: fatty fish, creamy peanut butter, ground flaxseed  –
Add olive oil to meals, smoothies, hummus and crackers, yogurt, and berries
Irritable bowel syndrome -Soluble fibers -Low- FODMAP-Fruits: kiwi, banana, blueberries, cantaloupe, grapes –
Vegetables: bok choy, carrots, green beans, zucchini, lettuce –
Dairy/Dairy Substitutes: lactose-free milk or yogurt, hard cheeses such as cheddar or swiss, almond or coconut milk -Protein: chicken, fish, egg, tofu
Gastroparesis –
Small and frequent meals with a small particle size diet		–
Fruits: soft fruits such as cantaloupe, honeydew, or kiwi with no peel –
Vegetables: should be cooked or mashed, blended into small particle size, no peel –
Protein: ground chicken or turkey, fish, creamy nut butter, tofu -Dairy: milk, sprinkle of cheese, yogurt
Metabolic dysfunction-associated steatotic liver disease–
Mediterranean diet –
Any type of WFPBD		-Fruits: all -Vegetables: all -Whole grains: all -Legumes: all -Proteins: fatty fish, flax seed, chia seeds, nuts
Celiac disease-Gluten-free diet -Fruits: any fresh or frozen -Vegetables: any fresh or frozen -Milk and/or dairy: milk, plain cheese, yogurt –
Gluten-free grains: quinoa, millet, sorghum, amaranth, buckwheat, teff, and wild rice –
Proteins: lean meats, eggs, beans, chickpeas, edamame, tofu
Gastroesophageal reflux disease-WFPBD –
minimize chocolate, peppermint, coffee, citrus, and spicy food		-Fruits: non-citrus fruit only -Vegetables: fresh and raw  -Whole grain: oatmeal, whole-grain bread, rice -Dairy: any –
Protein: lean meats that are grilled/ poached, broiled or baked -Use fresh herbs instead of spice for flavors
We recommend incorporating a variety of plant-based food in all meals, with portion sizes and frequency tailored to individual tolerance and preferences. As a starting point, patients can create a balanced plate using the My Plate method (https://www.myplate.gov/) or Mediterranean diet pattern (www.oldwayspt.org). From there, adjustments can be made based on personal needs, to further meet nutritional needs and ensure sustainability overtime. 
Table 3. A Summary of Recommended Diets for Gastrointestinal Disorders and Sample PBD28,30,31,32,40,41,44,45,48

WFPBDs and Gastrointestinal Disorders 

Inflammatory Bowel Disease 

The Western diet is recognized as a predominant environmental risk factor in IBD.23,24 A prospective study of long-term dietary fiber intake (median of 24.3g/day, mainly from fruits) demonstrated a reduced risk of Crohn’s disease in individuals who consumed higher quantities of fiber, particularly from fruit sources.24 Likewise, a trial of 92 patients with ulcerative colitis (UC) showed lower clinical relapse rates with the regimen of a WFPBD and induction therapy compared to induction therapy alone.25 

Another small two-year clinical study examined remission rates in Crohn’s disease (CD) patients, who had initially achieved remission through medical or surgical intervention. They were advised to maintain a semi-vegetarian diet and avoid processed foods. Among the sixteen patients who adhered to the diet, 100% remained in remission after 1 year, and 92% maintained remission after two years. In contrast, remission rates were only 67% at one year and 25% at two years among the six patients who did not follow the diet.26 Finally, the Diet to Induce Remission in Crohn’s Disease (DINE-CD) trial compared MD to the Specific Carbohydrate Diet and found no significant difference in symptomatic remission or inflammation reduction at six weeks between the two diets.27 Thus, data suggest that recommending less restrictive diets, like the MD, would be reasonable for symptom control in IBD. (See Table 3)

Patients with symptomatic or significant fibro-stricturing IBD often have concerns about fiber consumption. For these individuals, the quantity, type, and particle size of fiber are critical to ensure optimal tolerance.28 There is limited evidence on complete fiber restriction in individuals with strictures or active flares. Soluble fibers such as bananas, avocados, and most berries tend to be better tolerated.29 In contrast, insoluble fiber, such as raw kale or apple skin, may need modification to small particle size into blended, mashed, and minced forms.30 As an example, patients can replace apples with applesauce and garbanzo beans with hummus, and blend fruits and vegetables into a smoothie.31

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common GI disorder involving the gut-brain interaction. The 2021 American College of Gastroenterology (ACG) Clinical Guidelines recommend whole food soluble fiber such as oat bran and barley to treat global symptoms of IBS.32

As a highlight, controlled trials have demonstrated a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is effective in improving disease-specific quality of life, anxiety, and activity impairment in IBS patients with diarrhea predominance.33 However, more studies are still needed to evaluate its efficacy in patients with IBS-constipation.32 The low-FODMAP approach involves 3 phases. The first is the elimination phase, during which all high-FODMAP foods are replaced with low-FODMAPs for 4-6 weeks. In the reintroduction phase, patients gradually reintroduce a high-FODMAP food one at a time to learn foods that exacerbate their symptoms. The last phase, personalization, is for patients to customize their diet based on what was learned from the trials of reintroduction. Patients can then retain the well-tolerated high-FODMAP items and limit the portions of those that were not.33

A WFPBD can be tailored to fit the low-FODMAP with a few strategic adjustments. Low-FODMAP whole grains (e.g., oatmeal, quinoa), fruits (e.g., blueberries, kiwi), and vegetables (e.g., spinach, zucchini) can be included in WFPBD meals throughout the day. Research also shows that certain food processing methods can significantly reduce FODMAP content.34 For example, pickling artichokes, onion, or garlic lowered their FODMAP content by 80-90%, while canning and simmering beans or lentils reduces their oligosaccharide content, increasing options for patients personalizing their WFPBD to a low-FODMAP diet.34 

Gastroparesis

Gastroparesis (GP) is defined by symptoms suggestive of gastric food retention and objective evidence of delayed gastric emptying without mechanical obstruction.35 Traditionally, the dietary treatment for GP is low-fat and low-fiber meals 4-5 times daily, which came with its limitations such as malnutrition and digestive issues.35,36 In the recent years, the recommendation has shifted to modifying food consistency to small particle size by blending, mincing, mashing, or chopping.35,37 A 2018 experimental study explored how the particle size of food influenced gastric emptying. The study compared two solid meals with identical components but different gastric sizes, demonstrating that the smaller particle size diet significantly increased gastric emptying rates.38 Further supporting this, a 2014 randomized controlled trial showed a significant reduction of GP symptoms with use of a small particle size diet.37

For GP patients following a WFPBD, small and frequent meals in small particle size are often recommended to optimize tolerance. Plant foods with large particle sizes, such as food with husks or peels (e.g., pineapple, corn, and cabbage), foods with membranes (e.g., oranges and apples), raw vegetables, seeds, and grains should be cooked, ground, or blended.35

Metabolic Dysfunction-Associated Steatotic Liver Disease

MASLD is a spectrum of diseases, including steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and MASH-related hepatocellular carcinoma.39  The MASLD term replaced what was formerly known as non-alcoholic fatty liver disease (NAFLD).39 MASLD is thought to be the result of excess triglyceride storage in the liver in addition to at least one cardiometabolic risk factor.5 Obesity and diabetes mellitus strongly correlate with the development and progression of MASLD. MASLD/MASH and alcohol-associated liver disease are the two most common indications for liver transplantation among patients without hepatocellular carcinoma in the United States.39 Diet modification has been recommended to prevent and treat MASLD.5,40

A longitudinal analysis involving 1521 participants conducted from 1998-2011 demonstrated that adherence to a MD or a WFPBD over a six-year period led to reductions in liver fat accumulation and risk of MASLD.41 Like WFPBD, MD emphasizes minimally processed foods, with key elements including legumes, whole grain, healthy fats (from extra virgin olive oil and fats), vegetables and fruits, while limiting red meat and sweets. MD also encourages the intake of omega-3 fatty acid (EPA and DHA) from fish.27 These healthy components collectively improve insulin resistance, decrease central obesity, and reduce MASLD risk regardless of genetic susceptibility.42 

Celiac Disease

Treatment of celiac disease consists of a lifelong gluten-free diet (GFD). Strict adherence is necessary for improving the health of duodenal mucosa, alleviating symptoms, and normalizing celiac-specific antibodies. Microscopic mucosa recovery occurs six months to three years after initiating the GFD.43 For those following a WFPBD, providers can recommend gluten-free whole grains such as quinoa, millet, sorghum, amaranth, buckwheat, teff, and wild rice.44 These grains offer higher protein and fiber contents compared to wheat and are also rich in antioxidants like carotenoids, and essential vitamins and minerals such as iron, calcium, and thiamine.44-46 Furthermore, gluten-free grains and plant-based protein sources like soy milk, yogurt, tofu and flour from nuts, seeds, or legumes can enhance the nutritional value of WFPBD for individuals with celiac.44,46 

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is highly prevalent, with a global burden that has increased by 77.53% from 1990 to 2019, making it critical for clinicians and healthcare systems to prioritize preventative and management strategies.47 Acid suppression therapy and dietary changes are considered first-line medical therapies.48 

The 2022 ACG Clinical Guidelines suggests that alcohol, smoking, chocolate, peppermint, and high-fat foods reduce lower esophageal sphincter pressure, thereby worsening GERD symptoms. Additionally, coffee, citrus, and spicy food can irritate the esophageal lining, evoking symptoms.48 In 2023, Rizzo et al. conducted an online survey of the dietary habits of 4352 Italian individuals and found that those adhering to strict WFPBDs such as a vegan diet, had a reduced incidence of GERD compared to those following animal-based dietary patterns.49 WFPBDs provide a higher concentration of fiber and other nutrients such as vitamin C, β-carotene, folate, and vegetable protein, which have preventative and protective effects for GERD as well as esophageal and gastric cancers.50 

Making the Transition to a WFPBD

Patients often express concerns that plant-based meals will be less enjoyable, difficult to prepare, or ingredients may not be as readily available.51 Tools such as motivational interviewing with open-ended questions and collaborative discussions, can help healthcare providers assess patients’ current attitudes towards food and their motivations to explore the transition to a WFPBD.52 Dietitians, upon referral, play a key role in providing primary education and counseling on the benefits of a plant-based diet. They can also offer patient-specific ongoing guidance for WFPBD implementation that respects cultural and financial factors while aiming to treat and manage GI disorders.53

ResourcesDescription
Lifestylemedicine.orgCulinary medicine curriculum that is free to download on the American College of Lifestyle Medicine culinary medicine website
Culinarymedicine.orgA virtual culinary medicine curriculum from the culinary medicine program at Tulane university. Many medical schools, nursing schools and residency programs utilize this curriculum
Healthykitchens.orgHealthy Kitchen Healthy Lives is an annual culinary conference by Harvard Medical School in collaboration with the Culinary Institute of America. The goal is to empower healthcare providers to become advocates for lifestyle changes and culinary medicine
Culinary Health Education Fundamentals (CHEF) CoachingThe Institute of Lifestyle Medicine along with the Spaulding Rehabilitation Hospital and Harvard Medical School provide a virtual culinary medicine curriculum that includes coaching technique to promote behavior changes 
Culinary Connections“Culinary Connections” is a column of ACG magazine with culinary contributions from members of the gastroenterology community. Use #ACGfoodie to follow the content on social media
Plantforwardkitchen.orgCulinary institute of America and Harvard T.H. Chan School of public health launched the Plant Forward Kitchen, providing guidance to plant-forward food preparation and education 
Crohnscolitisfoundation.org/patientandcaregivers/gutfriendlyrecipesCrohn’s & Colitis Foundation Association (CCFA) gut friendly recipe database for IBD
Monashfodmap.com/recipe/Database for low-FODMAP recipes (with plant-based recipes)
Oldwayspt.org Database for Mediterranean diet plant-based recipes
Forksoverknives.comDatabase for gluten-free plant-based recipes
Vegetariantimes.comDatabase for gluten-free and dairy-free recipes
Table 4. Culinary Resources for Whole Food Plant-Based Diets

A practical technique to initiate patients on a new diet involves having them practice sectioning a plate into various plant-based food groups for at least one meal a day. For example, using the MD pattern, providers can recommend that half of the plate be filled with vegetables, while the other half is divided between plant-based protein (such as tofu or legumes) and whole grains, with a portion for dessert.54 This structure supports managing GI or liver disorders while ensuring a balanced meal. Animal-based protein such as poultry and fish are meant to be consumed in moderation, ideally 2-3 times per week.55 Online resources, food pyramids, smartphone apps, and social media can provide patients with culinary support and education.56 (See Table 4) Community and patient group cooking classes can also be a valuable tool for recipe demonstration, easing the transition to a WFPBD. (See Table 5)

Nutrient Challenges for WFPBDs

Protein

Protein consumption while on a WFPBD is often of concern, especially in the geriatric population, as they must consume adequate high-quality dietary protein to prevent age-related muscle loss. A meta-analysis using sixty-four studies across Europe, Asia, and North America showed a lower average protein intake in vegetarians and vegans; however, it was well within the recommended intake level.57  Older vegetarians should include high-protein foods such as soy products, legumes, nuts, and seeds two to three times daily. In patients with GI disorders such as IBS, plant-based protein sources such as quinoa and certain soy products like tempeh and soy cheese are low-FODMAP and may be better tolerated.58

Makes 1 individual serving
Ingredients
½ cup oats 
½ cup oat milk or almond milk
1 teaspoon chia seeds 
2 teaspoons pure grade A maple syrup 
1 teaspoon honey 
¼ cup blueberries 

Instructions
Mix all ingredients together in a mason jar or other container with a lid.
Place sliced kiwi and extra blueberries on top of mixture.
Refrigerate overnight (requires at least 4 hours minimum).
Eat cold or microwave for 1-2 minutes in the morning. 
Stays fresh in the refrigerator for approximately 3 days.

This recipe can be customized for various GI disorders. Ensure the oats are gluten-free for those with celiac disease as oats are not always gluten-free depending on how they are processed. The recipe can be also tailored to the low-FODMAP diet by replacing honey with extra pure maple syrup up to 2 tablespoons. Any fruit can be substituted for new combinations such as blueberries and bananas, strawberries and kiwis, or apple pieces and a sprinkling of cinnamon. Oatmeal versus overnight oats with a peeled kiwi and mashed blueberries can be used for those with gastroparesis.
Table 5. Overnight Oat, Blueberry, and Kiwi Recipe

Vitamin and Mineral Deficiencies

Individuals on WFPBD tend to have the same, if not higher, levels of key vitamins and minerals, including vitamin A, vitamin B1, vitamin B12, folate, vitamin C, vitamin E, calcium, magnesium, and phosphorus.59 However, strict versions of WFPBD, such as a vegan diet, which exclude animal-based, fish, and dairy products, can put patients at risk for vitamin D and calcium deficiencies. To counter this, patients on vegan WFPBD should ensure they consume calcium fortified plant-based dairy alternatives like fortified almond or soy milk or consider calcium supplements if necessary.59 Leafy greens, especially the low-oxalate ones like bok choy or kale have higher calcium bioavailability than cow’s milk, although they contain less total calcium.60 Therefore, compared to dairy products, though patients need a larger quantity to match the daily required calcium, leafy green can be a more efficient source for absorption.60 Amaranth, adzuki beans, navy beans, quinoa, and firm tofu are plant-based sources that also provide good sources of calcium and zinc.44,46 

Another major concern is vitamin B12, which is primarily found in animal products. Hence, WFPBD patients should incorporate plant-based B12 sources such as fortified grains like breakfast cereals, or plant-based dairy. Supplementation of B12 is an important consideration for patients with a strict vegan WFPBD.61 

Iron consumption is another concern regarding the adoption of a WFPBD. There are two primary forms of iron in food: heme iron (in animal products, well-absorbed 13-35%) and non-heme iron (in plant and animal products, lower absorption rate 2-20%). In addition, legumes and nuts contain phytate, one of the most potent iron absorption inhibitors.62 Vegetarian men are generally iron-sufficient in studies. Iron insufficiency is detected more frequently in premenopausal women. Iron study monitoring should, therefore, be considered in this population.62

Conclusion

WFPBDs have seen a surge in popularity over the past decade, primarily driven by increasing health awareness among patients and a growing body of scientific evidence that supports the role of WFPBDs in disease prevention and management. For patients with GI disorders, adopting the WFPBD can offer numerous health benefits, including GI symptom reduction, promoting diversity and composition of the gut microbiome, and modulating inflammation. Dietary recommendations must be patient-centered and tailored to meet individual needs to ensure sustainability and improve long-term outcomes. Achieving these outcomes is most effective when approached by a multidisciplinary team, including primary care providers, gastroenterologists, and dietitians. 

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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #19

Gastrointestinal and Nutrition Implications in Cystic Fibrosis

November 2024 • Volume XLVIII, Issue 11
Catherine M. McDonald,John F. Pohl

Read Article

The management of cystic fibrosis (CF) care continues to evolve rapidly with new medications and treatments. The advancements in specialized CF care have added years of life as well as improved life quality for people with cystic fibrosis (pwCF). Currently, more than half of the CF population is over the age of 18 years. As life expectancy for CF increases, the importance of overall physical and mental health maintenance has received more attention. Medical nutrition therapy (MNT) for children and adults with CF has shifted away from the so-called “CF legacy diet” with high fat, high energy foods to higher quality, individualized dietary patterns. Despite considerable improvements in respiratory function for many pwCF, gastrointestinal (GI) complications and nutritional deficiencies may persist. Effective management of GI symptoms assists in achieving nutrition goals and improving quality of life in this patient population.

Introduction

Cystic fibrosis (CF) is a genetic, multi-organ disorder affecting nearly 40,000 children and adults in the United States (US) and an estimated 105,000 people across 94 countries worldwide.1 Mutations in the CF transmembrane conductance regulator (CFTR) gene result in dysfunctional CFTR protein in the cell. Over 1,700 CF-causing CFTR mutations have been identified. Different mutations impact the production and function of the CFTR protein in a variety of ways, but the outcome is essentially similar for all mutations. Abnormally functioning CFTR protein limits chloride movement across cell surfaces, causing the presence of thick sticky mucus in the lungs, pancreas, liver, and GI tract resulting in significant morbidity and mortality.1

This review addresses practical nutritional guidance for pwCF as follows: 1) current recommendations in MNT in the era of CFTR modulator therapy and 2) management of common GI issues. 

CFTR Modulator Therapy

The treatment and prognoses of pwCF have changed dynamically since the 2012 introduction of CFTR modulator therapy (CFTRm).2  CFTRm can be “potentiators” (i.e., keeps the chloride channel open) or “correctors” (i.e., fixes the CFTR structure). These medications enable more normal chloride transfer across cell surfaces, thus treating the underlying causes of CF rather than just symptoms. At present, four CFTRm combinations are approved by the US Food and Drug Administration with more therapies under investigation (see Table 1).3-7 As of 2022, 86% of adults and an increasing number of children with CF in the US are receiving CFTRm therapies.2 

CFTRm improves or alleviates respiratory symptoms and may also improve non-respiratory symptoms associated with other organ systems in pwCF. Overall, median predicted survival for pwCF has increased while pulmonary exacerbations requiring intravenous antibiotics and lung transplants have decreased.2 People with CF receiving CFTRm are leading longer and healthier lives. Reported pregnancies in women with CF doubled between 2019 and 2022.2

The percentage of underweight adults with CF declined to 4.4% in 2022. Conversely, >40% of adults with CF are now categorized using body mass index (BMI) as overweight (BMI between 25 to < 30 kg/m2) with 12.8% classified as obese (BMI ≥ 30 kg/m2).2,8 MNT is evolving rapidly to individualize nutrition and dietary intervention for pwCF in the era of CFTRm.9-11 An emphasis on a nutrient-rich, healthy diet is important to prevent obesity and associated co-morbidities. Despite advances in CF care and therapies, there remain pwCF with advanced lung disease as well as pwCF who are not eligible for, cannot access, or do not tolerate CFTRm.2 Individualized nutrition therapies with the assistance of a dietitian with expertise in CF care must be employed to address specific needs for each pwCF in accordance with therapies received. 9-11

Although pulmonary manifestations of CF respond well to CFTRm, pwCF continue to experience a high gastrointestinal symptom burden.12 Common GI symptoms in  pwCF, regardless of age, include constipation, bloating, distension, early satiety, abdominal pain, and gastroesophageal reflux disease (GERD). Symptoms can be chronic and can negatively impact nutritional status and quality of life.2,12

Historical Perspective

In the early days of treatment for CF, MNT aimed to control malabsorption and associated GI symptoms by limiting dietary fat intake.13 Consequently, poor weight gain and growth stunting in children were common.14 In 1988, an epidemiological study compared two accredited CF centers one in Canada (Toronto) and the other in the US (Boston).15 The pwCF seen at the Canadian center received a more liberalized diet and pancreatic enzyme replacement therapy (PERT) regimen compared to those at the CF center in the US. As a result, the pwCF at the Canadian center were taller, weighed more, and had a survival advantage of nine years.15 

With this substantial difference in survival, the nutritional guidance for pwCF shifted from a low-fat to a high-fat and high calorie diet (the so-called “CF legacy diet”) to promote weight gain and to potentially extend survival. As a result, diet quality for pwCF received less attention. Subsequent dietary intake studies in pwCF indicated a reliance on energy-dense, nutrient-poor foods.16,17

CFTR Medication BrandChemical NameMechanism
Kalydeco® (Vertex)IvacaftorCFTR potentiator for patients with G551D mutation
Orkambi® (Vertex)Lumacaftor/ivacaftorCFTR potentiator / corrector for patients with homozygous F508del mutation
Symdeko® (Vertex)Tezacaftor/ivacaftorCFTR potentiator / corrector for patients with homozygous F508del mutation, heterozygous F508del mutation / residual CFTR function
Trikafta® (Vertex)Elexacaftor/tezcaftor/ivacaftorCFTR potentiator / corrector for patients with at least one F508del mutation or 177 other mutations
Table 1. Current CFTR Modulators

Current Nutrition Guidance

No evidence exists that pwCF require routine modification from a healthy, well-balanced, age-appropriate diet although energy needs may vary.9-11 A wide variety ofculturally acceptable foods associated with positive health outcomes in the general population should be emphasized for pwCF.10 It is reasonable to advise supplementation with energy and/or protein dense foods and/or oral or enteral nutritional supplements as needed to achieve or to maintain normal growth in children and a normal BMI status in adults (18.5-24.9 kg/m2).10,18,19 High nutrient density oral supplements are listed in Table 2. The use of these supplements should be tailored to the individual’s preferences, clinical status, nutritional needs, GI tolerance, and reimbursement options.18 

Vitamins and Minerals

Malabsorption of fats in pwCF is associated with deficiencies in fat-soluble vitamins (A, D, E, and K), calcium, and zinc.1 Most pwCF benefit from CF-specific vitamin/mineral supplementation (see Table 3).20,21. 

All forms of multivitamin supplements designed for pwCF include vitamin K, but not all over-the-counter multivitamins do.  Most CF specific multivitamin supplements contain zinc. No CF-specific multivitamins contain either calcium or iron. Initiation of CFTRm may impact vitamin/ mineral absorption, but further data are needed. Annual serum levels for fat soluble vitamins are recommended to guide supplementation.1,9,10,21

Fiber

The dietary fiber intake recommended for the general population does not increase the risk of constipation, distal intestinal obstruction syndrome or other GI symptoms for pwCF. Low amounts of dietary fiber may increase the risk of constipation and abdominal pain. Increased fiber intake above usual guidelines may exacerbate GI symptoms such as constipation, gas, and bloating in some pwCF. Dietary fiber recommendations should be adjusted according to individual tolerance and GI symptoms.10,11,21

Sodium

Excessive salt loss in sweat can cause electrolyte imbalances and hyponatremia in pwCF, and growth failure in infants and children with CF.19,21 Salt requirements are affected by physical activity, climate, and GI losses. The usual recommendation for pwCF is to eat salty foods and to use the saltshaker freely at meals and snacks.1,9,10,21 Guidelines from Australia and New Zealand suggest salt (sodium) supplementation for all pwCF (up to 500-1000 mg sodium/day for infants, 1000 mg sodium/day for children, and 6000 mg sodium/day for adolescents and adults) to compensate for loss in sweat.21 Individual requirements are guided by signs and symptoms of sodium depletion, exercise levels, and rate of sweat.9,11,21

Salt recommendations are being re-evaluated for pwCF who receive CFTRm as such patients may experience reduced salt and chloride excretion in their sweat. Decreased salt losses along with high salt intake may cause hypertension in some pwCF who use CFTRm.9 Blood pressure should be monitored at all clinical encounters for pwCF.9  Hypertension has been noted to range between 2.2 and 11.8% of adults with CF in the US, UK, and internationally.2,21

Salt recommendations may need to be modified on an individual basis, especially for pwCF who receive CFTRm or for individuals who are post-organ transplant and on immunosuppressive therapy.9,10,11,21 

Adiposity 

Nutritional quality of diet has been associated with body composition and clinical outcomes in adults with CF.22 A significant, positive association has been observed between fasting blood glucose concentration and visceral adipose tissue.23 Excess dietary sugar is significantly and positively associated with visceral adipose tissue in adults with CF.24

In pwCF, a normal BMI and body composition with sex- and age-appropriate fat mass and fat-free mass should be achieved and maintained to improve lung function and to prolong survival.4,5,10,22 Obesity should be avoided as it is associated with an increased risk of hypertension, hypercholesterolemia, liver steatosis, and diabetes.9,24,25 Gradual weight reduction is appropriate in cases of overweight or obesity.10 Rapid or extreme weight loss should be discouraged for pwCF as there can be detrimental effects on pulmonary function. 

The effect of CFTRm upon body weight and BMI varies according to the genetic variants of the individual with CF and the specific CFTRm prescribed. Increased weight gain and BMI in some pwCF have been documented with each of the CFTRm currently available, especially the triple combination elexacaftor/tezacaftor/ivacaftor. Anticipatory MNT should be provided prior to starting CFTRm with discussions of possible weight gain and potential body image concerns.9,10,11,25 Incorporation of healthy dietary patterns, and exercise routines should be encouraged.9,10,11,21  Individualized advice and regular nutrition monitoring should continue as part of standard CF care across the lifespan.9,10,11,21,25

ManufacturerSupplement
AbbottEnsure®, Ensure Plus®, Pediasure®
Fairlife Elite1.5 Core Power®
Kate FarmsKate Farms Standard® and Peptide®
Nature’s OnePediasmart®
NestleBoost®, Boost Plus®, Boost VHC®, Boost Kid Essentials®, Nutren Jr®, Nutren 1.5®, Nutren 2.0® 
Table 2. Examples of High Nutrient Density Oral Supplements

CF-Related Diabetes and Glucose Impairment

Current guidelines recommend screening pwCF for glucose intolerance and CF-related diabetes (CFRD) with annual oral glucose tolerance tests beginning at age 10 years if not previously diagnosed with CFRD.24,25,26 The prevalence of CFRD is increased across the lifespan, reaching above 40% in pwCF ≥40 years.2 Consultation with an endocrinologist who has expertise in CFRD is recommended.9,11,21

The primary nutrition goals for CFRD are to achieve and to maintain healthy weight and body composition with normalized blood glucose levels.21,23,24,26

1. Fat-soluble vitamins: A, D, E, K
2. Iron
3. Sodium
4. Zinc
5 Calcium
6. Magnesium
7. Essential fatty acids
8. Water-soluble vitamins 

*Supplements are available in drops, softgels, chewables and gummies with variable vitamin D levels ranging from 19 mcg to 125 mcg per dose including MVW Complete Formulation®,
MVW Modular Formulation® and DEKAsPlus®

Vitamin comparison chart available at: https://mvwnutritionals-assets.s3.amazonaws.com/wp-content/uploads/2024/04/11111124/Vitamin-Comparison-Chart-4_11_2024-FINAL.pdf
(last accessed 30 Sept 2024)  
Table 3.
Potential Vitamin and Mineral Deficiencies in Cystic Fibrosis

Common Gastrointestinal Complications of Cystic Fibrosis

GI symptoms, including fecal straining, abdominal distension, and abdominal pain, are quite common in pwCF but often go unrecognized.12 GERD with potential erosive esophagitis and aspiration have an estimated prevalence of 35% to 81% in pwCF.27,28  Thus, GI disorders and its associated symptoms are a significant burden for pwCF (see Table 4).12

Mouth

The sense of smell is impaired in many pwCF due to inflammation of the olfactory cleft which is the predominant location of olfactory neurons. Thus, pwCF experience an impaired sense of taste which can decrease food enjoyment and caloric intake.29 Factors such as oral aversion can lead to feeding problems and resultant weight loss common to many children with CF.30

Esophagus and Stomach

As food is masticated and passed into the esophagus, pwCF can experience GERD which leads to classic “heartburn” symptoms, increased cough, aspiration, and in severe cases, weight loss. GERD appears commonly in pwCF with up to 90% of patients potentially having associated symptoms.31,32 Other esophageal diseases such as eosinophilic esophagitis (EoE) may be increased in pwCF compared to the general population, especially in the pediatric age group.33,34

Although GERD is common, it is unclear if acid suppression therapy, including proton pump inhibitor (PPI) therapy, is beneficial in pwCF. Gastroesophageal reflux of bacteria-containing gastric fluid due to aggressive acid blockage from PPI use may increase risk for pneumonia and CF pulmonary exacerbations.35,36 It is unclear if anti-reflux surgery such as fundoplication is beneficial in reducing lung function decline in pwCF who have GERD, especially in children.37 Adult pwCF have an increased risk of Barrett’s esophagus.38

Gastric issues tend to be less concerning in pwCF compared to other aspects of GI physiology although gastroparesis and dumping syndrome can occur in this population. No increased risk of H. pylori infection is associated with pwCF.39,40 Gastroparesis may be more common in pwCF although research studying this phenomenon has not been standardized.41 Conversely, pancreatic enzyme replacement therapy (PERT) may be effective in slowing rapid gastric emptying (thus, reducing dumping syndrome risk) in pwCF via increasing levels of glucagon-like peptide 1 (GLP- 1).42

Small Intestine 

CFTR is present throughout the small intestine, and CFTR mutations impair transport of small intestinal fluid leading to inflammatory and obstructive intestinal mucous, similar to CF pathologic processes in the lungs.43 As a result, malabsorption and symptoms of small intestinal bacterial overgrowth (SIBO) can occur.  SIBO is common in pwCF presenting as abdominal pain, diarrhea, malabsorption, and distention.44,45 PPI use may precipitate SIBO due to the associated lack of gastric acid production leading to overgrowth of pathogenic bacteria.46 Antibiotics with enteral efficacy and minimal systemic absorption, such as rifaximin, can be used to treat SIBO.47

CF enteropathy is associated with enterocyte inflammation and probable intestinal dysbiosis which affects lung function through the “gut-lung axis.”48 CF enteropathy is associated with an elevated fecal calprotectin level, and adult patients with this disorder have a negative correlation between fecal calprotectin levels and pulmonary function.  Exocrine pancreatic insufficiency (EPI), CFRD, and use of PPIs also are risk factors for CF enteropathy.49 CF enteropathy is not a type of inflammatory bowel disease such as Crohn’s disease, but use of azathioprine has been reported as effective for some pwCF with this disorder.50

Although seemingly unrelated, celiac disease (CD), an autoimmune disease of the small bowel associated with gluten exposure, has been noted in pwCF. Research suggests that CD may be more common in pwCF compared to the rest of the population.51-53 The association between CF and CD is unclear, but the production of sticky, inflammatory mucous in CF and the increased response in inflammatory GI conditions such as CD suggest that changes in the intestinal microbiome to more pathogenic bacteria such as Escherichia coli may be causative.34,51-54

 Diagnosis of CD in pwCF does not differ from the rest of the population. Typically, CD diagnosis requires tissue transglutaminase IgA antibody (TTG IgA) serum testing with or without confirmatory duodenal biopsies (depending on TTG IgA level of elevation).55,56,57 The treatment of CD in pwCF is life-long adherence to a gluten free diet, and consultation with a dietitian who has expertise in CD is of paramount importance.55,58

Pancreas

The most well-known aspect of the GI tract in CF occurs with the pancreas in the setting of EPI; EPI is present in at least 85% of pwCF and presents as malabsorption, fat soluble vitamin insufficiency, and poor growth.59 Additionally, EPI is associated with worse lung function outcomes long-term.60 Due to CFTR malfunction, pwCF and EPI experience pancreatic ductal obliteration, pancreatic fibrosis, and pancreatic fatty infiltration.61 Diagnosis of EPI for pwCF typically is made through testing of fecal elastase-1 levels.62

Treatment of EPI requires appropriate PERT, fat soluble vitamin replenishment, and adequate fat intake. Consultation with a dietitian with expertise in CF is essential.10,63,64 Table 5 describes typical PERT dosing.65 No evidence exists for the timing of PERT dosing relative to intake, but PERT is commonly dosed immediately prior to the ingestion of fat-containing food or beverages. If meals are longer than 30 minutes, PERT can be dosed half at the beginning of the meal and the other half midway through the meal.1  Excessive PERT dosing (≥10,000 lipase units/kilogram/day) is associated with the rare but serious complication of fibrosing colonopathy.66,67 It should be noted that pwCF with endocrine pancreatic sufficiency can develop associated endocrine pancreatic insufficiency or CFRD as pancreatic damage progresses.65

CFTRm has reversed EPI in young children with CF, but not in older pwCF, although this issue remains under investigation as recovery of pancreatic function after CFTRm may occur after several years. Currently, no evidence-based algorithms exist for adjusting PERT with CFTRm for pwCF.68 Measurement of fecal elastase-1 after CFTRm initiation in young children or anyone suspected of a change in pancreatic status is clinically appropriate.4,69

Although less common than EPI, pwCF can develop pancreatitis (acute, acute recurrent, and chronic) in the setting of less severe CFTR genotypes. Pancreatitis also has been reported in the setting of CFTRm use in pwCF who have EPI.  In such clinical scenarios, pancreatitis should be considered in pwCF presenting with severe abdominal pain.70,71

Nutrition/GI DisorderPossible Therapies
Vitamin / mineral deficiency riskSupplementation and monitoring
FiberSame use as general population
Essential fatty acid deficiencySerum fatty acid profile with triene:tetraene ratio monitoring, adjust PERT, EFA supplementation with absorbable structured lipid (SeracalTM)
SodiumIncreased salt use need compared to general population
AdiposityPrevention of underweight/overweight over time
CFRDAnnual oral glucose tolerance test Insulin/consultation with endocrinology
Esophagus  (GERD, EoE, Barrett’s esophagus)PPI use, therapies for EoE Consider upper endoscopy with biopsy
Stomach
(gastroparesis, dumping syndrome)		Treatments for gastroparesis (prokinetics, pyloric botulinum toxin) Treatments for dumping syndrome (PERT, dietary changes)
Small intestine  (SIBO, CF enteropathy, celiac disease)Judicious enteral antibiotic use Judicious PPI use TTG IgA antibody titer Upper endoscopy with biopsy
Pancreas (EPI, pancreatitis)Treatments for EPI
(PERT, fat soluble vitamin supplementation, appropriate fat intake) Treatments for pancreatitis
(diagnostic amylase/lipase, diagnostic imaging including abdominal
ultrasound or magnetic resonance cholangiopancreatography) Typical medical/surgical treatments for pancreatitis, as warranted
Terminal ileum  (meconium ileus, DIOS)Hyperosmolar enemas Surgical intervention if warranted
Colon
(constipation, increased colon cancer risk)		Laxative therapy Early colon cancer screening
Gallbladder (delayed emptying, cholelithiasis)Cholecystectomy if warranted
Liver
(CFLD spectrum)		Screening for progression of liver disease Consultation with hepatology /liver transplant program if warranted
Table 4. Common Nutrition and GI Disorders in CF and Potential Therapy

Terminal Ileum/Colon

The terminal ileum is the site of early manifestations of CF in the setting of meconium ileus occurring during infancy. Dehydrated and acidic mucous due to CFTR dysfunction can lead to abdominal distention, emesis, and GI obstruction in the neonatal setting.72 Such patients typically are diagnosed by barium enema in which the obstruction is noted, and many of these neonates with CF will have an associated microcolon due to ileal blockage and colon disuse. Treatment is urgent removal of the obstruction either through the use of hyperosmolar enemas observed by fluoroscopy for stable infants or surgical intervention in unstable infants or infants who do not respond to enema therapy.73,74

Distal intestinal obstructive syndrome (DIOS) may manifest after the neonatal period and potentially can occur at any stage in life in pwCF. Fecal obstruction of the terminal ileum and colon occurs with DIOS and presents with severe constipation, signs and symptoms of a bowel obstruction, and a palpable right lower quadrant mass that can be demonstrated radiographically.75 Most cases of DIOS can be managed by high-volume osmotic therapy (such as with polyethylene glycol 3350) with surgical intervention required for severe cases.Constipation prevention via routine use of osmotic laxatives, especially polyethylene glycol 3350, is critical in reducing risk of DIOS in pwCF.76,77

Constipation, associated with hard stools, abdominal distention, and pain with defecation, is extremely common in pwCF affecting up to 41%.78,79 Such patients have associated prolonged colonic transit time.78 Treatment is supportive using osmotic laxative therapy (typically daily polyethylene glycol 3350).77 Fiber intake in line with the dietary reference intake for the general population and adequate hydration are recommended for pwCF for the prevention and management of constipation.10

AgeRangeUpper Limit
Infants1000-2500 lipase units/kg/feed10,000 lipase units/kg/day
1-4 years1000-2500 lipase units/kg/meal*10,000 lipase units/kg/day
4+ years500-2500 lipase units/kg/meal*                10,000 lipase units/kg/day
Table 5. PERT Dosing Guidelines

The risk of colorectal cancer in adults with CF is 5-10 times greater than the general population and is even higher in pwCF who receive a lung or other solid organ transplant.80 Colonic adenomas with the risk of malignant transformation occur in pwCF at a younger age compared to the general population.81 It is recommended that pwCF undergo screening colonoscopies no later than 40 years of age with repeat screening every 5 years. Such patients should undergo screening within 3 years if adenomas are noted.82 If a pwCF has undergone a solid organ transplantation, they should undergo screening at age 30 years if they are within 2 years of transplantation.82

Gallbladder and Liver

Abnormal gallbladder anatomy such as micro-gallbladder formation occurs in pwCF. Delayed gallbladder emptying and cholelithiasis (typically black pigmented stones from bile acidification) are common in pwCF.83 Most pwCF who have gallbladder abnormalities require simple observation over time, although cholecystectomy is warranted for symptomatic cholelithiasis.83,84

Liver manifestations in pwCF are defined as “cystic fibrosis-related liver disease” (CFLD), occurring in up to 30% of pwCF.82,85 CFLD is caused by CFTR mutations which decrease bile transport disrupting the intestinal microbiome changes leading to hepatic inflammation. Risk factors for CFLD include male sex, history of meconium ileus, and history of EPI.85,86 CFLD can vary from rare entities (neonatal cholestasis and sclerosing cholangitis) to more common presentations (steatosis). Hepatic fibrosis in pwCF can progress over time from focal biliary cirrhosis to multinodular biliary cirrhosis with associated portal hypertension and potential liver failure.87-90  

Treatment of pwCF with CFLD requires optimizing nutrition status, including normal weight and muscle stores, and appropriate vitamin and mineral stores, in a manner necessary for all pwCF, and treating end-stage complications of liver disease such as treatment of portal hypertension and potential liver transplantation.90 It is unclear if ursodeoxycholic acid use in pwCF with associated CFLD prevents progression to more severe liver disease.91

Conclusion

As the future for many pwCF anticipates less severe respiratory disease, longer lifespan, and less risk of undernutrition, more attention should be focused on preventive health management.92 Many challenges remain for both clinicians and pwCF to achieve optimal nutrition in an era of CFTRm.9,10,11,20,92 Not all pwCF are eligible for CFTRm, and some pwCF still face severe respiratory disease and many GI complications.2 Some individuals are at risk of malnutrition with increased medical needs, especially pwCF not eligible for CFTRm. Others are at risk of overweight/obesity and associated metabolic and cardiovascular complications as well as oncological sequelae such as colon cancer.92

As described above, pwCF now are at an increased risk of major adverse cardiovascular events with associated obesity, diabetes, and hypertension.19 In aging CF populations, individualized nutritional interventions, adequate hydration, and physical activity should aim to improve fat-free mass or to prevent its loss.9,10,11,20,92

Historically, these long-term complications were infrequently described due to the shortened life span for most pwCF. In the era of CFTRm, specific metabolic and cardiovascular screening programs need to be established. In the absence of specific recommendations for pwCF, standard screening guidelines for the general population should be employed.9,10,11,20,92 

The future health of children and adults with CF, whether receiving or not receiving CFTRm, benefit from individualized MNT and GI management conducted in collaboration with pwCF, their family, and the entire healthcare team. Nutritional management for infants, children, and adults with CF continues to evolve but remains essential for optimal outcomes for all pwCF.  

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