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

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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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55. Husby S, Murray JA, Katzka DA. AGA clinical practice
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56. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis
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in adults with cystic fibrosis. Arch Surg. 2008; 143: 601-603.
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Dispatches from the GUILD Conference, Series #64

Beyond the Gut: Integrating Mental Health in the Management of Inflammatory Bowel Disease

November 2024 • Volume XLVIII, Issue 11
Adar Zinger,Joëlle St-Pierre,Alyse Bedell,David T. Rubin

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Mental health and sleep disorders are common in inflammatory bowel disease (IBD), and have been associated with a bidirectional relationship with intestinal symptoms and gut inflammation. Studies show that mental health is an important contributor to quality of life and clinical outcomes in IBD patients, and thus it has been recommended to be addressed as a part of routine clinical care. This review discusses simple tools that can be used by primary care and specialist clinicians to screen for mental health and sleep disorders. It also describes the approach for preliminary treatment in cases when such disturbances are detected, and briefly reviews some of the emerging research in the field of gut and brain health, which may have important clinical implications in the future. 

Introduction

From the early days of medicine, gastrointestinal (GI) function and mental health were known to be very closely associated. This led to the presumption and belief that many GI symptoms were psychosomatic in nature. Over the years, as our understanding of diseases deepened, this psychosomatic conceptualization of GI disease has been critically re-evaluated and, in many cases, abandoned in favor of biological and neurochemical models of brain and gut interactions. Research in recent decades has started to decipher the biological basis of brain-gut communications, establishing a model of the “gut-brain axis”. The gut-brain axis is a bidirectional communication network that involves immunological, metabolic, neuronal, hormonal, and microbial components, all of which play an important role in both physiological and pathophysiological processes.1 It is now believed that psychological morbidities that commonly accompany GI disease, including IBD, may be reactive and associated with symptoms, but also have a “biological” component that is independent of symptoms. The growing interest in this gut-brain communication has laid the foundation for extensive clinical, translational, and basic research in the field. It has also highlighted the importance of the clinical aspects of the crosstalk between GI diseases and mental health. Specifically, in the field of IBD, it has led to the acknowledgment that psychological and social factors such as mood and sleep are important aspects of the disease which significantly affect quality of life and should be assessed and treated as a part of a holistic approach to patient care. 

Here, we review common psychosocial health issues in IBD and the bidirectional relationship of gastrointestinal diseases and psychological morbidities. We discuss an approach to screening for mental health issues in the setting of primary care and GI clinics, and suggest preliminary approaches to treatment. We also introduce some of the ongoing research in the field which may have important clinical implications.

Common Psychosocial Issues in IBD 

Patients with IBD face numerous psychosocial challenges that compound the physical symptoms of the disease (Figure 1). These issues, including mental health disorders, sleep disturbances, social stigma, and others significantly impact patients’ quality of life and well-being (definitions of common psychosocial issues outlined in Table 1).

Anxiety and depression are highly prevalent among IBD patients, though often undiagnosed and untreated. Approximately 20-32% of IBD patients experience symptoms of anxiety and 22-25% show symptoms of depression.2,3 Disease activity increases the risk, and patients with Crohn’s disease (CD) may be at greater risk than those with ulcerative colitis (UC). GI symptom-specific anxiety is also common, though its exact prevalence remains unclear.

Sleep disturbances are another major concern, with over half of IBD patients meeting the criteria for insomnia.4,5 Patients with active IBD, mood disorders, disability, and lower quality of life are particularly affected. Fatigue is also widespread, affecting 40-80% of IBD patients with active disease and 40-60% of those in remission.6,7

Stress and stigma greatly impact patients with IBD. Stress worsens disease activity, and patients with IBD experience higher stress levels than the general population. Around 10% of these patients may meet criteria for PTSD, often due to their disease experiences.8 In addition, many patients with IBD experience stigmatization, embarrassment and shame due to the unpredictable nature of bowel symptoms and potential social implications. Body image is also a concern for patients, with most patients reporting some form of concern about an aspect of their body image.9

Issues related to sexual function and satisfaction are common among patients with IBD, due to a combination of factors including active disease or surgical factors, body image concerns, or mental health comorbidities. Although sexual dysfunction is prevalent in IBD, it is infrequently discussed with their healthcare providers.

Concerns related to fertility is another common source of distress among individuals with IBD. While most IBD treatments do not impact fertility directly, voluntary childlessness is higher in this population, which may be, in part, due to misconceptions about disease heritability and transmission risks.10

In addition, patients with IBD have a significantly higher prevalence of disordered eating behaviors than the general population. Disordered eating may or may not be related to body image and in many cases, is thought to result from restrictions and modifications of diet resulting from attempts to control IBD and its symptoms. 

Untreated psychosocial issues negatively impact quality of life and complicate IBD management for both the patient and their healthcare team. It is therefore imperative that we address these issues in our management strategies and care for our patients. Moreover, further research is needed to explore less-studied mental health conditions in the IBD population (e.g., obsessive-compulsive disorder, panic disorder) in order to better identify and address them.

The Impact of Mental Health on IBD 

The nature of the association between IBD and psychological comorbidities remains an area of ongoing, active research, with many unanswered questions. Clinical and epidemiological studies in this field have been limited by the lack of a robust methodology, and results are therefore quite heterogeneous, as are the types and severities of IBD. Nonetheless, existing evidence supports a reciprocal relationship between IBD and mental health disorders, where one can trigger and modify the other.11

A study that evaluated patients with new-onset depression found that their risk to develop IBD within a mean follow-up time of 6.7 years was more than twice as high as the risk of patients with no depression.12 This was true for both CD and UC. Similarly, data from the U.S. Nurses’ Health Study showed that patients with CD were more likely be those with a prior diagnosis of depression compared to those without depression (HR 2.36; 95% CI 1.40-3.98).13 Interestingly, a similar association was not found in patients with UC in this study.

Conversely, some studies show that patients with IBD have an increased risk of developing mental health disorders after their diagnosis. Population-based studies from Canada and Sweden showed that the risk of patients with IBD developing depression or anxiety in the years following their diagnosis is about 50% greater than healthy matched controls.14,15 This was shown in adult-onset as well as in pediatric-onset IBD. 

In patients with IBD, mental health disorders were shown to adversely affect the disease course of the IBD. In a meta-analysis of 12 longitudinal studies, IBD patients with depressive symptoms were at increased risk of flare, hospitalization, need for therapy escalation, and IBD-related surgery.16 Psychological stress was also identified to have adverse effects on IBD. In a prospective study that included 124 patients with IBD, disease activity after highly stressful life events was monitored. It was found that patients who experienced the death of a family member or close friend, change in residence or job status, birth of a child, personal or familial health concern, marriage or divorce, were more than twice as likely to present with active disease within a 6-month follow-up period compared to patients who did not experience such an event.17 A study that followed 677 patients with IBD in Japan after the Great East Japan Earthquake in 2011 found an increased risk for disease flare in the 2 months after the earthquake, compared to a corresponding period in the 1 and 2 years after the earthquake.18 Together, these data show that IBD disease course can both affect and be affected by mental health disorders and psychological stress. These studies highlight the importance of psychological assessment in IBD care.

Psychosocial Assessment in IBD Patients 

Both self-report questionnaires and the clinical interview are valuable tools for the assessment of psychosocial concerns among patients with IBD. Direct patient-provider communication via the clinical interview lacks the uniformity of self-report questionnaires but is nonetheless a quick and useful method. This may require only a few questions, such as “How have you been coping with everything?” and “How has your IBD affected your life recently?” Direct communication strengthens the patient-provider relationship, demonstrates care to the patient, and can be easily integrated into the clinic visit (Table 2).

While self-report questionnaires offer a valid, uniform system of measurement that can be tracked over time both within and between patients, they are not without logistical and ethical burdens. Integration is challenging for many practices due to the time and personnel needed to administer, score, and document the assessments. Finally, the GI provider must have the time to review this information with the patient during the visit in order to have clinical utility, rather than become just a data point. Patients who are found to have more severe anxiety or depression, especially those who express suicidal ideation or plan, require an immediate action plan and intervention for the practice, resources that are not readily available or currently considered part of most primary or specialty practices. 

There are several validated tools for the screening of mental health symptoms in IBD. The Patient Health Questionnaire-9 (PHQ-9) for depression,19 and the Generalized Anxiety Disorder scale-7 (GAD-7) for anxiety,20 are easy to administer and score on paper or virtually. These measures have scoring ranges that can be used to indicate the severity of symptoms and the likelihood of a clinical diagnosis. GI symptom-specific anxiety refers to anxiety and fear related to the disease, its symptoms, or the context in which the symptoms occur. This is a common form of anxiety seen among IBD patients and is best captured by the Visceral Sensitivity Index (VSI).21 Keefer and colleagues present a comprehensive list of suggestions on the assessment of other psychosocial issues.22

Management of Mental Health Disorders in IBD

The success of a screening program is dependent on what happens after a positive screen: ideally, a referral for comprehensive assessment and treatment with a mental health professional. New research highlights the bidirectionality of IBD and mental health conditions; psychological interventions may improve both mental health and inflammatory markers in IBD,23 while psychotropic medications may have protective effects in IBD.24 

For many patients, and particularly those with more severe or longstanding depression or anxiety, a referral for psychotherapy with a general mental health therapist and/or a psychotropic medication evaluation with a psychiatry provider, is appropriate. If the GI provider is aware of a more specific issue such as an eating disorder or substance abuse, this may warrant referral to a more specialized clinic or provider. Developing relationships with mental health providers either within the institution, or with community partners, is paramount to referring patients appropriately.

For patients whose depression, anxiety, or overall stress level is closely related to their IBD experience, a gastrointestinal psychologist is an ideal referral. The growing specialty of gastrointestinal psychology includes psychologists who typically work with patients with IBD to develop stress management and adaptive coping strategies, reduce symptoms of anxiety and depression, and to utilize behavioral tools to cope with and reduce ongoing GI symptoms. IBD-specific virtual support programs exist and can help fill this gap if a gastrointestinal psychologist is not part of your practice.

Sleep Disturbances in IBD 

Sleep is a major contributor to health and good quality of life. Increasing evidence shows that sleep disturbances are linked to dysfunction of multiple body systems, including the function of the immune system and the GI tract.25 This prompted further investigation into the effect of sleep on the course of IBD. The prevalence of sleep disorders in patients with IBD is believed to be high but is not well-defined. A study that prospectively screened 166 IBD patients found that 67.5% of them suffered from sleep disturbance.26 Studies assessing sleep quality in patients with IBD identified active IBD as a contributor to sleep deprivation. This may, in turn, trigger further immune activation and perpetuate a vicious cycle of worsening symptoms that would further adversely affect patients’ quality of life.25 In CD, poor sleep quality has been associated with disease activity and higher risk of hospitalization and surgery.27 Patients with active IBD were shown to have fewer episodes of deep sleep compared to patients in remission. Interestingly, patients in clinical remission who report abnormal sleep have a high likelihood of subclinical disease activity, indicating that poor sleep is not only driven by symptoms such as nocturnal diarrhea, but also may be affected by abnormal immune function.28 There are validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) that can be used for assessing sleep quality. However, in everyday clinical practice, simple questions can be used, such as: “How do you sleep at night?”, “Any trouble falling asleep or staying asleep?” and “Do you wake up feeling refreshed?” (Table 2). All patients who report poor sleep quality should be educated on sleep hygiene practices. Referral to a sleep specialist for evaluation of specific sleep conditions, such as obstructive sleep apnea or restless legs syndrome (which may also be associated with iron deficiency), should be considered if clinically relevant. In patients with active disease, poor sleep may be a symptom of active inflammation, and should prompt optimization of the anti-inflammatory treatment. For patients with insomnia, cognitive behavioral therapy for insomnia (CBT-I) is a highly effective treatment, and should be considered in patients with insomnia related to IBD as well.29

Future Directions in Mental Health and IBD Research

Current research on the interface between gut and mental health focuses on elucidating a better understanding of the biological mechanisms and careful investigation of novel clinical interventions. A major interest in this field is the changes in gut-derived metabolites, which may mediate gut-brain interaction. Tryptophan is an example of such a mediator. It is metabolized by both host cells and the gut microbiome; both are affected by gut inflammation. It is a precursor of multiple neuroactive metabolites, including serotonin and melatonin, metabolites that play a central role in controlling mood and sleep. It was shown that tryptophan metabolism is altered in patients with active IBD.30 Whether it influences mental health in these patients is yet to be determined. Interestingly, it has been found that the penetrance of the blood-brain barrier31 and the choroid plexus32 changes in response to gut inflammation, which may alter the exposure of the central nervous system (CNS) to various peripheral compounds. Identifying key mediators that are relevant in this context may open the door for therapeutic interventions that target specific mediators and compounds. 

Several studies have shown the benefits of incorporating psychological treatment into medical care in IBD patients.33 The growing number of GI-specialized therapists may significantly contribute to patient care and quality of life. Interestingly, there are ongoing studies that utilize virtual reality and artificial intelligence technologies to treat symptoms in patients with irritable bowel syndrome (IBS).34 Using these tools in IBD may increase the accessibility of psychological care and may be a novel approach to more effectively and extensively address mental health concerns. 

Conclusion

Mental health conditions and sleep disorders are very common among patients with IBD. They have a bidirectional relationship with gut inflammation and intestinal symptoms, and current evidence supports the notion that one may trigger and modify the other. Given its clear impact on quality of life and the evolving understanding of the biological connection between the brain and gut, addressing psychosocial issues should be part of the comprehensive care for our patients with IBD. While standardized questionnaires may be time-consuming, simple questions can be easily incorporated into routine clinical practice and serve as a preliminary screening method. Identification of mental health conditions and sleep disorders in patients with active inflammation of the bowel should prompt optimization of their IBD treatment. Referral to a specialized GI therapist should be strongly considered when appropriate, but there is a clear need for additional research and resources for treatment and management in this evolving and clinically important field. 

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15. Ludvigsson JF., Olén O., Larsson H., Halfvarson J., Almqvist C., Lichtenstein P., et al. Association Between Inflammatory Bowel Disease and Psychiatric Morbidity and Suicide: A Swedish Nationwide Population-Based Cohort Study With Sibling Comparisons. J Crohns Colitis 2021;15(11):1824–36. Doi: 10.1093/ecco-jcc/jjab039.

16. Fairbrass KM., Lovatt J., Barberio B., Yuan Y., Gracie DJ., Ford AC. Bidirectional brain-gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis. Gut 2022;71(9):1773–80. Doi: 10.1136/gutjnl-2021-325985.

17. Duffy LC., Zielezny MA., Marshall JR., Byers TE., Weiser MM., Phillips JF., et al. Relevance of major stress events as an indicator of disease activity prevalence in inflammatory bowel disease. Behavioral Medicine (Washington, DC) 1991;17(3):101–10. Doi: 10.1080/08964289.1991.9937553.

18. Miyazawa T., Shiga H., Kinouchi Y., Takahashi S., Tominaga G., Takahashi H., et al. Long-term course of inflammatory bowel disease after the Great East Japan Earthquake. J Gastroenterol Hepatol 2018;33(12):1956–60. Doi: 10.1111/jgh.14286.

19. Kroenke K., Spitzer RL., Williams JBW. The PHQ-9. J Gen Intern Med 2001;16(9):606–13. Doi: 10.1046/j.1525-1497.2001.016009606.x.

20. Spitzer RL., Kroenke K., Williams JBW., Löwe B. A Brief Measure for Assessing Generalized Anxiety Disorder. Arch Intern Med 2006;166(10):1092. Doi: 10.1001/archinte.166.10.1092.

21. Labus JS., Mayer EA., Chang L., Bolus R., Naliboff BD. The Central Role of Gastrointestinal-Specific Anxiety in Irritable Bowel Syndrome: Further Validation of the Visceral Sensitivity Index. Psychosom Med 2007;69(1):89–98. Doi: 10.1097/PSY.0b013e31802e2f24.

22. Keefer L., Bedell A., Norton C., Hart AL. How Should Pain, Fatigue, and Emotional Wellness Be Incorporated Into Treatment Goals for Optimal Management of Inflammatory Bowel Disease? Gastroenterology 2022;162(5):1439–51. Doi: 10.1053/j.gastro.2021.08.060.

23. Seaton N., Hudson J., Harding S., Norton S., Mondelli V., Jones ASK., et al. Do interventions for mood improve inflammatory biomarkers in inflammatory bowel disease?: a systematic review and meta-analysis. EBioMedicine 2024;100:104910. Doi: 10.1016/j.ebiom.2023.104910.

24. Kristensen MS., Kjærulff TM., Ersbøll AK., Green A., Hallas J., Thygesen LC. The Influence of Antidepressants on the Disease Course Among Patients With Crohn’s Disease and Ulcerative Colitis—A Danish Nationwide Register–Based Cohort Study. Inflamm Bowel Dis 2019;25(5):886–93. Doi: 10.1093/ibd/izy367.

25. Kinnucan JA., Rubin DT., Ali T. Sleep and inflammatory bowel disease: exploring the relationship between sleep disturbances and inflammation. Gastroenterol Hepatol (N Y) 2013;9(11):718–27.

26. Marinelli C., Savarino E V., Marsilio I., Lorenzon G., Gavaruzzi T., D’Incà R., et al. Sleep disturbance in Inflammatory Bowel Disease: prevalence and risk factors – A cross-sectional study. Sci Rep 2020;10(1):507. Doi: 10.1038/s41598-020-57460-6.

27. Sofia MA., Lipowska AM., Zmeter N., Perez E., Kavitt R., Rubin DT. Poor Sleep Quality in Crohn’s Disease Is Associated With Disease Activity and Risk for Hospitalization or Surgery. Inflamm Bowel Dis 2020;26(8):1251–9. Doi: 10.1093/ibd/izz258.

28. Erondu A., Singer J., Yi Y., Sossenheimer PH., Rubin DT. Sa1801 INFLAMMATORY BOWEL DISEASE PATIENTS WITH ACTIVE DISEASE HAVE FEWER EPISODES OF DEEP SLEEP COMPARED WITH PATIENTS IN REMISSION. Gastroenterology 2020;158(6):S-430. Doi: 10.1016/S0016-5085(20)31761-3.

29. Salwen-Deremer JK., Godzik CM., Jagielski CH., Siegel CA., Smith MT. Patients with IBD Want to Talk About Sleep and Treatments for Insomnia with Their Gastroenterologist. Dig Dis Sci 2023;68(6):2291–302. Doi: 10.1007/s10620-023-07883-8.

30. Nikolaus S., Schulte B., Al-Massad N., Thieme F., Schulte DM., Bethge J., et al. Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Gastroenterology 2017;153(6):1504-1516.e2. Doi: 10.1053/j.gastro.2017.08.028.

31. Logsdon AF., Erickson MA., Rhea EM., Salameh TS., Banks WA. Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Exp Biol Med (Maywood) 2018;243(2):159–65. Doi: 10.1177/1535370217743766.

32. Carloni S., Bertocchi A., Mancinelli S., Bellini M., Erreni M., Borreca A., et al. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science 2021;374(6566):439–48. Doi: 10.1126/science.abc6108.

33. Li C., Hou Z., Liu Y., Ji Y., Xie L. Cognitive-behavioural therapy in patients with inflammatory bowel diseases: A systematic review and meta-analysis. Int J Nurs Pract 2019;25(1). Doi: 10.1111/ijn.12699.

34. Lacy BE., Cangemi DJ., Spiegel BR. Virtual Reality: A New Treatment Paradigm for Disorders of Gut-Brain Interaction? Gastroenterol Hepatol (N Y) 2023;19(2):86–94.

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from the pediatric literature

Dermatologic Complications in Pediatric Inflammatory Bowel Disease

November 2024 • Volume XLVIII, Issue 11

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Children with inflammatory bowel disease (IBD) can have associated dermatologic disease. Erythema nodosum (EN) and pyoderma gangrenosum (PG) are two such common skin lesions seen in this setting. The authors of this study attempted to determine rates of EN and PG in pediatric patients with IBD and evaluated for IBD complications in the setting of EN and PG.

This study was longitudinal and evaluated patient data from the international pediatric IBD registry, ImproveCareNow™. Deidentified patient data were evaluated to determine patient baseline characteristics as well as follow-up clinic visit characteristics, duration of IBD, presence of EN or PG, and other factors associated with IBD. The following disease activity scales also were used in this study: Physician Global Assessment (PGA), the short Pediatric Crohn’s Disease Activity Index (PCDAI), and the Pediatric Ulcerative Colitis Activity Index (PUCAI). Patients were characterized as having Crohn’s disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). It should be noted that IC also is known as Inflammatory Bowel Disease – Unclassified (IBD-U). Pediatric patients with IBD with associated EN or PG were compared to pediatric patients with IBD who had no skin manifestations.

A total of 285,913 clinic visits from 32,497 pediatric patients (≤ 21 years of age) were included in the study. A diagnosis of EN was made in 509 patients (401 CD, 90 UC, and 18 IC), and the rate of EN in this patient population was 1.57% (95% confidence interval (CI), 1.43-1.71%). A diagnosis of PG was made in 291 patients (203 CD, 67 UC, and 21 IC), and the rate of PG in this patient population was 0.90% (95% CI, 0.80-1.00%).  Co-occurrence of EN and PG was present in 99 patients, and the rate of both diseases occurring simultaneously was 0.30% (95% CI, 0.25-0.37%). Most patients (90%) with simultaneous EN and PG had both diseases occurring during at least one clinic visit.

Significantly more patients with EN or PG were female compared to pediatric patients with IBD and no skin disease. There was no statistical difference between patients with IBD and EN or PG versus pediatric patients with IBD and no skin disease regardless of age, gender, or age of IBD diagnosis. Higher scoring (indicating worse disease) using the PGA, short PCDAI, and PUCAI was significantly increased in patients with associated EN and PG. Poor growth and nutrition were significantly associated with a higher rate of EN and PG while continuous disease remission was significantly associated with a reduced rate of EN and PG. A history of ileostomy or colostomy, peri-anal disease, uveitis, or arthritis was associated with a significantly increased risk of EN or PG. An elevated erythrocyte sedimentation rate (ESR), an elevated C-reactive protein level (CRP), and a reduced albumin level were all significantly associated with a higher risk of EN or PG while improving albumin levels at follow-up clinic visits significantly reduced the risk of having EN or PG. In terms of IBD treatment, only corticosteroid use was significantly associated with the presence of EN or PG. Multivariable analysis demonstrated that CD, high PGA score, arthritis, uveitis, elevated ESR, low albumin level, and corticosteroid use were associated with EN while a high PGA score, history of colectomy/colostomy/ileostomy, arthritis, uveitis, and low albumin level were associated with UC.

This study provides new information about the frequency of important dermatologic manifestations seen in pediatric IBD, specifically EN and PG. The authors have identified specific risk factors in the pediatric IBD population associated with EN and PG.  Once EN and PG are identified in a pediatric patient with IBD, concern should be raised that the patient may have a more severe IBD phenotype.

Yousif M, Ritchey A, Mirea L, Patel A, Price H, O＊Haver J, Montoya L, Gonzalez-Llanos L, Smith J, Zeblisky K, Pasternak B.  The Association Between Erythema Nodosum and Pyoderma Gangrenosum and Pediatric Inflammatory Bowel Disease.  J Pediatr Gastroenterol Nutr 2024; doi: 10.1002/jpn3.12370. Online ahead of print.

Can Abnormal Weight be Associated with Child Maltreatment?

Pediatric gastroenterologists are in a unique position to address nutrition issues in children, while at the same time, discovering social challenges in families. The authors of this study determined if child maltreatment or exposure to intimate partner violence affected both childhood weight and diagnosis type.

This retrospective study occurred at a pediatric center specializing in child maltreatment, and data over a 3-year period were collected. Only children 17 years or younger with ICD-10 codes for child maltreatment were studied. Five types of child maltreatment were considered: physical, sexual, neglect, psychological/emotional, and exposure to intimate partner violence. Patients with neonatal abstinence syndrome or an organic disease that could affect weight were excluded. Patients were determined to be underweight, normal weight, overweight, or obese based on weight-for-length z scores if a child was under 24 months of age or based on body mass index (BMI) z scores if a child was equal to or older than 24 months of age. 

A total of 855 subjects were included in the study, and the median age was 29 months (interquartile range 5-83 months). Normal weight classification was present in 59.4% of children while classifications of underweight, obese, and overweight was present in 15.3%, 12.9%, and 12.4%, respectively. All types of child maltreatment were significantly associated with all weight types. Patients with one type of child maltreatment were statistically younger while patients with more than one type of child maltreatment were statistically older. Neglect was the most common type of child maltreatment (68.7%), and neglect was significantly associated with children who were normal weight and underweight. Physical abuse (33.6% of children) was significantly lower in normal weight children. Sexual abuse (16.8%) increased significantly as patient weight increased and was most common in children characterized as obese. Psychological/emotional abuse (10.8%) was most common in children characterized as obese while children exposed to intimate partner violence (9.8%) were more likely to be characterized as overweight. Finally, having one category of child maltreatment was significantly associated with normal weight. The presence of more than one category of child maltreatment was associated with abnormal weight, but the association was not statistically significant.

This study provides a potential way to screen for risk factors for abuse in children by considering their weight, weight-for-length z score, or BMI z score, especially if the provider suspects child maltreatment is occurring. This study occurred at a single center in Pennsylvania, and more research is needed in other parts of the United States to see if such findings can be more universalized.

Esernio-Jenssen D, Morrobel A, Hansen S, Kincaid H. Exploring Associations Between Abnormal Weight Classifications and Child Maltreatment Diagnoses. Clin Pediatr 2024; 63: 1056-1061.

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FRONTIERS IN ENDOSCOPY, SERIES #92

Endoscopic Management of Small Intestinal and Colorectal Anastomotic Strictures

November 2024 • Volume XLVIII, Issue 11
Michael B. Andrews,Douglas G. Adler

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INTRODUCTION

Small intestinal and colorectal anastomotic strictures are often difficult-to-treat post-surgical adverse events. Surgical re-intervention was previously first-line therapy, but advancements in endoscopic techniques have made endoscopy the first-line treatment approach. This review will assess the efficacy and adverse events of the currently available endoscopic management techniques for the treatment of small intestine and colorectal anastomotic strictures.2,3

Small Intestinal Anastomotic Strictures

Etiology

Small intestinal anastomotic strictures are post-surgical adverse events following small bowel resection for malignant or benign conditions including perforation, ischemia, and Crohn’s disease.1 Surgical resection is required in 50-80% of patients with Crohn’s disease within the first 10 years of diagnosis, and approximately one-third of patients will require at least a second surgery due to development of an anastomotic stricture.2,3

Risk Factors

Risk factors for anastomotic complications have been studied extensively in patients with Crohn’s disease and show an increased risk with pre-operative poor nutritional status, weight loss, steroid use, and longer duration of disease.4 However, more studies are needed to identify the patient risk factors specifically for small bowel anastomotic stricture development.

Choy et al. performed a meta-analysis comparing surgical anastomotic closure techniques among 1,125 patients which showed no difference in anastomotic stricture rates between hand-sewn and linearly stapled anastomoses.5

Clinical Manifestations

Patients commonly present with obstructive symptoms including abdominal pain, distention, bloating, nausea, and/or vomiting.6

Endoscopic Balloon Dilation

Technique

Endoscopic balloon dilation (EBD) is most commonly performed using inflatable through-the-scope (TTS) balloon dilators available in various lengths (3-8cm) and diameters (6-20mm).2,3,7,8 The balloon dilator is positioned across the stricture with or without guidewire assistance followed by inflation using a handheld device to inject saline or contrast.7 The main challenge using EBD to treat small intestinal anastomotic strictures compared to more proximal anastomotic strictures is reaching the stricture, which often requires push enteroscopy or balloon-assisted enteroscopy.8

Efficacy

Clinical success rates for EBD for small intestinal anastomotic strictures across multiple studies range from 44-89% following a mean of approximately two sessions.2,3,9,10 Ding et al. performed a retrospective cohort study of 54 patients with Crohn’s disease-related anastomotic strictures and observed a decrease in repeat EBD with escalation of medical therapy, strictures <40mm long, and shorter disease duration at the time of initial EBD.2 Hassan et al. and Ferreira-Silva et al. reported similar improved outcomes (higher success rates with decreased need for surgical re-intervention) when anastomotic strictures were <40mm long.3,10 Unfortunately, stricture recurrence remains a problem following EBD, occurring in 46-62% of patients and requiring use of other endoscopic therapies or surgical re-intervention.3,10

Adverse Events

Perforation was the most frequent adverse event with Ding et al. reporting perforation in 1.85% (1/54) of patients and 0.6% (1/151) of procedures whereas Hassan et al. reported perforation in 3.7% (13/347) of patients and 1.9% (13/695) of procedures.2,3

Self-Expandable Metal Stents

Technique

Self-expandable metal stents (SEMS) are composed of metal mesh which can be covered with overlying silicone or plastic to resist tumor or tissue ingrowth. SEMS for small intestinal use are either uncovered (UCSEMS) or partially covered (PCSEMS).11 These include the uncovered Wallstent and Wallflex stents (Boston Scientific, Natick, Massachusetts, United States) and the uncovered or partially covered Hanarostents (M. I. Tech, Seoul, Korea) available in various diameters (20-22mm) and lengths (60-170mm).11,12 SEMS work by exerting constant radial force against the anastomotic stricture until removal during a subsequent endoscopic procedure.11

Efficacy

Branche et al. and Das et al. published case series with a combined 26 patients, all having anastomotic stricture lengths <6cm treated with the partially-covered Hanarostent, and observed clinical success rates of 100% and 81%, respectively.12,13 However, Branche et al. noted recurrence in 33% of patients at six-month follow-up.12 Ferreira-Silva et al. reported clinical success rates of 36-100% in 71 total patients across case reports and series.10

Adverse Events

Migration was the most reported adverse event seen in as many as 15.8% (3/19) of patients in Das et al.’s case series using PCSEMS.10,12,13 It is important to understand stent migration is not always a true adverse event and instead may occur following stricture resolution as there is no stenosis to anchor the stent in place. Nonetheless, anchoring techniques have been used to reduce migration rates including endoscopic suturing and TTS or over-the-scope (OTS) clips attaching the stent to adjacent mucosa. In a case series of seven patients, Senol. et al. described successful use of TTS clips to affix jejunal SEMS with a 0% migration rate.14

Lumen-Apposing Metal Stents

Technique

The AXIOS stent (Boston Scientific, Natick MA, United States) is the only commercially available lumen-apposing metal stent (LAMS) in the United States and was originally designed with FDA approval for draining pancreatic fluid collections.15,16 However, LAMS are commonly used in an off-label manner for the treatment of luminal strictures, including small intestinal anastomotic strictures.15 LAMS are 8-15mm long with diameters of 6, 8, 10, 15, and 20mm.15,16 LAMS are deployed across the anastomotic stricture using a guidewire under a combination of endoscopic and fluoroscopic visualization.15

The AXIOS catheter is often not long enough to reach distal small intestinal anastomotic strictures. Ferrell et al. reported a modified technique to assist in reaching distal small intestinal anastomotic strictures. The AXIOS stent was deployed into sterile water followed by twisting the ends in opposite directions and backloading the stent into the distal end of the working channels of a colonoscope and double-balloon enteroscope.17 Once the stricture was reached, the stent was manually deployed using biopsy forceps. In general, LAMS are deployed across strictures within reach of an upper endoscope, which includes duodenal and proximal jejunal strictures. 

Efficacy

Ferrell et al. utilized the modified technique described above to reach distant small intestinal anastomotic strictures in two patients with strictures <1cm long that were previously refractory to EBD.17 Both patients remained asymptomatic without signs of stricture recurrence at three-month follow-up.17 Axelrad et al. reported a case with successful use of LAMS in a patient with a 1cm small intestinal anastomotic stricture refractory to EBD. The stent was removed after 60 days, and the patient remained asymptomatic without signs of stricture recurrence at 90-day follow-up.18

Adverse Events

Neither Ferrell et al. nor Axelrad et al. reported adverse events in the three cases.17,18

Biodegradable Stents

Technique

Biodegradable stents (BDS) were designed to treat esophageal strictures but have been used off-label for treatment of other luminal strictures, including small intestinal anastomotic strictures.19,20 The SX-ELLA BDS (ELLA-CS, Hradec Kralove, Czech Republic) is the only commercially available BDS but is not approved for use in the United States. BDS range in diameter (18-25mm) and length (60-135mm) with flared ends (23-27mm wide) designed to reduce stent migration.10,19,20 BDS are constructed of synthetic polymers which supply radial force against the stricture for 4-6 weeks before degrading and fragmenting over the next 6-24 weeks, after which they spontaneously pass.10,19

BDS require assembly prior to placement. These devices are advanced across a stricture using a guidewire under endoscopic and/or fluoroscopic visualization.19,20 Positioning of the stent is facilitated by locating the radiopaque ends of the stent with fluoroscopy.19 The main limitation to using BDS for small intestinal anastomotic strictures is the potential inability of the BDS delivery system to reach distal strictures.19

Efficacy

Rejchrt et al. performed a case series with 11 patients including 8 who had small intestinal anastomotic strictures treated with BDS.19 All patients underwent EBD prior to stent placement.19 62.5% (5/8) of patients were asymptomatic at follow-up ranging from 12-26 months, and complete BDS degradation was noted at a mean of four months.19

Adverse Events

Rejchrt et al. reported stent migration in 37.5% (3/8) of patients.19 No other adverse events were reported.19

Colorectal Anastomotic Strictures

Etiology

Colorectal anastomotic strictures may result following partial or complete colonic and/or rectal resection. (Figure 1) Common indications for resection include malignant or benign conditions including diverticulitis, inflammatory bowel disease, perforations, and ischemic bowel. Post-operative colorectal anastomotic strictures occur in 2-30% of patients.21,22,23,24 Jain et al. noted most colorectal anastomotic strictures are diagnosed within one year of surgery.24

Risk Factors

Patients are at increased risk of developing colorectal anastomotic strictures if they are male, smoke tobacco, underwent neoadjuvant or adjuvant radiation therapy, or experienced perioperative anastomotic leakage.22,24,25 Anastomotic leaks increase the risk for anastomotic stricture formation by promoting local inflammation with resultant fibrosis and stenosis.24 Risk factors for anastomotic leakage include male sex, diabetes, obesity, kidney disease, cardiovascular disease, radiation therapy, smoking, heavy alcohol use (>35 drinks/week) and the use of immunosuppressive medications such as steroids.26

Slesser et al. performed a meta-analysis of 10 randomized controlled trials with 1,969 patients examining the risk for colorectal anastomotic strictures among different surgical anastomotic closure techniques.27 They reported no difference in colorectal anastomotic stricture rates between hand-sewing, stapling, or using compression rings to create anastomoses.27 One surgical technique shown to reduce risk of colorectal anastomotic strictures is mobilization of the splenic flexure which was observed by Surek et al. in a retrospective cohort study of 375 patients.28

Clinical Manifestations

Patients may experience abdominal pain, bloating, distention, nausea, vomiting, constipation, and/or weight loss.29 While symptoms often occur within the first year following surgery, there have been reports of onset as early as one month after surgery and as late as 12 years after surgery.24

Endoscopic Balloon Dilation

Technique

EBD is first-line therapy for treating colorectal anastomotic strictures using the same techniques described previously for small intestinal anastomotic strictures.8,23,30 Most colorectal anastomotic strictures are reachable with standard colonoscopes, but, rarely, strictures may require push enteroscopy or balloon-assisted enteroscopy in certain cases such as patients with tortuous colons.8 Klag et al. cautioned dilation beyond 25mm due to a perceived increased risk of perforation.8

Efficacy

Hong et al. noted clinical success rates of 88-100% using EBD with recurrence rates of 30-88%.21 Clifford et al. performed a systematic review including ten studies with 380 patients treated with EBD which showed clinical success rates of 80.6-100% after a mean range of 1-3 dilation sessions.22 Araujo et al.’s case series of 24 patients and Di Giorgio et al.’s prospective cohort study of 30 patients observed clinical success in 91.7% and 100% of patients following a mean of 2.3 and 2.6 dilation sessions, respectively.23,30

Despite initial clinical success rates that are high, stricture recurrence is common after EBD. Biraima et al., in a retrospective cohort study of 76 patients, found that 49% of patients required more than two dilation sessions to achieve clinical success, and stricture recurrence occurred in 11% of patients at 12 months, 22% of patients at 24 months, and 25% of patients at 60 months.31

Thomas-Gibson et al. performed a retrospective cohort study of 53 patients with Crohn’s disease related colorectal anastomotic strictures and observed initial success in 82% of patients. However, long-term clinical success (remaining asymptomatic after six months) was observed in only 42% of patients at mean follow-up of 21 months.32 58% of patients required another surgery within a median of 4.9 months following EBD.32

Adverse Events

Perforation was reported in 1.18% (6/509) of patients across multiple studies.22,31,32 Other infrequently reported adverse events included minor bleeding and fever.22

Self-Expandable Metal Stents

Technique

SEMS for colorectal use were originally designed for, and continue to be used for, treatment of malignant large bowel obstruction.21 Because these stents were intended to either be left in place as a palliative device or to be removed by surgery, they are only available as UCSEMS in the United States. Epithelization of these stents commonly occurred but was not considered an adverse event.21 As their use expanded to include treatment of benign strictures, including colorectal anastomotic strictures, fully covered (FCSEMS) colorectal stents were manufactured which reduced epithelialization and made stent removal feasible, but these are not available in the United States.21

Commercially available SEMS include Wallflex colonic stents (Boston Scientific, Natick MA, United States) available in various diameters (22-25mm) and lengths (60-120mm).11 The colonic Z-stent and Evolution stents (Cook Medical, Winston-Salem, NC) are also available in various lengths (40-120mm) with a 25mm diameter.11 Stent placement near the dentate line should be avoided to reduce the risk of tenesmus and pain.33

Efficacy

Clinical success rates using SEMS ranged from 25-70% across three case studies with a combined 48 patients.21,33,34 Caruso et al. performed a case series of 16 patients in Italy and observed a significant difference (p-value 0.035) in clinical success rates between patients treated with smaller FCSEMS 20-22mm in diameter (17%) compared to larger FCSEMS 24-26mm in diameter (80%).34

Adverse Events

Stent migration was the most common adverse event reported among the 48 patients.21,33,34 Caruso et al. and Lamazza et al. treated anastomotic stricture patients with FCSEMS and noted stent migration in 19% and 37.5% of patients, respectively.33,34 Hong et al. and Lamazza et al. treated patients with UCSEMS and noted stent migration in 17% and 0% of patients, respectively.21,33 Hong et al. also noted UCSEMS epithelialization in 17% of patients with a median follow-up time of 16.7 months.21 Other reported adverse events included pain and minor bleeding without any reports of perforation.21,33,34

Lumen-Apposing Metal Stents

Technique

Using the previously described technique, LAMS can be used in an off-label manner to treat short (<1-1.5cm long) colorectal anastomotic strictures.34,35 (Figure 2) Pre-stent or in-stent dilation may be utilized at the discretion of the operator.

Efficacy

Xu et al. described successful use of LAMS with in-stent dilation to treat a <1cm long malignant colorectal anastomotic stricture previously refractory to EBD.35 The LAMS remained patent at six months, and the patient remained asymptomatic at 14-month follow-up, the last follow-up prior to the case report’s publication.35

Kankotia et al. performed a retrospective cohort study of 29 patients comparing EBD (N=18) and LAMS (N=11) for treatment of benign colorectal anastomotic strictures.36 They observed no significant difference in clinical success (EBD 66.7% vs. LAMS 81.8%; p-value 0.67) or stricture recurrence (EBD 33.3% vs. LAMS 11.1%; p-value 0.35), but the trend favored LAMS overall.36

Adverse Events

The most common adverse event reported by Kankotia et al. was LAMS migration seen in 46% (5/11) of patients.36 However, stent migration is not always a true adverse event and may instead be a surrogate marker of stricture resolution. There were no reports of perforation, bleeding, or pain in the LAMS group.36

Biodegradable Stents

Technique

BDS have been used outside the United States in an off-label manner to treat colorectal anastomotic strictures via the previously described technique.36,37

Efficacy

Repici et al. and Janik et al. performed case series with a combined 14 anastomotic stricture patients treated with BDS following pre-stent dilation.37,38 Repici et al. observed a less-than-ideal clinical success rate of 45% (5 of 11 patients) whereas Janik et al. observed clinical success in 100% (3/3) of patients with stent degradation noted at 4-5 months.37,38

Adverse Events

Janik et al. reported no adverse events.38 Repici et al. noted BDS migration in 36% (4/11) within two weeks.37 No other adverse events were reported.37

Endoscopic Incisional Therapy

Technique

Endoscopic incisional therapy (EIT) is a commonly utilized modality to treat esophageal strictures and has been successfully used to treat colorectal anastomotic strictures.22,38,39 Multiple radial incisions of operator-dependent length and depth are made around the stricture with or without excision of the fibrosed mucosal tissue in-between incisions.40 Operators have an array of instruments available to create the incisions including sphincterotomes, needle knives, insulation-tip (IT) knives or other endoscopic submucosal dissection (ESD) knives, and even polypectomy snares with argon plasma coagulation (APC) as seen in one study.40

Efficacy

Clifford et al. performed a systematic review including three retrospective cohort studies with a combined 455 patients treated with EIT which showed clinical success rates ranging from 71.4-100%.22 Jain et al. performed a meta-analysis with 186 patients treated with EIT alone or in combination with other modalities such as EBD or steroid injection.40 95.5% of patients treated with EIT alone achieved clinical success with stricture recurrence in 2.8% of patients.40 87.8% of patients treated with combined EIT and EBD achieved clinical success with stricture recurrence in 12.5% of patients.40 91.2% of patients treated with combined EIT and steroid injection achieved clinical success.40

Adverse Events

Jain et al. reported pain in 3.8% (7/186) of patients.40 Clifford et al. did not report any adverse events among their 455 patients.22

Conclusion

Small intestinal and colorectal anastomotic strictures pose a significant clinical challenge, and endoscopic management techniques continue to advance providing many solutions, each with varying efficacies and associated adverse events. For both small intestinal and colorectal anastomotic strictures, endoscopic balloon dilation remains first-line therapy but is hindered by high recurrence rates. Stenting with SEMS, LAMS, or BDS serves as another treatment option while endoscopic incisional therapy is another solution for small bowel and colorectal anastomotic strictures.  

References

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doi:10.1136/flgastro-2021-101827
7 ASGE Technology Committee, Siddiqui UD, Banerjee S,
et al. Tools for endoscopic stricture dilation. Gastrointest
Endosc. 2013;78(3):391-404. doi:10.1016/j.gie.2013.04.170
8 Klag T, Wehkamp J, Goetz M. Endoscopic Balloon Dilation
for Crohn’s Disease-Associated Strictures. Clin Endosc.
2017;50(5):429-436. doi:10.5946/ce.2017.147
9 Saritas U, Ustundag Y. Biodegradable stents: another
big step in the field of non-surgical therapy for fibrostenotic
Crohn’s disease. Endoscopy. 2012;44(4):435-436.
doi:10.1055/s-0031-1291639
10 Ferreira-Silva J, Medas R, Girotra M, Barakat M,
Tabibian JH, Rodrigues-Pinto E. Futuristic Developments
and Applications in Endoluminal Stenting. Gastroenterol
Res Pract. 2022;2022:6774925. Published 2022 Jan 11.
doi:10.1155/2022/6774925
11 ASGE Technology Committee, Varadarajulu S, Banerjee S,
et al. Enteral stents. Gastrointest Endosc. 2011;74(3):455-
464. doi:10.1016/j.gie.2011.04.011
12 Branche J, Attar A, Vernier-Massouille G, et al. Extractible
self-expandable metal stent in the treatment of Crohn’s
disease anastomotic strictures. Endoscopy. 2012;44 Suppl 2
UCTN:E325-E326. doi:10.1055/s-0032-1309854
13 Das R, Singh R, Din S, et al. Therapeutic resolution of
focal, predominantly anastomotic Crohn’s disease strictures
using removable stents: outcomes from a single-center
case series in the United Kingdom. Gastrointest Endosc.
2020;92(2):344-352. doi:10.1016/j.gie.2020.01.053
14 Şenol S, Özdemir DB. A novel stent fixation method for
anastomotic leaks after gastrectomy: anchoring of the distal
flare to the jejunum by using through-the-scope endoclips.
Prz Gastroenterol. 2023;18(4):416-420. doi:10.5114/
pg.2022.121045
15 Larson B, Adler DG. Lumen-apposing metal stents for gastrointestinal
luminal strictures: current use and future directions.
Ann Gastroenterol. 2019;32(2):141-146. doi:10.20524/
aog.2018.0337
16 Santos-Fernandez J, Paiji C, Shakhatreh M, et al. Lumenapposing
metal stents for benign gastrointestinal tract strictures:
An international multicenter experience. World J
Gastrointest Endosc. 2017;9(12):571-578. doi:10.4253/wjge.
v9.i12.571
17 Ferrell M, Mounzer R, Pitea T, Gabbert C. Endotherapy
for distant anastomotic strictures with a twist: reaching new
depths in lumen-apposing metal stent placement. Gastrointest
Endosc. Published online April 8, 2024. doi:10.1016/j.
gie.2024.04.008
18 Axelrad JE, Lichtiger S, Sethi A. Treatment of Crohn’s
Disease Anastomotic Stricture With a Lumen-apposing
Metal Stent. Clin Gastroenterol Hepatol. 2018;16(3):A25-
A26. doi:10.1016/j.cgh.2017.05.016
19 Rejchrt S, Kopacova M, Brozik J, Bures J. Biodegradable
stents for the treatment of benign stenoses of the small
and large intestines. Endoscopy. 2011;43(10):911-917.
doi:10.1055/s-0030-1256405
20 Gkolfakis P, Siersema PD, Tziatzios G, Triantafyllou
K, Papanikolaou IS. Biodegradable esophageal stents for
the treatment of refractory benign esophageal strictures.
Ann Gastroenterol. 2020;33(4):330-337. doi:10.20524/
aog.2020.0482
21 Hong JT, Kim TJ, Hong SN, Kim YH, Chang DK, Kim ER.
Uncovered self-expandable metal stents for the treatment of
refractory benign colorectal anastomotic stricture. Sci Rep.
2020;10(1):19841. Published 2020 Nov 16. doi:10.1038/
s41598-020-76779-8
22 Clifford RE, Fowler H, Manu N, Vimalachandran D.
Management of benign anastomotic strictures following
rectal resection: a systematic review. Colorectal Dis.
FNRUTORNITTIIOENR SIS ISNU EESN DINO GSACSOTPRYO,E SNETRERIEOSL O#9G2Y, SERIES #174
Endoscopic Management of Small Intestinal and Colorectal Anastomotic Strictures
32 PRACTICAL GASTROENTEROLOGY • NOVEMBER 2024
2021;23(12):3090-3100. doi:10.1111/codi.15865
23 Di Giorgio P, De Luca L, Rivellini G, Sorrentino E, D’amore
E, De Luca B. Endoscopic dilation of benign colorectal anastomotic
stricture after low anterior resection: A prospective
comparison study of two balloon types. Gastrointest Endosc.
2004;60(3):347-350. doi:10.1016/s0016-5107(04)01813-9
24 Jain D, Sandhu N, Singhal S. Endoscopic electrocautery
incision therapy for benign lower gastrointestinal tract anastomotic
strictures. Ann Gastroenterol. 2017;30(5):473-485.
doi:10.20524/aog.2017.0163
25 He F, Yang F, Chen D, et al. Risk factors for anastomotic
stenosis after radical resection of rectal cancer: A systematic
review and meta-analysis. Asian J Surg. 2024;47(1):25-34.
doi:10.1016/j.asjsur.2023.08.209
26 Favuzza J. Risk Factors for Anastomotic Leak, Consideration
for Proximal Diversion, and Appropriate Use of Drains. Clin
Colon Rectal Surg. 2021;34(6):366-370. Published 2021
Nov 23. doi:10.1055/s-0041-1735266
27 Slesser AA, Pellino G, Shariq O, et al. Compression versus
hand-sewn and stapled anastomosis in colorectal surgery:
a systematic review and meta-analysis of randomized
controlled trials. Tech Coloproctol. 2016;20(10):667-676.
doi:10.1007/s10151-016-1521-8
28 Surek A, Donmez T, Gemici E, et al. Risk factors affecting
benign anastomotic stricture in anterior and low anterior
resections for colorectal cancer: a single-center retrospective
cohort study. Surg Endosc. 2023;37(7):5246-5255.
doi:10.1007/s00464-023-10002-3
29 Yang FF, Chan RH. Mucus Impaction Related to
Postoperative Anastomosis Site Obstruction: A Rare Case.
Cureus. 2024;16(4):e58048. Published 2024 Apr 11.
doi:10.7759/cureus.58048
30 Araujo SE, Costa AF. Efficacy and safety of endoscopic balloon
dilation of benign anastomotic strictures after oncologic
anterior rectal resection: report on 24 cases. Surg Laparosc
Endosc Percutan Tech. 2008;18(6):565-568. doi:10.1097/
SLE.0b013e31818754f4
31 Biraima M, Adamina M, Jost R, Breitenstein S, Soll C.
Long-term results of endoscopic balloon dilation for treatment
of colorectal anastomotic stenosis. Surg Endosc.
2016;30(10):4432-4437. doi:10.1007/s00464-016-4762-8
32 Thomas-Gibson S, Brooker JC, Hayward CM, Shah SG,
Williams CB, Saunders BP. Colonoscopic balloon dilation
of Crohn’s strictures: a review of long-term outcomes. Eur J
Gastroenterol Hepatol. 2003;15(5):485-488. doi:10.1097/01.
meg.0000059110.41030.bc
33 Lamazza A, Fiori E, Schillaci A, Sterpetti AV, Lezoche
E. Treatment of anastomotic stenosis and leakage after
colorectal resection for cancer with self-expandable metal
stents. Am J Surg. 2014;208(3):465-469. doi:10.1016/j.amjsurg.
2013.09.032
34 Caruso A, Conigliaro R, Manta R, et al. Fully covered selfexpanding
metal stents for refractory anastomotic colorectal
strictures. Surg Endosc. 2015;29(5):1175-1178. doi:10.1007/
s00464-014-3785-2
35 Xu A, Banerjee D, Barlass U, Sánchez-Luna SA. Long-term
palliation of a malignant colonic anastomotic stricture using
a lumen-apposing metal stent (LAMS). BMJ Case Rep.
2024;17(1):e257706. Published 2024 Jan 5. doi:10.1136/
bcr-2023-257706
36 Kankotia RJ, Kwon RS, Philips GM, et al. Comparison of
lumen-apposing metal stents versus endoscopic balloon dilation
for the management of benign colorectal anastomotic
strictures. Gastrointest Endosc. 2024;100(1):136-139.e3.
doi:10.1016/j.gie.2024.03.008
37 Repici A, Pagano N, Rando G, et al. A retrospective analysis
of early and late outcome of biodegradable stent placement
in the management of refractory anastomotic colorectal
strictures. Surg Endosc. 2013;27(7):2487-2491. doi:10.1007/
s00464-012-2762-x
38 Janík V, Horák L, Hnaníček J, Málek J, Laasch HU.
Biodegradable polydioxanone stents: a new option for therapy-
resistant anastomotic strictures of the colon. Eur Radiol.
2011;21(9):1956-1961. doi:10.1007/s00330-011-2131-5
39 Bravi I, Ravizza D, Fiori G, et al. Endoscopic electrocautery
dilation of benign anastomotic colonic strictures: a
single-center experience. Surg Endosc. 2016;30(1):229-232.
doi:10.1007/s00464-015-4191-0
40 Jain D, Sandhu N, Singhal S. Endoscopic electrocautery
incision therapy for benign lower gastrointestinal tract anastomotic
strictures. Ann Gastroenterol. 2017;30(5):473-485.
doi:10.20524/aog.2017.0163

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Dispatches from the GUILD Conference, Series #63

Functional Medicine and Inflammatory Bowel Disease: An Evolving New Approach to IBD Care

October 2024 • Volume XLVIII, Issue 10
Thomas M. Strobel,Dawn B. Beaulieu

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Inflammatory bowel disease is a global disease with incidence and severity rising in Western and industrialized cultures. This increase in autoimmune diseases such as IBD can be influenced by many things: genetics, environment, nutrition, and lifestyle. Functional Medicine is a science-based, personalized approach to healthcare that focuses on understanding the underlying root causes of disease and illness. It seeks to uncover the complex connections between genetics, environmental factors and lifestyle choices contributing to disease manifestation and progression. The principles of Functional Medicine can be utilized to help patients with IBD by making connections between a person and modifiable lifestyle factors. Using a multi-modal functional medicine-based program for IBD, patients can experience improvement in both symptoms and gut inflammation. As the treatment of IBD patients evolves, Functional Medicine can play a significant role in the overall care of the IBD patient resulting in improvement in quality of life and patient outcomes. 

Introduction

In the early 1990s, a group in Victoria, British Columbia, Canada, laid the groundwork for what would become The Institute for Functional Medicine. The goal was to merge traditional medical care with advanced scientific research. This initiative was inspired by the historical concept of functional medicine, dating back to the 19th century. Functional medicine is a holistic, science-based, personalized approach to healthcare that focuses on understanding the underlying causes of disease and illness. It views the body as an interconnected system rather than separate, individual parts. The principles of functional medicine are rooted in lifestyle choices and nutrition with the goal of restoring health and improving overall function. It is not a substitute for conventional medicine, but the principles can be applied as adjunct care to conventional medicine and serve as a model for the management of chronic, complex diseases. In functional medicine each patient is an n-of-1 and rejects the “one size fits all” concept of care. 12 Functional medicine care aims to improve clinical outcomes and quality of life, create balance and self-discovery, and guide the practice of preventative healthcare.

Inflammatory Bowel Disease (IBD) is an umbrella term that encompasses the diseases Crohn’s disease (CD) and ulcerative colitis (UC). It affects millions globally and presents a significant burden to individuals and healthcare systems alike. Traditional treatment modalities have predominantly focused on symptom management through pharmacological interventions. Recently, the use of functional medicine as a transformative approach to IBD management has begun emerging. 

Conventional medicine focuses on arriving at a diagnosis and treating symptoms. It is disease-oriented, provider focused, and treatment is symptom-based and disease-specific. Functional medicine practitioners attempt to understand why the disease occurred and notice the linkages between lifestyle, nutrition, mental health, socioeconomic influences, and environmental factors. It treats the body and focuses on root causes while encouraging prevention. In functional medicine, every person has their own origin story. 

We live in an era where chronic disease is an epidemic. Roughly 50% of adults have at least one chronic health condition and 25% have 2 or more.1,2 With the rise in incidence of chronic disease, costs have risen as well. Chronic disease management accounts for 86% of all healthcare costs, and this figure continues to grow.3 The incidence and prevalence of IBD continues to rise globally in Western and newly industrialized Asian countries.4 It is becoming quite clear that pharmacologic treatment alone is not enough for this growing epidemic. Our pharmacologic advances in the treatment of IBD over the past 20 years have grown, but the disease is not slowing down. It is unlikely medications alone are going to reverse this trend.

Genetics, the Immune System, and the Environment

The pathogenesis of IBD is best described as an interplay of three domains: genetics (notably, first degree relatives), the innate and adaptive immune system, and environmental exposures. With this in mind, we can further divide these contributors into modifiable and non-modifiable factors. Diet and lifestyle can modify both the risk of developing IBD and overall severity of disease. Lifestyle choices, such as smoking and exercise, contribute to the environment you live in while your diet influences the biochemical makeup and microbiome of the gut. Both factors are the focal points of a functional medicine practitioner’s evaluation and management. Functional medicine challenges genetic determinism in that diet, lifestyle, and our environment can determine health outcomes.12

Disease Modifiers and Environmental Risk Factors

The increase in IBD prevalence may partially be explained by modifiable lifestyle factors. For example, changes in the composition of the gut microbiome can negatively or positively modify the risk for IBD. While certain strains such as Bifidobacterium and Firmicutes are protective, Escherichia coli and Enterobacteriaceae are known to increase the risk of IBD. Higher intake of ultra-processed foods such as cheeses, sweets, and pastries are associated with a higher risk of Crohn’s disease.5 Chen et al. showed a nearly 2-fold increase in the risk of CD in patients with higher intake of ultra-processed foods. Patients with pre-existing IBD have also been shown to have higher intake of ultra-processed foods and are four times as likely to have had an IBD-related surgery. Sasson and colleagues expertly described the causation between diet and inflammation.6 Certain dietary patterns and nutrition status can modify the diversity of the microbiome, increase gut permeability, and alter immune cell dysfunction. All of these contribute to the development and progression of IBD. In a functional medicine model, we think about things in relation to the mnemonic DIGIN: Digestion, Intestinal permeability, Gut microbiome, Inflammation, and Nervous system. 

The Functional Medicine Roadmap: The 5 R’s

In addition to diet, other environmental triggers such as smoking, antibiotic use in childhood, oral contraceptives, history of appendectomy, and vitamin D deficiency have all been shown to increase the risk of IBD. Conversely, breastfeeding and tea or coffee consumption have been shown to be effective in lowering risk.4,7 For children with CD, those who had exposure to maternal smoking were at higher risk of hospitalization within the first 3 years of diagnosis. Conversely, children with CD who were breastfed as infants were less likely to progress to structuring or penetrating phenotypes.8 These are just a few of the many examples of how modifiable lifestyle factors influence the risk and severity of IBD.

Functional medicine focuses on the effects of sleep, exercise, nutrition, stress, and human relationships and their contributions to the overall health of the human body. For IBD, a functional medicine model can promote microbiome diversity resulting in a healthy gut microenvironment. “The 5 R’s” is a functional medicine framework for gut restoration: Remove, Replace, Re-inoculate, Repair, and Re-balance.

In the REMOVE phase, the goals are to identify and remove dietary triggers, consider any current medications that can trigger dysbiosis or inflammation, and examine other dietary and lifestyle factors that drive dysbiosis. In some patients an elimination diet is helpful to promote body awareness of food, identify food triggers, use phytonutrients to heal the gut and support a healthy microbiome. The elimination diet focuses on common triggers of inflammation including dairy, eggs, gluten, peanuts, shellfish, beef/red meat, soy, corn, refined sugar, coffee/caffeine, and alcohol. Any diet changes or elimination diets should always be supervised by an experienced functional medicine provider or trained dietitian (Figure 2).  

In the REPLACE phase, the goals are to support digestion and health by replacing nutrients that are essential to gut healing while focusing on dietary and lifestyle factors that promote wellness. This can be done through nutrients (example: vitamin D, zinc, magnesium, B12), supporting digestion, and focusing on dietary and lifestyle factors that promote health. In the REINOCULATE phase, the focus is to provide care plans to build a healthy microflora and look at the utility of using probiotics, prebiotics, synbiotics (prebiotics + probiotics), post biotics (inanimate microorganisms and their healthy byproducts), and short chain fatty acid as potential tools for care with the goal of supporting disordered intestinal permeability and reversing dysbiosis. It is helpful to remember that one cannot out supplement a bad diet and the “food first” approach should be step one when thinking in terms of how to REINOCULATE the gut.

Diet can either drive dysbiosis or promote a healthy microbiome.9 In the REPAIR phase, we add back healthy nutrients to support cellular health and prevent inflammation. Vitamin D, L-glutamine, curcumin, botanicals, and immunoglobulins are a few examples that may repair damage from chronic inflammation. Increasing and optimizing phytonutrients are a key component of the REPAIR phase. These nutrients are derived from colorful fruits and vegetables. The aim should be for at least nine servings of phytonutrient-rich foods daily. This is much more than the average American, who gets 2-4 servings daily. Interestingly, each color of food comes with its own benefits in addition to anti-inflammation and vascular health. Eat the rainbow is a term often used in functional medicine. Red and orange foods typically confer anti-bacterial effects while promoting cardiovascular and brain health, prostate health, and cellular protection. Red foods also provide anti-cancer effects. Yellow foods promote digestive, immune, and eye health while supporting anti-inflammatory and protective cellular effects. Green foods support metabolic and hormonal health. Blue, purple, and black foods support liver and digestive health. White, tan, and brown foods support immunity, metabolism, and digestion. IBD patients often cannot tolerate a high fiber diet so this goal can be difficult in patients with active disease. Start slow and go slow should be the guidance given to patients with IBD. Be mindful that active inflammation and those IBD patients with strictures need to be on a low fiber diet. Each patient is unique in their inflammatory burden and disease severity, so each dietary plan should also be personalized to them.

If we can recognize that certain foods exert positive influence on overall health on a biochemical level, then such foods can be thought of as medicine. For example, quercetin and vitamin E are known inhibitors of phospholipase A2 – a precursor to arachidonic acid and prostaglandins, which promote inflammation. Quercetin, turmeric, ginger, green tea, and Boswellia are all inhibitors of 5-LOX, a precursor to leukotrienes. Other foods such as garlic, willow, and barberry are COX-2 inhibitors, which downregulates prostaglandin production. All of these are examples of the anti-inflammatory properties of certain foods. Some of these foods have been studied as treatment for IBD. Gut specific turmeric in combination with Qing Dai are examples that have shown promise as a gut-specific treatment for IBD.13

The last phase of the 5 R’s is REBALANCE, but this should be a focus throughout the IBD care plan from day one. IBD patients are often in a “fight or flight” mode with sympathetic overdrive. Trying to build resilience, reducing stress, and relaxation training should be a focus of care. Some examples of tools to rebalance and support a healthy gut microbiome are mindfulness, stress management, hypnotherapy, heart rate variability tools, and yoga nidra. Engaging in positive lifestyle modifications are the most cost-effective and safe treatments available and are often overlooked in traditional medical care.

Modifiable Lifestyle Factors

How a patient lives is often more important than any time spent with a provider. Chronic disease states often involve multi-system dysfunction. In addition to nutrition, the foundations of health in functional medicine are sleep and relaxation, exercise and movement, stress, and relationships. Data has shown that sleep loss appears to be associated with changes in the microbiota and insomnia can alter the gut microbiome. There are numerous physiologic changes associated with inactivity. Helping patients embrace an active lifestyle will benefit overall wellness. Moreover, stress management can help increase resilience and optimize immune function. Lastly, human relationships play a profound role in human biology. The social threads that connect us are often more impactful and powerful than the genetic threads. 

A real-world example of functional medicine in practice is the Functional Medicine Clinic (FMC) at Vanderbilt University Medical Center. This program utilizes one-on-one and shared group visits to implement the principles of functional medicine. In the one-on-one visits, patients meet with an FMC provider, a wellness coach, and a dietician. During these visits, patients tell their own story of their health and disease. Clinicians elicit key factors predisposing to disease such as their genetic risk and environmental factors, looking for triggering events and mediators or perpetuators of inflammation, such as medication use or past infections. Focusing on modifiable lifestyle behaviors such as sleep, exercise, nutrition, stress, and relationships is the backbone of the program, emphasizing that how a patient lives is vital to their overall health and wellness.

In shared group visits, patients participate in group-based educational sessions every other week over 12-weeks. Each session includes a nutrition and a lifestyle intervention. Topics are described in Figure 3, and all of these are aimed at addressing the root causes of chronic disease. Another program available is a 6-week Nervous System Regulation Program (NSRP). Patients make weekly visits, and sessions are broken down into educational topics followed by an intervention (Figure 4). 

The structured FMC program has demonstrated clinical improvement in IBD patient reported outcomes in measures of fatigue, sleep, global symptoms, and IBD-related symptoms.10 Additionally, a small cohort in the FMC program who had elevated fecal calprotectin levels (a marker of gut-specific inflammation), normalized following completion of the program, with each participant citing motivation to continue the changes they learned from the FM program.11 In the NSRP, patients have demonstrated improvement in global fatigue and global symptoms. 14

The benefits of functional medicine may best be described with the following clinical vignette: A woman who was diagnosed with UC after a diarrheal illness and while taking NSAIDs had poor clinical response to conventional mesalamine therapy. Per convention, she was offered escalation to biologic therapy, but she instead expressed willingness to try a functional medicine approach. Listening to her story and timeline, the fundamental issues that stood out were the following: she slept only 5-6 hours per night, was a chronic NSAID user, ate mostly processed foods and drank alcohol weekly. She had limited exercise and a long history of antibiotic use from recurrent UTIs. Additionally, she reported stress from her parents who divorced in high school, and she was bottle-fed as a baby. Upon completion of her personal 5R program, she had marked improvement in symptoms, normalization of a vitamin D deficiency, and normalization of inflammatory markers including fecal calprotectin. 

Personalized Treatment Plans

A cornerstone of functional medicine is personalized treatment plans. In other words, it is tailored to the individual’s specific health needs and goals. This might include targeted supplementation to address nutrient deficiencies, nutritional changes to support gut health, and natural compounds with anti-inflammatory properties. These personalized interventions are designed to restore balance and functionality to the body and promote long-term remission and improved quality of life for IBD patients.

Functional Medicine and the Future of IBD Care

Functional medicine does not stand in opposition to conventional treatments, but rather complements them. It supports that a portion of health outcomes are influenced by the interaction between genes that are impacted by lifestyle, nutrition, environment, and human relationships. Research has shown thus far that functional medicine can improve outcomes in conditions such as irritable bowel syndrome, inflammatory arthritis, and Hashimoto’s thyroiditis. A synergistic approach that consists of pharmacological treatments and functional medicine strategies can provide the most comprehensive care for IBD patients. It gives patients a more proactive role in the management of their health. This model encourages collaboration between patients and healthcare providers. 

References

1. Ward BW, Schiller JS, Goodman RA. Multiple chronic conditions among US adults: a 2012 update. Prev Chronic Dis. 2014;11: E62.

2. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459-1544.

3. Leroy L, Bayliss E, Domino M, et al. The Agency for Healthcare Research and Quality Multiple Chronic Conditions Research Network: overview of research contributions and future priorities. Med Care. 2014;52 Suppl 3:S15-22.

4. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-321.e2.

5. Chen J, Wellens J, Kalla R, et al. Intake of Ultra-processed Foods Is Associated with an Increased Risk of Crohn’s Disease: A Cross-sectional and Prospective Analysis of 187 154 Participants in the UK Biobank. J Crohns Colitis. 2023;17(4):535-552.

6. Sasson AN, Ananthakrishnan AN, Raman M. Diet in Treatment of Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2021;19(3):425-435.e3.

7. Ananthakrishnan AN, Kaplan GG, Bernstein CN, et al. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus. Lancet Gastroenterol Hepatol. 2022;7(7):666-678.

8. Lindoso L, Mondal K, Venkateswaran S, et al. The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn’s Disease in Children. Am J Gastroenterol. 2018;113(10):1524-1529.

9. Myles IA. Fast food fever: reviewing the impacts of the Western diet on immunity. Nutr J. 2014;13:61.

10. Strobel TM, Nguyen C, Riggs T, et al. Functional Medicine Approach to Patient Care Improves Sleep, Fatigue, and Quality of Life in Patients with Inflammatory Bowel Disease. Crohns Colitis 360. 2022;4(3).

11. Strobel, TM. A Functional Medicine Program for Patients with Inflammatory Bowel Disease Improves Fecal Calprotectin Levels. Poster presentation: American College of Gastroenterology Annual Meeting 2023; October 22, 2023; Vancouver, BC.

12. Bland J. S. (2022). Functional Medicine Past, Present, and Future. Integrative medicine, 21(2), 22–26.

13. Ben-Horin S, Salomon N, Karampekos G, Viazis N, Lahat A, Ungar B, Eliakim R, Kuperstein R, Kriger-Sharabi O, Reiss-Mintz H, Yanai H, Dotan I, Zittan E, Maharshak N, Hirsch A, Weitman M, Mantzaris GJ, Kopylov U. Curcumin-QingDai Combination for Patients with Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial. Clin Gastroenterol Hepatol. 2024 Feb;22(2):347-356.e6.

14. Emily Spring, Thomas Strobel, Sarah Campbell, Randi Robbins, Julia Carlson, Sydney Elliot, Stephanie Ardell, Dawn B. Beaulieu. Nervous System Regulation Program Improve Fatigue and Medical Symptoms in Inflammatory Bowel Disease Patients. Poster presentation: IFM AIC. May 2024; Las Vegas, NV

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Nutrition Reviews in Gastroenterology, SERIES #18

Management of CRBSI: How to Extend the Lifeline for Home PN Patients

October 2024 • Volume XLVIII, Issue 10
Yichun Fu,Edwin McDonald

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Catheter-related bloodstream infections (CRBSI) are a dreaded complication for patients who require home parenteral nutrition (HPN) for survival. Patients with CRBSI usually present with fever, chills, and malaise. Clinicians should maintain a high level of suspicion for CRBSI to prevent severe illness and mortality. Healthcare providers should obtain blood cultures from both peripheral veins and the central venous access device (CVAD) at the first sign of infection. Antibiotic selection depends on the severity of the infection and antibiotic susceptibilities. Catheter salvage and preserving venous access have been proven successful in CRBSI. Establishing an institution-specific protocol for education, prevention, and treatment of CRBSI is essential for improving long-term outcomes of patients dependent on HPN.

Introduction

Home parenteral nutrition (HPN) is an alternative form of nutrition when enteral nutrition is infeasible or insufficient.1,2 HPN improves quality of life and disease outcomes by optimizing patients’ nutritional status.1 In the United States, an estimated 20,883 adult patients received HPN in 2013 based on Medicare and Medicaid Services data.3 Catheter-related bloodstream infection (CRBSI) is a significant cause of morbidity and mortality in patients receiving parenteral nutrition (PN).4–9 The infections develop after microbial biofilms form on the surface of the central venous access devices (CVAD).10 Studies have shown that patients receiving PN experience CRBSI at higher rates compared to other patients with chronic infusion needs.3–5,11,12 

Many interventions reduce CRBSI and its mortality in the HPN population. Further, several societies have issued CRBSI guidelines, including the European Society for Clinical Nutrition and Metabolism (ESPEN), the American Society for Parenteral and Enteral Nutrition (ASPEN), and the Infectious Diseases Society of America (IDSA).2,9,13 This review aims to provide an overview of the standard practices in diagnosing, treating, and preventing CRBSI.

Epidemiology and Risk Factors

According to ASPEN’s Sustain registry of both adult and pediatric HPN populations, black and male patients were more likely to have at least one episode of CRBSI.14 Rates of CRBSI vary due to different diagnostic definitions, heterogeneity of study populations, and variability in institutional experience. In a meta-analysis, Reitzel et al. reported the incidence of CRBSI as 0.0-11.89 per 1000 CVAD days.12 Known patient risk factors for CRBSI include having an ostomy or wound, underlying malignancy, and body mass index less than 18.5 kg/m.2,15,16 Similarly, a retrospective study of 155 HPN patients established male sex and underlying malignancy as independent risk factors for CRBSI (HR 1.69 and 2.38 respectively, p= 0.009, <0.001).17 In a Danish study of HPN patients, peripherally inserted central catheter (PICC) lines were associated with higher CRBSI rates (1.43 ± 0.20 vs. 0.95 ± 0.390, per 1000 CVAD days, p < .001) and shorter time intervals (83.91 ± 93.754 vs. 297.21 ± 386.910, p < .001) to a CRBSI episode compared to tunneled catheters.18 Additionally, using intravenous lipid emulsion (ILE) more than twice weekly and catheters with multiple lumens may increase CRBSI.16

Making the Diagnosis 

Promptly diagnosing CRBSI is crucial. However, diagnosing CRBSI is challenging due to multiple factors, including variable bacteria culture methods and lack of CVAD tip cultures when attempting to salvage the CVAD. Practitioners should maintain a high suspicion for CRBSI when patients report fever, rigor, and malaise, especially within 30 minutes of initiating an infusion.4 However, clinical findings alone do not reliably establish a diagnosis. Fever and hypotension are sensitive but not specific. Purulent drainage at CVAD sites may solely indicate an exit-site infection without a concomitant bloodstream infection.13 Further, an observational study of 548 adult patients on HPN at a Danish center employed six strict microbiological criteria based on different sources of blood culture methods. Out of 3,188 blood culture episodes obtained for clinical signs of infection, a mean blood culture positivity rate was only 40%, with 30% fulfilling a CRBSI diagnosis.19

When there is concern for CRBSI, it is imperative to obtain blood cultures before initiating antibiotics to diagnose CRBSI definitively (Figure 1). According to the IDSA, patients should have two sets of blood cultures drawn, with at least one set drawn percutaneously.13 Notably, CVAD and percutaneous blood cultures have better negative predictive values than positive predictive values. Hence, a positive percutaneous culture must be interpreted within the clinical context, while a negative percutaneous culture is better at excluding a CRBSI (Table 1).13,20

Culturing the CVAD tip with quantitative or semi-quantitative methods is the most reliable approach to diagnosing CRBSI, but it is not readily available in many laboratories. Quantitative cultures utilize the highly accurate pour plate method.4,13 According to the pour plate method, CRBSI occurs when CVAD and percutaneous cultures yield the same organisms, with CVAD colony counts at least 3-fold greater than percutaneous counts.13 The differential time to positivity method is widely available among qualitative cultures. Microbial growth from the central CVAD blood sample occurring at least 2 hours earlier than the percutaneous blood sample provides a comparably accurate diagnosis to quantitative methods.13,21,22 However, qualitative methods may falsely interpret contamination as an infection.4 The IDSA guidelines recommend culturing the tip or a segment of the CVAD only when CRBSI is confirmed.13 However, many patients require long-term access. A recent study showed that CVAD tip culture may not change antibiotic management when paired blood cultures confirm a CRBSI.23 Therefore, septic shock or failed CVAD salvage should prompt performing CVAD tip cultures. 

Finally, diagnosing certain pathogens requires specific blood culture protocols. A single blood culture growing coagulase-negative staphylococcus species necessitates additional blood samples from both the CVAD and a peripheral vein to rule out contamination. Patients with Corynebacterium, Bacillus, and Micrococcus species also require at least two positive blood cultures from different sites to secure a diagnosis.13 Malassezia furfur is a lipophilic fungus within normal skin flora that is difficult to detect with routine blood culture methods. For patients with unexplained septic shock, it is important to perform a catheter tip culture on Dixon agar to rule out Malassezia furfur fungemia.24,25

Management of CRBSI

Antibiotic Selection and Duration

After the appropriate blood cultures are obtained, intravenous antimicrobials should be started immediately in patients with signs of sepsis. The initial therapy should be tailored to the severity of the patient’s clinical condition, the most likely pathogens, and the likelihood of resistant organisms based on the patient’s history and the local antimicrobial resistance patterns. Coverage for gram-positive and gram-negative species with vancomycin and a fourth-generation cephalosporin is generally necessary.13 Neutropenia, critical illness, or a history of multi-drug resistant pathogens warrant coverage for Pseudomonas aeruginosa. If the patient has a femoral CVAD and septic shock, empiric treatment should cover gram-negative bacilli and Candida species. Patients who develop severe sepsis should receive coverage for Candida.13

Following pathogen identification, the decision to remove or retain the CVAD should occur, as well as distinguishing complicated CRBSI from uncomplicated CRBSI. Complicated infections include those with suppurative thrombophlebitis, endocarditis, and osteomyelitis. 

The IDSA guideline in 2009 provides detailed approaches to specific pathogens. Notably, the most common causes of CRBSI are coagulase-negative staphylococci. Most staphylococci exhibit methicillin resistance. Regardless of resistance, staphylococci infections can be generally treated with 14 days of antibiotics if the CVAD is retained and 5-7 days if the CVAD is removed.13 Staphylococcus lugdunesis and Staphylococcus aureus CRBSI require CVAD removal and generally 4-6 weeks of antibiotic treatment. Patients with S. lugdunesis and S. aureus are eligible for a shorter duration of antibiotics (2 weeks minimum) if they do not have diabetes, immunosuppression, prosthetic intravascular device, or complicated infections. These patients must resolve bacteremia within 72 hours of antibiotic initiation and a trans-esophageal echocardiogram (TEE) to ensure the absence of valvular vegetations. For CRBSI with Enterococcus species, ampicillin is the antibiotic of choice in non-resistant cases. In the presence of resistance, vancomycin is appropriate. The treatment is generally 7-14 days with CVAD retention. Signs or risks of endocarditis warrant evaluation with TEE. Critically ill patients with a history of gram-negative bacilli require two antibiotics of different classes with gram-negative activity to cover multidrug-resistant species. In addition, patients with a Candida CRBSI should have an ophthalmologic exam to assess for Candida endophthalmitis—patients on PN are at particular risk (odds ratio 6.02, interval 3.58-13.36).26,27 Although societal guidelines recommended CVAD removal in S. aureus, Pseudomonas, and fungal species, many HPN patients struggle with limited vascular access sites. As such, there are cases of successful CVAD salvage in Staphylococcus aureus, Pseudomonas, and Candida species.28,29 

When narrowing the antibiotic coverage, one should take special consideration in patients with short bowel syndrome because of decreased absorption of many oral antimicrobial therapies. Some patients, such as those having sufficient length of jejunum in continuity with more than half of the colon, may have adequate medication absorption.30,31 In general, micro-emulsified and liquid formulations have better absorption, while lipid-soluble medications are often poorly absorbed.31,32 Certain medications with high solubility and high permeability, such as levofloxacin and metronidazole, have better absorption in patients with short bowel.31 Two systematic reviews similarly showed adequate absorption of metronidazole and fluconazole, whereas cephalexin, clindamycin, and trimethoprim-sulfamethoxazole had decreased absorption despite achieving therapeutic levels.30,32,33 In contrast, ciprofloxacin and gentamicin had decreased bioavailability.32,33  Comprehensive data in this area is limited as patients’ anatomy varies. Individualized drug monitoring and subsequent dose titration are recommended. In addition, patients with severe dysmotility or bowel obstruction may also have difficulty tolerating oral antibiotics and require intravenous alternatives.

CRBSI Complications and Disseminated Diseases 

Several severe complications of CRBSI require additional testing and management, including suppurative thrombophlebitis, endocarditis, and osteomyelitis. Suppurative thrombophlebitis entails a venous thrombus with persistent bacteremia despite at least three days of antimicrobial therapy. Radiographic evidence of the thrombus is necessary for the diagnosis. Patients should receive a minimum of 3-4 weeks of antibiotics. If the superficial vein is purulent or the infection extends beyond the vessel wall, the vessel should be surgically resected. The benefit of antithrombotic agents such as heparin is not clear.13 

Patients with persistent bacteremia and prosthetic valves or implanted cardiac devices (pacemakers) should have endocarditis excluded with a TEE. TEE should happen at least one week from the initial positive blood culture to ensure the test’s sensitivity. Notably, a negative transthoracic echocardiogram does not exclude endocarditis.13

Back pain, joint tenderness, or swelling raise the suspicion for osteomyelitis or septic arthritis in CRBSI. Serum biomarkers such as erythrocyte sediment rate and C-reactive protein are highly sensitive for osteomyelitis, but establishing the diagnosis requires radiographic studies such as magnetic resonance imaging.34 In septic arthritis, synovial fluid analysis and cultures are necessary.35 Treatment of osteomyelitis typically involves 6-8 weeks of parenteral or highly bioavailable oral antibiotics. Likewise, both  2-4 weeks of antibiotics and surgical drainage are necessary for managing septic arthritis.34,36,37

Management of the CVADs

Septic shock, port abscesses, complicated CRBSI, or certain organisms, including S. aureus, P. aeruginosa, fungi, or mycobacteria, warrant removal of long-term CVAD.2,13 Otherwise, IDSA and ESPEN guidelines support CVAD salvage since patients with HPN often require long-term venous access.2,13 Of note, two studies did show comparable success rates of CVAD salvage in S. aureus infections.28,29 Antibiotic lock therapy (ALT) may facilitate CVAD salvage. Ampicillin, cefazolin, and vancomycin locks are appropriate for gram-positive organisms. Cefazolin, ciprofloxacin, and gentamicin locks are usually suitable for gram-negative organisms. Tailoring line lock therapy to sensitivities from culture results is common.38 In various institutional protocols, the duration of ALT ranged between 3 and 28 days.29,38 The 2009 IDSA guidelines recommend ALT for 7-14 days in CVAD salvage with re-instillation every 24 hours, while the ESPEN guidelines in 2023 recommend 14 days of ALT with systemic antibiotics.2,13 The success rates for salvage vary between 60% and 80%, with 53% of the patients CRBSI-free at one year.38,39 Studies define successful salvage as clinical resolution of infection, negative blood cultures for 48 hours, and no evidence of CRBSI at 90 days after completing treatment.4 While it is possible to salvage CVADs, CVAD salvage is associated with higher rates of new infections than CVAD removal.39 

Salvage or wire exchange of a CVAD remains a viable option if patients have limited venous access sites or significant risks for procedural complications.40 The overall success rate for CVAD salvage depends on the offending organisms: it ranges from 14.2% for Candida species, 26.7% in methicillin-resistant S. aureus, to 86.8% in methicillin-sensitive S. aureus.28 The re-infection rate within 30 days was 4.4% in one study.29 In the case of wire exchange, an antibiotic-impregnated CVAD is preferred.13 Therefore, salvaging or exchanging a CVAD is often a multidisciplinary decision with interventional radiology and infectious disease providers. Finally, inserting a new CVAD should occur after blood cultures are negative for 2-3 days in patients who underwent CVAD removal, per IDSA guidelines.13 Conversely, ESPEN recommends waiting 5-10 days after the first negative blood culture result or until the completion of the systemic antibiotic therapy before placing a new CVAD.2 

Definition MetAdditional Criteria
Positive catheter tip culture None required
Positive catheter blood culture and percutaneous culture with identical microorganismsThe colony count of the catheter specimen is at least 3-fold greater than the colony count from peripheral blood  OR The catheter blood culture grows the organism at least two hours before the percutaneous culture
Percutaneous blood cultures and positive
catheter tip with identical microorganisms		None required 
Table 1. Criteria for CRBSI Diagnosis

Management of Parenteral Nutrition

During the initial evaluation for CRBSI, it is reasonable to hold PN and avoid accessing the retained CVAD. It is safe to resume PN after 72 hours of negative blood cultures following the initiation of appropriate antibiotic therapy.29,38,39 Some institutions also withhold intravenous lipid emulsions (ILE) and continue a lipid-free PN solution when a patient has fever, leukocytosis, or sepsis but no evidence of bacteremia. The concern that ILE increases the risk of CRBSI or worsens CRBSI outcomes underlies this practice. Historical studies suggest intravenous sunflower and safflower oil promote the growth of bacteria and Candida. Several early prospective studies showed a higher odds ratio of infection with ILE containing PN.41,42 Mundi et al. summarized several potential mechanisms for the increased risk of infection associated with ILE.3 Notably, ILE affects cell membrane fluidity and decreases the clearance capacity of the reticuloendothelial system, both of which can promote pro-inflammation.43–45 However, in a prospective study with over 4000 patients, receiving ILE did not significantly contribute to bacteremia after adjusting for baseline characteristics.46 Another retrospective study showed that ILE was not associated with higher rates of CRBSI, but patients with ILE had more frequent bloodstream infections from gastrointestinal translocation.47 In addition, in a meta-analysis comparing the growth ratios of various species, only a portion of species survived exclusively in lipids. In contrast, some species rapidly grew in lipid-containing and lipid-free media.48 Therefore, no substantial evidence supports withholding lipids in the case of suspected bacteremia or sepsis.

TopicTeaching Points
Catheter Care• Hand hygiene
• Aseptic technique – catheter flushing, preparation of the infusion bag, connection, and disconnection
• Cleansing the catheter hub
• Catheter cap placement and removal
• Catheter insertion site care – dressing and line securement
• Recognition of catheter complications
Home Environment• Setting up a clean, hard (non-porous) area for aseptic infusion bag preparation
• Restriction of animals from the area
• Sanitary water supply
• Safe refrigerated storage and inspection of infusion bags
• Clean storage of infusion supplies
Patient-Purchased Supplies• Liquid hand soap
• Hand sanitizer
• Paper towels
• Antibacterial wipes
Table 2. Sample Patient Education Checklist54,55

Prevention of CRBSI

Strategies for preventing HPN-associated CRBSI target known risk factors for CRBSI. For example, using a tunneled CVAD with the lowest number of lumens necessary may decrease CRBSI.14,49 Another strategy for mitigating CRBSI is minimizing the frequency of accessing CVAD lumens by designating their use solely for PN or antibiotics.16 ESPEN guidelines recommend taurolidine line locks for the primary prevention of CRBSI.2 Several prospective studies demonstrate that taurolidine is superior to placebo and other line locks in preventing CRBSI and biofilm formation. Taurolidine is also cost-effective and has few adverse reactions.50–52 Taurolidine line locks are currently unavailable in the United States. Conversely, the IDSA and ESPEN guidelines recommended against using ethanol locks to prevent CRBSI due to systemic toxicity and its potential to occlude or damage the CVAD.2,13 Studies of line locks against Candida biofilms are mostly still in the pre-clinical stage.53 

Clinician and patient education also play a crucial role in preventing CRBSI (Table 2).50–52,54,55 Keohane et al. showed that teaching from a trained nurse decreased CRBSI rates from 11.5% in patients with tunneled CVADs to 4%.49 In an Italian center, detailed training for HPN patients reduced CRBSI by 50% (6/1000 CVAD days to 3/1000 CVAD days, p<0.005) compared with standard education. In a study by Reimund et al., CRBSI incidence decreased since the opening of a dedicated HPN center, and the rates were inversely related to the years of experience of the nutrition support team.53 

Conclusion

Clinicians should employ accurate and prompt diagnostic and management tools to diagnose, treat, and prevent CRBSI and its complications in patients with PN. CVAD salvage is an evidenced-based strategy for preserving venous access. There are ongoing studies regarding effective CRBSI prevention strategies. A dedicated nutrition support team and institution-specific protocols can significantly reduce the risk of CRBSI in patients with PN. 

References

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2. Pironi L, Cuerda C, Jeppesen PB, et al. ESPEN guideline on chronic intestinal failure in adults – Update 2023. Clin Nutr. 2023;42(10):1940-2021. 

3. Mundi MS, Pattinson A, McMahon MT, Davidson J, Hurt RT. Prevalence of Home Parenteral and Enteral Nutrition in the United States. Nutr Clin Pract. 2017;32(6):799-805. 

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7. Russell MK, Wischmeyer PE. Supplemental Parenteral Nutrition: Review of the Literature and Current Nutrition Guidelines: Nutrition in Clinical Practice. Nutr Clin Pract. 2018;33(3):359-369.

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9. Kovacevich DS, Corrigan M, Ross VM, McKeever L, Hall AM, Braunschweig C. American Society for Parenteral and Enteral Nutrition Guidelines for the Selection and Care of Central Venous Access Devices for Adult Home Parenteral Nutrition Administration. J Parenter Enter Nutr. 2019;43(1):15-31.

10. Yousif A, Jamal MA, Raad I. Biofilm-Based Central Line-Associated Bloodstream Infections. In: Donelli G, ed. Biofilm-Based Healthcare-Associated Infections. Vol 830. Advances in Experimental Medicine and Biology. Springer International Publishing; 2015:157-179. 

11. Ishizuka M, Nagata H, Takagi K, Kubota K. Total Parenteral Nutrition Is a Major Risk Factor for Central Venous Catheter-Related Bloodstream Infection in Colorectal Cancer Patients Receiving Postoperative Chemotherapy. Eur Surg Res. 2008;41(4):341-345. 

12. Reitzel RA, Rosenblatt J, Chaftari A, Raad II. Epidemiology of Infectious and Noninfectious Catheter Complications in Patients Receiving Home Parenteral Nutrition: A Systematic Review and Meta-Analysis. J Parenter Enter Nutr. 2019;43(7):832-851. 

13. Mermel LA, Allon M, Bouza E, et al. Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45. 

14. Ross VM, Guenter P, Corrigan ML, et al. Central venous catheter infections in home parenteral nutrition patients: Outcomes from Sustain: American Society for Parenteral and Enteral Nutrition’s National Patient Registry for Nutrition Care. Am J Infect Control. 2016;44(12):1462-1468.

15. Xue Z, Coughlin R, Amorosa V, et al. Factors Associated With Central Line–Associated Bloodstream Infections in a Cohort of Adult Home Parenteral Nutrition Patients. J Parenter Enter Nutr. 2020;44(8):1388-1396.

16. Buchman AL, Opilla M, Kwasny M, Diamantidis TG, Okamoto R. Risk Factors for the Development of Catheter-Related Bloodstream Infections in Patients Receiving Home Parenteral Nutrition. J Parenter Enter Nutr. 2014;38(6):744-749. 

17. Elfassy S, Kassam Z, Amin F, Khan KJ, Haider S, Armstrong D. Epidemiology and Risk Factors for Bloodstream Infections in a Home Parenteral Nutrition Program. J Parenter Enter Nutr. 2015;39(2):147-153. 

18. Bech LF, Drustrup L, Nygaard L, et al. Environmental Risk Factors for Developing Catheter-Related Bloodstream Infection in Home Parenteral Nutrition Patients: A 6-Year Follow-up Study. J Parenter Enter Nutr. 2016;40(7):989-994. 

19. Tribler S, Brandt CF, Hvistendahl M, et al. Catheter-Related Bloodstream Infections in Adults Receiving Home Parenteral Nutrition: Substantial Differences in Incidence Comparing a Strict Microbiological to a Clinically Based Diagnosis. J Parenter Enter Nutr. 2018;42(2):393-402. 

20. DesJardin JA, Falagas ME, Ruthazer R, et al. Clinical Utility of Blood Cultures Drawn from Indwelling Central Venous Catheters in Hospitalized Patients with Cancer. Ann Intern Med. 1999;131(9):641. 

21. Beekmann SE, Diekema DJ, Huskins WC, et al. Diagnosing and Reporting of Central Line–Associated Bloodstream Infections. Infect Control Hosp Epidemiol. 2012;33(9):875-882. 

22. Raad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM, Tarrand J. Differential Time to Positivity: A Useful Method for Diagnosing Catheter-Related Bloodstream Infections. Ann Intern Med. 2004;140(1):18. 

23. Ulrich P, Lepak AJ, Chen DJ. Diagnostic and Therapeutic Utility of Positive Intravascular Catheter Tip Cultures. Carroll KC, ed. Microbiol Spectr. 2022;10(6):e04022-22. 

24. Rhimi W, Theelen B, Boekhout T, Otranto D, Cafarchia C. Malassezia spp. Yeasts of Emerging Concern in Fungemia. Front Cell Infect Microbiol. 2020;10:370. 

25. Iatta R, Battista M, Miragliotta G, Boekhout T, Otranto D, Cafarchia C. Blood culture procedures and diagnosis of Malassezia furfur bloodstream infections: Strength and weakness. Med Mycol. 2018;56(7):828-833. 

26. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50. 

27. Phongkhun K, Pothikamjorn T, Srisurapanont K, et al. Prevalence of Ocular Candidiasis and Candida Endophthalmitis in Patients With Candidemia: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2023;76(10):1738-1749. 

28. Edakkanambeth Varayil J, Whitaker JA, Okano A, et al. Catheter Salvage After Catheter-Related Bloodstream Infection During Home Parenteral Nutrition. J Parenter Enter Nutr. 2017;41(3):481-488. 

29. Dibb MJ, Abraham A, Chadwick PR, et al. Central Venous Catheter Salvage in Home Parenteral Nutrition Catheter-Related Bloodstream Infections: Long-Term Safety and Efficacy Data. J Parenter Enter Nutr. 2016;40(5):699-704. 

30. Severijnen R, Bayat N, Bakker H, Tolboom J, Bongaerts G. Enteral Drug Absorption in Patients with Short Small Bowel: A Review. Clin Pharmacokinet. 2004;43(14):951-962. 

31. Meade U, Gabriel N, Patel R, et al. Drug Absorption in Patients with a Short Bowel. In: Nightingale JMD, ed. Intestinal Failure. Springer International Publishing; 2023:699-716. 

32. Hong WBT, Tan WK, Law LSC, Ong DEH, Lo EAG. Changes of Drug Pharmacokinetics in Patients with Short Bowel Syndrome: A Systematic Review. Eur J Drug Metab Pharmacokinet. 2021;46(4):465-478. 

33. Korzilius JW, Gompelman M, Wezendonk GTJ, et al. Oral antimicrobial agents in patients with short bowel syndrome: worth a try! J Antimicrob Chemother. 2023;78(8):2008-2014.

34. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adultsa. Clin Infect Dis. 2015;61(6):e26-e46.

35. Parvizi J, Tan TL, Goswami K, et al. The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria. J Arthroplasty. 2018;33(5):1309-1314.e2.

36. Gjika E, Beaulieu JY, Vakalopoulos K, et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial. Ann Rheum Dis. 2019;78(8):1114-1121.

37. Mathews CJ, Coakley G. Septic arthritis: current diagnostic and therapeutic algorithm. Curr Opin Rheumatol. 2008;20(4):457-462. 

38. Gompelman M, Paus C, Bond A, et al. Comparing success rates in central venous catheter salvage for catheter-related bloodstream infections in adult patients on home parenteral nutrition: a systematic review and meta-analysis. Am J Clin Nutr. 2021;114(3):1173-1188.

39. Ait Hammou Taleb MH, Mahmutovic M, Michot N, Malgras A, Nguyen-Thi PL, Quilliot D. Effectiveness of salvage catheters in home parenteral nutrition: A single-center study and systematic literature review. Clin Nutr ESPEN. 2023;56:111-119.

40. Martínez E, Mensa J, Rovira M, et al. Central venous catheter exchange by guidewire for treatment of catheter-related bacteraemia in patients undergoing BMT or intensive chemotherapy. Bone Marrow Transplant. 1999;23(1):41-44.

41. Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K. A Prospective, Randomized Trial of Intravenous Fat Emulsion Administration in Trauma Victims Requiring Total Parenteral Nutrition: J Trauma Inj Infect Crit Care. 1997;43(1):52-60.

42. McCowen KC, Friel C, Sternberg J, et al. Hypocaloric total parenteral nutrition: Effectiveness in prevention of hyperglycemia and infectious complications—A randomized clinical trial: Crit Care Med. 2000;28(11):3606-3611.

43. Calder PC, Yaqoob P, Harvey DJ, Watts A, Newsholme EA. Incorporation of fatty acids by concanavalin A-stimulated lymphocytes and the effect on fatty acid composition and membrane fluidity. Biochem J. 1994;300(2):509-518.

44. Wanten GJ, Naber AHJ. Human Neutrophil Membrane Fluidity After Exposure to Structurally Different Lipid Emulsions. J Parenter Enter Nutr. 2001;25(6):352-355.

45. Seidner DL, Mascioli EA, Istfan NW, et al. Effects of Long-Chain Triglyceride Emulsions on Reticuloendothelial System Function in Humans. J Parenter Enter Nutr. 1989;13(6):614-619.

46. Pontes-Arruda A, Dos Santos MCFC, Martins LF, et al. Influence of Parenteral Nutrition Delivery System on the Development of Bloodstream Infections in Critically Ill Patients: An International, Multicenter, Prospective, Open-Label, Controlled Study—EPICOS Study. J Parenter Enter Nutr. 2012;36(5):574-586.

47. Gavin NC, Larsen E, Runnegar N, et al. Association between parenteral nutrition–containing intravenous lipid emulsion and bloodstream infections in patients with single-lumen central venous access: A secondary analysis of a randomized trial. J Parenter Enter Nutr. 2023;47(6):783-795.

48. Austin PD, Hand KS, Elia M. Systematic review and meta-analyses of the effect of lipid emulsion on microbial growth in parenteral nutrition. J Hosp Infect. 2016;94(4):307-319.

49. Keohane PP, Attrill H, Northover J, et al. Effect of catheter tunneling and a nutrition nurse on catheter sepsis during parenteral nutrition. The Lancet. 1983;322(8364):1388-1390.

50. Daoud DC, Wanten G, Joly F. Antimicrobial Locks in Patients Receiving Home Parenteral Nutrition. Nutrients. 2020;12(2):439.

51. Bisseling TM, Willems MC, Versleijen MW, Hendriks JC, Vissers RK, Wanten GJ. Taurolidine lock is highly effective in preventing catheter-related bloodstream infections in patients on home parenteral nutrition: A heparin-controlled prospective trial. Clin Nutr. 2010;29(4):464-468.

52. Wouters Y, Theilla M, Singer P, et al. Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition. Aliment Pharmacol Ther. 2018;48(4):410-422.

53. Rosenblatt J, Reitzel R, Vargas-Cruz N, Chaftari AM, Hachem R, Raad I. Comparative Efficacies of Antimicrobial Catheter Lock Solutions for Fungal Biofilm Eradication in an in Vitro Model of Catheter-Related Fungemia. J Fungi. 2017;3(1):7.

54. Nickel B, Gorski L, Kleidon T, et al. Infusion Therapy Standards of Practice, 9th Edition. J Infus Nurs. 2024;47(1S):S1-S285.

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Fundamentals of ERCP, Series #14

Chronic Pancreatitis

October 2024 • Volume XLVIII, Issue 10
Thiruvengadam Muniraj

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Introduction

Chronic pancreatitis (CP) is a chronic progressive fibroinflammatory condition of the pancreas characterized by progressive scarring resulting in permanent loss of both exocrine (acinar) and endocrine (islet cells) tissue along with morphological changes in both the pancreatic duct and the parenchyma. The annual incidence of CP1,2 ranges from 5 to 14 per 100,000; the prevalence of CP is about 50 per 100,000 persons.2 (See Figure 1) 

The clinical presentation of CP occurs as a large duct disease or a small duct disease and as variants of both, with and without calcifications. Most often, pain is the major clinical symptom and presents early in the course of the disease and significantly impacts quality of life. About 30-50% of CP patients develop chronic exocrine pancreatic insufficiency resulting in malabsorption and maldigestion, with a clinical presentation of steatorrhea and weight loss. Depending on the duration of follow-up and cohorts, 26-80% of CP patients develop diabetes mellitus due to progressive loss of islet cells.5 In this article, we mainly focus on the indications and techniques of endoscopic retrograde cholangiopancreatography (ERCP) endoscopic therapy in CP patients. 

ERCP – Pancreatic Endotherapy 

Pain associated with CP is multifactorial. One of the primary mechanisms for pain in CP is elevated intraductal pressures,6 along with other causes such as interstitial pressure, neural inflammation, ongoing acute pancreatitis with tissue inflammation, and the presence of fluid collections.  

The main goal of ERCP-based endotherapy is to decompress the main pancreas duct (MPD), to achieve complete duct clearance by alleviating outflow obstruction of the MPD (from stones or strictures), evacuating focal fluid collections, and diverting the flow from a fistula or a pancreatic duct leak.7-10 When MPD drainage is established via ERCP endotherapy, the flow of pancreatic juice to the duodenum increases and resistance to outflow decreases, thereby reducing or inhibiting the severity of exocrine pancreatic insufficiency and its symptoms such as steatorrhea. However, steatorrhea is not an indication to initiate ERCP unless the patient also has concomitant pain. While pain may improve with ERCP, improvement or preservation in pancreatic function is often uncertain and one does not guarantee the other. One prospective randomized trial of 41 patients showed endoscopic therapy with ERCP slowed the progression of exocrine insufficiency along with a reduction in pain but with no change in overt diabetes.11

ERCP for ductal decompression therapy has become an established first-line method for the treatment of painful obstructive chronic pancreatitis. In a large prospective multicenter U.S. cohort (n = 521), 52% underwent endoscopic therapy, and pancreatic surgery was performed only on 18 % of patients.12 The clinical response to endoscopic therapy is quite variable even if adequate duct clearance is achieved.10 In a cohort of >1000 CP patients with pain who underwent ERCP, MPD obstruction was caused by pancreatic stones alone, ductal strictures alone, and a combination of stones and strictures in 18%, 47%, and 32% of cases, respectively. Decompression of the MPD with ERCP yielded similar results in all these different categories of patients, with 51% of patients having no pain at all at a mean follow-up of 4.9 years.13

Management of MPD obstruction via ERCP can be achieved using pancreatic sphincterotomy, and removal of the ductal stones, with or without extracorporeal short-wave lithotripsy [ESWL] or mechanical lithotripsy, dilation of strictures, placement of pancreatic stents, and providing transpapillary drainage of pancreatic fluid collections. 

Selection of Patients and Pre-ERCP Work Up

Proper patient selection results in a favorable long-term outcome with endoscopic management. Only patients with a clinical presentation of pain should be considered for ERCP. The presence of a MPD stricture in the head, neck, or proximal body of the pancreas with dilation of the upstream pancreas duct in a chronic disease with or without the presence of stone would be an indication for endoscopic therapy. ERCP should be avoided in asymptomatic patients even in the presence of MPD stricture unless malignancy is suspected and an intraductal tissue sampling is desired. Patients with an MPD obstruction located only in the tail of the pancreas are not considered candidates for ESWL and/or endoscopic therapy.14 Some studies have shown that favorable prognostic factors related to endoscopic therapy and/or ESWL include complete stone removal and MPD stricture resolution after stenting.14,15

The risk of pancreas cancer is high among patients with CP. In addition to standard laboratory testing, the pre-ERCP workup should include cross-sectional imaging to rule out pancreatic cancer and to provide high quality images of the ductal anatomy. An abdominal Computed Tomography (CT) scan with and without IV contrast (Figure 2, Figure 3) and Magnetic resonance cholangiopancreatography (MRI/MRCP) (Figure 4) will help accurately delineate the location of calcified stones in relation to the duct, the presence of any mass lesion, and an excellent overview of the ductal anatomy. Some patients may have extensive parenchymal calcifications along with ductal calcifications that may not be amenable for any endoscopic therapy. (Figure 5) CT scan before and after the ERCP therapy can also help to accurately confirm the completeness of the stone extraction. (Figure 6) 

Secretin-stimulated MRCP provides better information on pancreatic ductal anatomy and may also be used to quantify pancreatic exocrine function and predict the effects of pancreatic duct drainage procedures. A recent study by Sherman et al. found that S-MRI in comparison to MRCP may better identify patients who would benefit from therapeutic ERCP.16

Endoscopic Ultrasound (EUS) may be useful in selected CP patients, although the EUS-guided sampling seems to be less sensitive to diagnose a pancreatic cancer in the presence of CP vs. absence of CP (54 % vs. 89 %).17 The yield of EUS with contrast-enhanced harmonic EUS may improve the accuracy of EUS-guided sampling.18 Still, in current practice, EUS is the mainstay of technology for the diagnosis of pancreatic cancer.

Endoscopic Pancreatic Sphincterotomy (EPS) 

MPD cannulation and endoscopic pancreatic sphincterotomy (EPS) are the initial steps in the endoscopic therapy. EPS is a well-known mode of therapy and can offer symptomatic relief even without stenting in a subset of patients with papillary stenosis and allow access to removal of stones in the MPD. In a small retrospective study of 11 early onset CP patients, more than 2/3rd of patients had good pain relief following EPS alone.19 In patients with chronic pancreatitis, EPS with a standard sphincterotome or with a needle-knife offers an effective and reliable approach to both access and decompress the pancreatic duct system and the complication rate of EPS in CP patients appears to be lower than the complication rate of biliary sphincterotomy for other indications.20

When performing EPS for pain relief in CP, a routine biliary sphincterotomy is not indicated unless the common bile duct is dilated or there is an elevation of alkaline phosphatase or other clinical indication.21 An endoscopic biliary sphincterotomy (EBS) is performed prior to EPS in the setting of obstructive jaundice, cholangitis or when it is technically easier to have biliary sphincterotomy to facilitate access to the MPD. If EPS is performed after EBS, the MPD orifice is usually located between the 2 and 6 o’clock position to the right margin of the sphincterotomy. (Figure 7) 

After contrast injection and obtaining a pancreatogram, the guidewire is maneuvered through into the MPD, crossing strictures as needed. (Figure 8) EPS is then performed over the guidewire using either standard or taper pull type sphincterotome. When compared to EPS with a pull sphincterotome (followed by pancreatic stenting) or a needle knife over a pancreatic stent, EPS is safer when performed with a needle knife over a pancreatic stent.22 The common expected complication of EPS are post-ERCP pancreatitis, bleeding, perforation and restenosis. Using pure cutting current for the EPS incision would avoid coagulative injury, thereby decreasing the risk of pancreatitis, although most endoscopists currently used alternating cutting and coagulating currents as are common on modern electrosurgery generators for ERCP. In a large study of 398 patients who underwent EPS, post-ERCP pancreatitis was minimized with either pancreatic duct stent placement or nasopancreatic drainage.23 EPS in CP patients has shown to have a 14% restenosis rate during a 4 year follow up.24

Minor Papilla Sphincterotomy in CP Patients

The benefit of minor papilla sphincterotomy is dependent upon the clinical setting. Lehman et al. reported that minor papilla sphincterotomy helps patients with acute recurrent pancreatitis more frequently than those with chronic pancreatitis (76.5% vs. 27.3%, p = 0.01).25 Vitale et al. followed 24 CP patients with pancreas divisum and reported significant pain relief on 2-year follow up following minor papilla sphincterotomy and stenting.26 A recent Japanese study showed that endoscopic balloon dilation (EBD) of the minor papilla is feasible and effective for the management of symptomatic pancreas divisum in CP patients.27 The same technique as EPS with a tapered pull type sphincterotome can be utilized to perform minor papilla sphincterotomy or a stent can be placed in the dorsal pancreas duct and minor papilla sphincterotomy performed over a needle knife. (Figure 9) 

Pancreatic Duct Stone Management

Pancreatic duct calculi are often seen in patients with CP and cause pain by obstructing the pancreatic ducts and producing upstream ductal hypertension. Pancreatic stones may appear either as calcified stones or as radiolucent protein plugs that may or may not become calcified. A majority of the pancreatic stones are calcified and radiopaque. Although alcoholic CP often presents with calcified pancreatic stones, the stones seen in tropical pancreatitis and hereditary pancreatitis can be larger in size than those seen in the setting of alcoholic CP. Larger stone size often makes endotherapy difficult, whereas stones < 5mm are more amenable to endoscopic extraction after pancreatic sphincterotomy alone. However, in 70–90% of cases, pancreatic stones cannot be extracted without pre-ERCP fragmentation (by mechanical and/or extracorporeal shock wave lithotripsy [ESWL]).7,28 If the pancreatic duct stone is larger than 5mm, it is often preferable to perform stone extraction after ESWL or intra-ductal lithotripsy. 

Extracorporeal Shock Wave Lithotripsy

ESWL is now accepted as the standard of care in the management of large MPD calculi >5 mm not amenable to routine endotherapy.29,30 ESWL is very effective in fragmenting both radio-opaque and radio-lucent calculi in the MPD. European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend ESWL prior to ERCP for large MPD calculi.2 A meta-analysis of 17 studies with a total of 588 patients looked at pain relief and duct clearance as the primary end point. They noted a duct clearance rate of 37%-100% and good pain relief, and a  mean effect size (weighted correlation coefficient) for pain was 0.6215 and for duct clearance was 0.7432 (indicates moderate to high practical significance).31

ESWL is routinely used in Urology for clearance of nephrolithiasis. In many U.S. centers, Urologists perform ESWL for PD stones. Components of ESWL machines include (1) a shock wave generator, (2) a focusing system, (3) a coupling mechanism, and (4) a localization unit.32 Shock waves are generated via piezoelectric technology and the focusing system concentrates shock waves into a precise target volume where fragmentation of hard structures will take place. The coupling mechanism between the shock wave generator and the patient’s body currently consists of a cushion surrounding the shock wave generator, which is closely applied onto the patient’s skin (with a special gel similar to that used in transabdominal ultrasonography). The localization unit allows maintaining the target stone inside the target volume, using simultaneous fluoroscopy. Localization of stones using fluoroscopy is more reliable than using ultrasound. If the stone is not radiopaque, then placing a pancreatic duct stent that terminates at the level of the stone often helps in the localization of the target for ESWL. The patient is positioned prone or supine with a slight tilt to prevent the spine from being in the target volume. 

If there are several stones present, the one located inside the MPD closest to the papilla is targeted first; and then the focus is gradually moved to more proximal MPD stones once distal ones have been fragmented. Usually, the stones in the tail and the side branches are not targeted as they do not significantly impede the outflow of pancreatic fluid and, if targeted, resulting stone fragments can potentially migrate into the MPD and cause worsening obstruction.32

High energy shock waves are delivered until the stone is fragmented (as seen via fluoroscopy) and although there is limited evidence on the maximum number of shock waves that may be administered per session, 5000-6000 are typically performed per session and patients are scheduled for further supplementary sessions as needed. In most centers, ESWL is done as an ambulatory procedure under general anesthesia and an abdominal radiograph is obtained 1 to 2 weeks later to assess the need for further ESWL. The most common complication of ESWL is acute pancreatitis, and this has been reported in 4.2% in a meta-analysis.33 (Figure 10)

Combining ERCP with ESWL at the Same Time

In some centers, the extracorporeal lithotripter is located within the endoscopy unit and ERCP is used in combination with ESWL and is performed by the endoscopist during same anesthesia session. In a study of 55 patients randomized to ESWL alone or ESWL combined with endoscopy, both groups had similar rates of pain relief (62% vs. 55%) and the authors concluded that combining systematic endoscopy with ESWL adds to the cost of patient care, without improving the outcome of pancreatic pain.29 A study by Cotton et al. that combined use of ESWL with endotherapy was shown to prevent pancreatic surgery in the majority of patients.34  In most studies of ESWL (alone or combined with endoscopic drainage), more than 70 to 80% patients had short term pain relief and about 60% had long term pain relief (2 to 5 years).35-37 ESWL is a relatively safe and well-tolerated procedure.38

Secretin ESWL 

Injection of human secretin increases bicarbonate rich pancreatic fluid secretion. To see if this could facilitate excretion of pulverized pancreatic stones during ESWL, Choi et al. studied 233 consecutive cases and observed that secretin use resulted in significantly higher rate of complete MPDS clearance (63% vs. 46%, p = 0.021).39

Intraductal Lithotripsy

Lithotripsy is commonly used for biliary stones, but occasionally mechanical lithotripsy is also used in treating pancreatic calcifications (prior to referring patients to undergo ESWL). Standard lithotripter-compatible baskets can be used in the pancreatic duct during ERCP and, if these baskets can capture and crush stones more aggressive treatments may be obviated.28 Intraductal lithotripsy via a pancreatoscope can be performed using per oral pancreatoscopy (POP)-guided intracorporal lithotripsy using either of the two techniques: Electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL). A recent meta-analysis, showed high clinical success rates with EHL (67%) and LL (88%).40 (Figures 11,12,13)

Stone Extraction 

After stone fragmentation with ESWL and pancreatic sphincterotomy, tiny stone fragments may pass spontaneously through the papilla and ERCP may not be even necessary. Endoscopic therapy is needed in patients without spontaneous clearance of pancreatic stones after adequate fragmentation by ESWL.2 If the stone is located upstream from a stricture, the stricture is generally dilated first using a dilation balloon (Hurricane; Boston Scientific, Natick, MA) or a graduated dilating catheter (Soehendra dilators; Cook Endoscopy, Winston-Salem, NC) to facilitate the stone removal.Then a small Dormia basket or stone extraction balloon is used to remove the stone fragments. (Figures 14a,b,c,d,e)

If the stones are visible on fluoroscopy, a guidewire is introduced in the duct and with minimal or no contrast injection, a basket or balloon introduced, manipulated to extract the stones starting with those closer to papilla and progressing upstream. A dormia basket may be more useful than a stone extraction balloon as often the fragmented pancreatic stones are sharp and frequently rupture the balloon. 

When a pancreatic duct stricture is tight, catheter (balloon or bougie) passage may be impossible. In this setting a Soehendra stent retriever with a screw tip (8.5Fr) can be spanned through the stricture to enable subsequent passage of the dilating balloon or bougie, although this maneuver carries with it some risk of pancreatic injury. 

Pancreatic duct strictures

Management of strictures secondary to CP is often challenging. Along with pancreatic duct strictures, patients often present with distal biliary strictures resulting from ongoing inflammation and fibrotic reactions in the pancreatic head, which can in turn produce a biliary stricture. The most important aim is to rule out malignancy during the initial work up if there is any concern r.e. cancer. As CP is associated with an increased risk of pancreas cancer, the emphasis should be to reasonably exclude pancreatic cancer if a MPD stricture is detected, particularly in the absence of pancreatic calcifications and in the presence of exocrine insufficiency or new late onset diabetes, without smoking or alcohol history.41,42 It has been shown that approximately 5% of patients with pancreatic cancer are initially misdiagnosed as CP.43

MPD strictures are defined as dominant strictures by the presence of at least one of the following characteristics: upstream MPD dilatation ≥ 6 mm in diameter, prevention of contrast medium outflow alongside a 6-Fr catheter inserted upstream from the stricture, or abdominal pain during continuous infusion of a naso-pancreatic catheter inserted upstream from the stricture with 1 L saline for 12 – 24 h.2 The latter maneuver is virtually never performed in modern practice, and this classification system is often not put into practice. (Figures 15a,b,c)Technical success in the management of such a dominant stricture would be defined by some as stent insertion across a dominant MPD stricture or up to the tail MPD if multiple strictures occur in the MPD. Before a stent is placed, if malignancy is still suspected, a brush cytology could be obtained. Although a clear definition for short term clinical success is lacking, the absence of pain during a full year following the stent removal implies clinical success. Refractory MPD strictures are defined as symptomatic dominant strictures that persist or relapse after 1 year of single pancreatic stent placement, or can be diagnosed in patients who cannot function without an indwelling pancreatic duct stent.2

Stricture Dilation and a Single Plastic Stent

ERCP intervention (endotherapy) is ideal for single strictures in the head while isolated strictures in the tail or multiple strictures in the body with a chain of lake appearance have unfavorable outcomes with the endotherapy.44

Historically, stricture dilation alone was used to treat single MPD strictures, but in current endoscopy practice dilation alone is not felt to represent an adequate treatment. Dilation is routinely followed by placement of a plastic pancreatic stent. MPD strictures are single in >80% of CP patients and a placement of a single plastic stent has been widely used as the initial endoscopic therapy.45

On relieving MPD stricture obstruction, pain relief was reported at short and long-term follow-up in 70–94% and 52–82% of patients, respectively.32,44 In a meta-analysis of 9 studies, long-term pain relief (24 months) was reported in 67.5 % of 536 patients (95 % confidence interval [CI] 51.5 % – 80.2 %).46

Leaving the PD stent in place for periods of up to 6 months does not always yield an adequate clinical response and stents are often needed for a longer duration.47 Prior to stent placement, tight strictures sometimes need to be dilated with Teflon bougies, a Soehendra stent retriever or a balloon dilator.48

Plastic stents are placed across the stricture and typically exchanged every 2 to 6 months or “on-demand” when the symptoms recur. Large bore stents of size 7Fr to 10Fr are progressively used when treating MPD strictures, if possible. The stent size is usually limited by the unaffected downstream duct (close to the pancreas head). In general, stent exchanges are performed for about 24 months. There is no clear consensus data on whether or not a pancreatic sphincterotomy should be performed prior to placement of plastic MPD stent, but most patients with CP often find their way to undergoing this maneuver as well.49

Criteria used for ‘definitively’ removing a stent (with no intent to replace the stent again) usually consist of (1) adequate outflow of contrast medium into the duodenum within 1 to 2 min after ductal filling upstream from the dilated stricture, immediately after stent removal plus the extraction of ductal debris, and (2) easy passage of an ERCP catheter through the dilated stricture.8

After definitive stent removal, recurrence of symptoms and strictures was reported in 27 to 38% of patients after 2 years of follow up. Mean time to recurrence of pain after definitive removal is around 2.1 years.45 The most important factor associated with higher re-stenosis rates in CP patients is the presence of concomitant pancreas divisum.45 (Figure 16)

Multiple Plastic Stenting

MPD stricture management has evolved from single stents to the placement of multiple side-by-side stents. Two 7Fr or 8.5Fr plastic stents can be placed once the stricture is dilated to 6mm with a balloon. The number of stents can be increased based on the degree of dilation in the upstream MPD beyond the stricture. Such multiple stent placements are facilitated by having two guidewires in the pancreas duct across the stricture subsequently followed by successive stent placements. 

Costamagna et al. who initially proposed using multiple plastic stenting for MPD strictures not responding to a single stent placement, reported a study of 19 patients who had a MPD stricture that persisted immediately after removal of a single pancreatic stent, multiple plastic stents (8.5-11.5Fr diameter) were placed. A mean of 3 stents were used and the stents were removed after a mean of 7 months. Stricture resolution was seen in 95% and pain relief in 84% on a 38 month follow up.50 The main advantages of this technique include a low number of ERCP sessions (two) and a large dilation diameter that might account for the absence of pain relapse during a relatively long follow-up. However, further prospective controlled studies are needed to confirm these promising results. 

Self-Expandable Metal Stents

Fully covered self-expanding metal stents (FCSEMS) were initially developed for palliation of malignant biliary strictures, and have subsequently been used in benign biliary strictures. Placement of FCSEMS in the MPD may be an alternative to placing multiple plastic stents or when the stricture is refractory despite several sessions of plastic stent placements. Due to tissue in-growth, only FCSEMS are used in PD strictures and FCSEMS used in this manner are applied in an “off label” manner. FCSEMS can be used only in strictures close to the papilla in the head of the pancreas and reachable by a single stent. The MPD should be large enough to accommodate 8 to 10mm stents and the stents should be shorter so that they do not extend beyond the stricture site and seal the side branches. (Figure 17)

Poley et al., in a study of 13 CP patients, demonstrated better results using FCSEMS when compared with progressive plastic stenting protocols.51 A major limitation of FCSEMS is frequent stent migration (5-33%). To reduce the risk of migration, anti-migration features such as anchoring flaps and flared ends were introduced, and these modified stents have been studied in MPD strictures in CP patients by Moon et al.52 In a systematic review of 4 prospective case series (n=61), placement of FCSEMS provided pain improvement in 85 %.53 A study of 10 patients with follow-up period of 19.8 months showed the use of FCSEMS in MPD strictures feasible, safe and effective.54 Similarly, in a U.S multicenter retrospective study of 33 CP patients with MPD strictures that were refractory to plastic stents, FCSEMS were shown to be effective, with a clinical success rate of 93%.55 The recurrence rate for treated strictures with FCSEMS was 0 % after a median follow-up of 8 months (range 5 – 14).55 About 20% of patients who receive FCSEMS for PD strictures may not tolerate these implants and develop significant post-procedure pain. This post-procedure pain is hypothesized mainly due to the greater stent diameter, and if a smaller-diameter (6 mm) FCSEMS is available, that should be further investigated regarding the post-procedure pain and development of iatrogenic strictures when using over-sized stents. 

Due to the lack of controlled data, further trials are needed to assess the long-term safety and efficacy of using FCSEMS in intrapancreatic strictures in the setting of CP before this method can be adopted in routine clinical practice, but it is within the standard of care to consider and use these devices in this setting.

Transpapillary Endoscopic Drainage of Pancreatic Fluid Collections and Leaks 

Pancreatic Fluid Collections (PFC) may be drained via a transpapillary or transmural approach or, sometimes, a combination of both. Transpapillary endoscopic drainage with plastic stent placement is recommended for pseudocysts communicating to the MPDs, ductal leaks in CP, and if the site of MPD disruption could be reached or site of obstruction could be bypassed. However, if bridging the ductal obstruction or disruption is unsuccessful, then transmural or percutaneous drainage would typically be necessary.

The main advantage of transpapillary drainage of PFCs and leaks is a near-total avoidance of bleeding. If a symptomatic PFC communicates with the MPD and is not approachable transmurally, placement of a plastic pancreatic stent with or without EPS is a helpful approach. The upstream end of the stent, if unable to bridge the site of the leak then, should terminate in the PFC itself. An ideal approach would be to bridge the disruption site as that would restore the duct into continuity. A successful resolution of PD disruption by transpapillary stent placement depends on the ability to bridge the disrupted duct with a stent.56 If there is an obstructive lesion such as a stone or stricture between the leak site and the duodenal papilla, it is prudent to place a stent bridging across the obstruction. In a retrospective study of 110 patients, a combined transpapillary PD stenting improves treatment outcomes in patients undergoing endoscopic transmural drainage of PFC, although in practice if transmural drainage is performed then transampullary drainage is not usually warranted.57

While transpapillary stenting helps with improved outcomes in walled-off necrosis, a large multicenter retrospective study showed that transpapillary stenting may have no added benefit in the treatment outcomes in patients undergoing EUS-guided transmural drainage of pancreatic pseudocysts.58 Most endoscopists perform ERCP with pancreatic duct stenting in patients with pancreatic duct disruption during endotherapy for walled-off pancreatic necrosis but not during transmural drainage in patients with pancreatic pseudocysts, even in cases of confirmed main pancreatic disruption as it negatively affects treatment outcomes. However, large prospective randomized trials are necessary to confirm these conclusions.

Biliary Strictures Secondary to CP 

Biliary strictures occur secondary to CP in 3% – 23% of patients.59 Clinical presentation of biliary strictures in CP varies widely from asymptomatic lab abnormalities (elevated alkaline phosphatase) to jaundice with or without cholangitis. Patients with persistent biliary obstruction would benefit from biliary decompression with dilation and stent placement.

Summary 

In patients with symptomatic obstructive chronic pancreatitis with a dilated pancreatic duct, ERCP is the first line of management to treat stones and strictures. Further studies are needed in using FCSEMS for pancreatic duct strictures and EUS-guided novel interventions. 

References

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43. Munigala S, Kanwal F, Xian H, Agarwal B. New diagnosis of chronic pancreatitis: risk of missing an underlying pancreatic cancer. The American journal of gastroenterology. 2014;109(11):1824-30.

44. Tringali A, Boskoski I, Costamagna G. The role of endoscopy in the therapy of chronic pancreatitis. Best practice & research Clinical gastroenterology. 2008;22(1):145-65.

45. Eleftherladis N, Dinu F, Delhaye M, Le Moine O, Baize M, Vandermeeren A, et al. Long-term outcome after pancreatic stenting in severe chronic pancreatitis. Endoscopy. 2005;37(3):223-30.

46. Jafri M, Sachdev A, Sadiq J, Lee D, Taur T, Goodman A, et al. Efficacy of Endotherapy in the Treatment of Pain Associated With Chronic Pancreatitis: A Systematic Review and Meta-Analysis. Jop. 2017;18(2):125-32.

47. Ponchon T, Bory RM, Hedelius F, Roubein LD, Paliard P, Napoleon B, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointestinal endoscopy. 1995;42(5):452-6.

48. Delhaye M, Matos C, Deviere J. Endoscopic technique for the management of pancreatitis and its complications. Best practice & research Clinical gastroenterology. 2004;18(1):155-81.

49. Clarke B, Slivka A, Tomizawa Y, Sanders M, Papachristou GI, Whitcomb DC, et al. Endoscopic therapy is effective for patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2012;10(7):795-802.

50. Costamagna G, Bulajic M, Tringali A, Pandolfi M, Gabbrielli A, Spada C, et al. Multiple stenting of refractory pancreatic duct strictures in severe chronic pancreatitis: long-term results. Endoscopy. 2006;38(3):254-9.

51. Poley JW, Cahen DL, Metselaar HJ, van Buuren HR, Kazemier G, van Eijck CH, et al. A prospective group sequential study evaluating a new type of fully covered self-expandable metal stent for the treatment of benign biliary strictures (with video). Gastrointestinal endoscopy. 2012;75(4):783-9.

52. Moon SH, Kim MH, Park do H, Song TJ, Eum J, Lee SS, et al. Modified fully covered self-expandable metal stents with antimigration features for benign pancreatic-duct strictures in advanced chronic pancreatitis, with a focus on the safety profile and reducing migration. Gastrointestinal endoscopy. 2010;72(1):86-91.

53. Sofi AA, Khan MA, Ahmad S, Khan Z, Peerzada MM, Sunguk J, et al. Comparison of clinical outcomes of multiple plastic stents and covered metal stent in refractory pancreatic ductal strictures in chronic pancreatitis- a systematic review and meta-analysis. Pancreatology. 2021;21(5):854-61.

54. Giacino C, Grandval P, Laugier R. Fully covered self-expanding metal stents for refractory pancreatic duct strictures in chronic pancreatitis. Endoscopy. 2012;44(9):874-7.

55. Sharaiha RZ, Novikov A, Weaver K, Marfatia P, Buscaglia JM, DiMaio CJ, et al. Fully covered self-expanding metal stents for refractory pancreatic duct strictures in symptomatic chronic pancreatitis, US experience. Endosc Int Open. 2019;7(11):E1419-e23.

56. Varadarajulu S, Noone TC, Tutuian R, Hawes RH, Cotton PB. Predictors of outcome in pancreatic duct disruption managed by endoscopic transpapillary stent placement. Gastrointest Endosc. 2005;61(4):568-75.

57. Trevino JM, Tamhane A, Varadarajulu S. Successful stenting in ductal disruption favorably impacts treatment outcomes in patients undergoing transmural drainage of peripancreatic fluid collections. J Gastroenterol Hepatol. 2010;25(3):526-31.

58. Yang D, Amin S, Gonzalez S, Mullady D, Hasak S, Gaddam S, et al. Transpapillary drainage has no added benefit on treatment outcomes in patients undergoing EUS-guided transmural drainage of pancreatic pseudocysts: a large multicenter study. Gastrointest Endosc. 2016;83(4):720-9.

59. Abdallah AA, Krige JE, Bornman PC. Biliary tract obstruction in chronic pancreatitis. HPB (Oxford). 2007;9(6):421-8.

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Dispatches from the GUILD Conference, Series #62

Updates in Eosinophilic Esophagitis

September 2024 • Volume XLVIII, Issue 9
Priya Kathpalia,Rena Mei

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Eosinophilic esophagitis (EoE) is a chronic, immune mediated (T helper 2), inflammatory condition of the esophagus characterized by loss of barrier function, eosinophilic infiltration and subsequent remodeling of the esophagus. If left untreated this can lead to development of strictures and fibrostenotic disease. The clinical presentation varies depending on the age at time of diagnosis and chronicity of symptoms. The diagnosis of EoE requires clinical symptoms of esophageal dysfunction together with histologic evidence of esophageal eosinophilia (with ≥15 eos/hpf (about 60 eos/mm2)) without an alternative cause. Therapies for EoE include dietary (elimination diet, allergy testing-based diet, elemental diet) or pharmacologic (proton pump inhibitors (PPI), topical steroids, dupilumab) strategies coupled with esophageal dilation (balloon, bougie) if structuring disease is present. The goal of therapy is ultimately to achieve resolution of clinical symptoms coupled with endoscopic and histologic remission.

Introduction

Eosinophilic esophagitis (EoE) is a chronic immunologic disease of the esophagus that has only been newly recognized over the past few decades. It was first characterized in the late 1970s1,2 but more formally defined in the 1990s3-5 and has evolved from being considered as rare case reports or as a feature of gastroesophageal reflux disease to now a common standalone clinical diagnosis. The first diagnostic guidelines for EoE were published in Gastroenterology in 2007 and has transformed over the following decade.6 In this condition, the esophagus is infiltrated by eosinophils, resulting in an inflammatory reaction that leads to a variety of symptoms relating to esophageal dysfunction, including dysphagia, nausea, regurgitation, heartburn, and food impactions.

EoE has been reported in North and South America, Asia, Europe, and Australia. Within the United States, the prevalence of EoE has been estimated to be 1 to 5 patients per 10,000 and is increasing, from 2.7 to 5.2 per 10,000 in 2009 to 2013.7 A systematic review of population-based studies from North America, Europe and Australia showed a pooled incidence rate of EoE of 3.7/100,000 people per year and pooled prevalence of 22.7/100,000 people.8 EoE can affect people of all age groups, though there is a demonstrated bimodal age distribution with a peak at 12 years and at 41 years. It is more common in males compared to females, with a two- to three-fold increased prevalence in males.

There is a strong association between EoE and other atopic conditions including eczema, asthma, allergic rhinitis, and allergies, with about two-thirds of EoE patients having other allergic diseases.9 EoE also has a strong familial component, and studies have explored genetic variants which confer a greater risk of developing the condition.10 Alexander et al. showed a 57.9% ± 9.5% disease concordance in monozygotic twins compared with 36.4% ± 9.3% in dizygotic twins, a difference which did not reach statistical significance (p=0.11) but suggestive of genetic patterning.11 Similarly, nuclear family heritability was 72% and twin combined gene-environment heritability 99.5%, but additive genetic heritability accounting for a common family environment was lowered to 14.5%, emphasizing the strong impact of environmental factors on development of EoE.

Pathogenesis

Ongoing research attempt to elucidate the pathophysiology of EoE, which is attributed to a complex intersection between genetic risk and environmental exposures. Certain types of food contain antigenic proteins that can trigger a T helper 2 (Th2) response triggering the release of cytokines (IL-4, IL-5, IL-13), which stimulate esophageal squamous cells to secrete eotaxin-3 to recruit eosinophils along with other granulocytes to the esophageal epithelium. The interleukins additionally work through inducing basal cell hyperplasia and dilated intracellular spaces and disrupting the epithelial barrier via inflammation and eventual fibrosis.12-14

Clinical Presentation

The presenting symptoms of EoE vary by age of onset. Young children often present with feeding difficulties, failure to thrive, nonspecific abdominal pain, and vomiting, whereas adolescents and adults tend to present with more localizing symptoms including dysphagia, food impaction, and chest or upper abdominal pain.15-16 Both age groups can commonly present with gastroesophageal reflux. Dysphagia to solids is the most common symptom. 35% of patients in a Swiss Esophageal Esophagitis Database experienced food impactions requiring endoscopic bolus removal,17 with likely higher rates of self-resolved food impaction that do not present to clinical care. Patients with undiagnosed EoE will often modify their diet and eating behavior which can contribute to delays in diagnosis, with one Swiss study showing a median delay in diagnosis of six years.18 Some patients will present with esophageal strictures, an advanced feature of EoE. Schoepfer et al. found that diagnostic delay was the only risk factor for esophageal strictures at the time of EoE diagnosis. The prevalence of stricture formation significantly correlated in a time-dependent manner with the duration of undiagnosed and untreated disease, from 17.2% in a diagnostic delay of 0-2 years to 70.8% in a diagnostic delay of >20 years.

Diagnosis

When a suspicion of EoE is raised based on clinical symptoms, diagnosis is confirmed using a combination of endoscopic and histologic criteria. Updated international consensus criteria for EoE diagnosis were published following a conference held by A Working Group on PPI-Responsive Esophageal Eosinophilia (AGREE) in 2018.19 Diagnosis of EoE requires all of the following criteria to be met: (1) clinical symptoms of esophageal dysfunction; (2) esophageal mucosal biopsies showing ≥15 eos/hpf (about 60 eos/mm2); and (3) negative evaluation for non-EoE disorders which can contribute to esophageal eosinophilia (e.g., gastroesophageal reflux disease (GERD), Crohn’s disease, drug hypersensitivity reactions). Previous iterations of diagnostic criteria required a trial of proton pump inhibitors (PPI) to distinguish EoE from GERD, or a hypothesized condition coined “PPI-responsive esophageal eosinophilia (PPI-REE)”, but this criterion was removed in the most recent consensus guidelines as PPI-REE is now simply EoE, or at least along the same spectrum of disease.20

Endoscopic findings quantified using the Endoscopic Reference Score (EREFS) can support the diagnosis of EoE, although they are not diagnostic for the disease. Endoscopic appearance of the esophagus can be normal in 10-25% of patients with EoE.21-22 EREFS is a composite of Edema, Rings, Exudates, Furrows, Stricture, with a score for each component based on either its presence or absence, or severity of the finding. It is integral to document the EREFS score when performing endoscopy on EoE patients to compare findings from one procedure to another. When obtaining esophageal biopsies, two to four biopsies should be obtained from at least two esophageal levels (e.g., proximal and distal esophagus) with the goal of increasing diagnostic yield when biopsies are performed on multiple levels.23 EoE cannot be ruled out  when there is a non-diagnostic amount of eosinophilia on esophageal biopsies in the context of active PPI use. Thus, at time of index endoscopy, it is integral that patients are off PPI so as not to mask endoscopic and histologic findings of EoE.

There is significant overlap between EoE and GERD despite being separate entities, and the two conditions can co-exist. Currently there is no single test that can be used to reliably distinguish between the two. Clinicians need to use a combination of patient’s history and symptomatology, endoscopic clues (e.g., erosive esophagitis), histologic features, and at times, ambulatory reflux monitoring to come to a clinical diagnosis.

Treatment

EoE is a chronic condition that requires lifelong treatment. Untreated EoE can lead to esophageal fibrosis and remodeling that can result in stricture formation and food impactions. The goal of treatment is both symptomatic improvement and histologic reduction in eosinophil count to <15 eos/hpf. There are several treatment options with comparable efficacy that can be selected based on shared decision making between the clinician and the patient based on factors such as patient preference, drug availability, cost, and ease of therapy. Treatment modalities include dietary therapy, pharmacologic therapy, and dilation of esophageal strictures (Figure 1).

Dietary Therapy

Dietary therapy is an effective non-pharmacologic therapy option that involves eliminating food allergens from the diet. There are three major types of dietary therapy: empiric elimination diet, allergy testing-based diet, or elemental diet. Elimination diet is the most common first-line dietary therapy, and it involves eliminating foods that commonly cause immediate food hypersensitivity reactions. One approach is the six-food elimination diet (6FED) which excludes cow’s milk, wheat, egg, soy, peanuts/tree nuts, and fish/shellfish. This diet has shown great efficacy rates in clinical and histologic remission.24-27 However it is quite restrictive, so subsequent four-food (cow’s milk, wheat, egg, soy) and two-food elimination diets (dairy and wheat) were proposed. Efficacy rates for less restrictive diets include 54% and 64% for four-food elimination diet in adults and children respectively and 43% for two-food elimination diet.28 More recently, Kliewer et al. found that a one-food elimination diet (1FED) excluding only dairy showed no significant difference in histologic remission between 1FED and 6FED at 6 weeks in a cohort of 129 patients (34% vs. 40%, p=0.58).29 Therefore, elimination of dairy alone has become the most common initial elimination diet, with step-up therapy as needed.

Allergy testing-based diet and elemental diets are far less common treatment methods. In allergy testing-based elimination diet, dietary elimination is guided by results of common allergy tests such as skin prick test, serum immunoglobulin E (IgE) test, or atopy patch test. However, allergy testing is typically based on detecting IgE antibodies to identify allergens, but EoE is not an IgE mediated disease. This therapy has therefore shown mixed results, with pediatric studies and some adult studies showing effectiveness30-32 but other adult studies showing lack of reliability of allergy testing predicting food triggers for EoE.33-34 Elemental diet exclusively consists of an amino acid-based liquid formula, which eliminates all potential food triggers. Although an elemental diet is the most effective approach with a 91% remission rate35, this is rarely recommended given its significant restriction, decreased quality of life, and high cost.

Pharmacologic Therapy

There are three major pharmacologic treatment options for EoE that come in various modes of administration, including oral PPI, topical swallowed steroids, and injectable biologic drugs.

Although not FDA approved for treatment of EoE, PPIs have been one of the mainstays of therapy since the condition was first defined. In addition to acid suppression, PPIs have anti-inflammatory effects that can treat esophageal eosinophilia. PPIs have been known to block eotaxin-3 expression, which is a key eosinophil chemoattractant in the pathophysiology of EoE.36-37 Systematic reviews and meta-analyses of EoE patients on PPI have demonstrated a histopathologic remission rate of 42% compared to placebo, and 61% rate of symptomatic improvement.38-39 Treatment with PPI typically begins with an eight-week trial of the highest dosage taken twice daily, followed by reassessment for symptomatic and histologic remission. Once remission is achieved, the patient can then taper the PPI to the lowest effective dose for chronic maintenance therapy.40 An alternative strategy is to start with full dose taken once daily for four weeks, then increase to twice daily if symptoms do not improve. PPIs are a commonly preferred first-line therapy due to ease of administration, low cost, and favorable side effect profile.

Topical steroids are an effective pharmacological option, particularly for patients who are averse to systemic therapy. Budesonide (EohiliaTM) became the first oral FDA approved medication for eosinophilic esophagitis in early 2024. Prior to recent FDA approval, various budesonide formularies were being used or swallowed fluticasone (metered dose inhaler) was used. Eohilia is a novel oral budesonide suspension that has thixotropic properties, meaning it is more liquid when shaken but becomes viscous when swallowed. Eohilia is supplied as 2 mg/mL single-dose packs while fluticasone comes in the form of a metered dose inhaler. These topical steroids have limited systemic absorption and thus are generally well tolerated while still being able to act directly on the gastrointestinal tract.41 A systematic review of five studies including 174 patients with EoE showed complete histologic remission in adults and children with an overall effectiveness correlated to an OR of 25.12 (95% CI 5.46, 115.62) in fluticasone versus placebo and OR of 17.17 (95% CI 3.66,80.40) in budesonide versus placebo.42 A more recent meta-analysis showed topical steroids induced complete histologic response compared to placebo with an OR of 35.82 (95% CI 14.98, 85.64).43 With regards to Eohilia, there were two double-blind, parallel-group, randomized, placebo-controlled trials that lead to approval of the medication; in patients 11 to 56 years, histologic remission was achieved in 53% vs. 1% placebo and in patients 11 to 42 years, histologic remission was achieved in 38% vs. 2% placebo at 12 weeks.44-45 It should be noted that Eohilia has not been proven to show benefit beyond 12 weeks and hence the maximum recommended duration of treatment advised by the FDA is 12 weeks.

Dupilumab (Dupixent®) is another FDA approved drug for treatment of EoE in patients ≥ 1 year of age; it is the only medication FDA approved in the pediatric population. It is a human monoclonal antibody that blocks interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling, which play key roles in multiple atopic conditions. It has been previously approved for atopic dermatitis, asthma, and rhinosinusitis with nasal polyposis. The dosing for dupilumab varies based on the atopic condition; EoE dosing is 300 mg subcutaneous injection once weekly. Parts A and B of a phase 3 trial demonstrated histologic remission (defined as ≤6 eosinophils/hpf) at 24 weeks in: (A) 60% versus 5% in weekly dupilumab use compared to placebo; (B) 59% in weekly dupilumab use versus 60% in every two-week dupilumab use versus 6% in placebo.46 Part C of the trial was continued up to 52 weeks demonstrating sustained treatment effects. 82% of patients who received weekly dupilumab in part A-C had <15 eosinophils/hpf at 52 weeks. In part B-C, the placebo group in part B was switched to either weekly or every two-week dupilumab dosing, and patients who had been on the weekly and every two-week dupilumab dosing were continued on their assigned therapy. At 52 weeks, histologic remission rates were 85% in weekly/weekly dupilumab group, 68% in the placebo/weekly dupilumab group, 74% in every 2 weeks/every 2 weeks dupilumab group, and 72% in the placebo/every 2 weeks dupilumab group.47 It should be noted these studies were performed in PPI-refractory patients though the drug has been FDA approved for EoE independent of a PPI trial. Dupilumab has shown good efficacy on treatment of EoE with a favorable safety profile. The most common side effects include injection site reactions, conjunctivitis, upper respiratory tract infections, arthralgia, and herpes viral infections. Its injectable form and cost, however, may be barriers for some patients. 

Esophageal Dilation

Although the primary goal of EoE treatment is to attain histologic remission, endoscopic dilation of the esophagus can provide symptomatic relief of dysphagia related to stenoses, such as strictures or rings, that can be a complication from the chronic inflammation in EoE.48 Dilations may be particularly beneficial for those with fibrostenotic disease as opposed to an inflammatory phenotype. Dilation therapy alone is not recommended but should be used in conjunction with other medical therapies. Through-the-scope (TTS) balloon dilation can be considered for short-segment strictures, whereas bougie dilation can be used for long-segment strictures or multiple strictures. Often repeat dilations with gradual increases (typically no more than 3mm per session) in the dilation diameter may be necessary to safely achieve an adequate esophageal diameter and symptomatic remission. A goal esophageal diameter of 15 – 18mm is recommended.49 Risks of dilation include esophageal tears and perforations, bleeding, and chest pain. There was earlier concern that the esophageal tissue is more fragile in EoE particularly when there is ongoing inflammation. However, dilations have been repeatedly shown to be a relatively safe therapeutic procedure, with reported perforation rates of 0.033%.50

Combination Therapy

There are currently no systematic guidelines for multimodal pharmacologic therapy. However, this can be considered in patients who are refractory to single agent therapy and have failed multiple single agents. Combination therapy may also be needed in patients who have concomitant GERD with EoE that is refractory to PPI therapy. 

Goal of Therapy

Ultimately the goal of therapy is to not only minimize symptoms but a ‘treat to target’ approach as first proposed in the inflammatory bowel disease literature.51 What has similarly been proposed in EoE is to achieve deep remission – meaning resolution of clinical, endoscopic (improvement in EREFS score), and histologic findings (defined as <15 eos/hpf) identified at time of EoE diagnosis (Figure 2). Generally lifelong therapy (if pharmacologic, at the lowest effective dose; if dietary, must also continue) is indicated for this chronic condition. Clinical symptoms, however, do not always correlate with endoscopic or histologic findings, and so endoscopic surveillance is essential to assess response to therapy and confirm ongoing overall remission.52

Conclusion

EoE is a chronic atopic condition of the esophagus characterized by eosinophilic infiltration and subsequent remodeling of the esophagus which, if untreated, can lead to strictures, fibrosis, and food impactions. EoE is diagnosed when clinical symptoms of esophageal dysfunction are present with esophageal mucosal biopsies showing ≥15 eos/hpf (about 60 eos/mm2) without an alternative cause. Therapies for EoE include dietary (elimination diet, allergy testing-based diet, elemental diet), pharmacologic (PPI, topical steroids, dupilumab), and esophageal dilation (balloon, bougie). The goal of therapy is ultimately to achieve deep remission, with clinical, endoscopic, and histologic resolution of disease, though further data on this is needed. 

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43. Hao L, Lu Y, Gong B. A meta-analysis of efficacy of topical steroids in eosinophilic esophagitis: From the perspective of histologic, clinical, and endoscopic outcome. Gastroenterol Hepatol. 2021;44(4):251-260.

44. Hirano I, Collins MH, Katzka DA, Mukkada VA, Falk GW, Morey R, Desai NK, Lan L, Williams J, Dellon ES; ORBIT1/SHP621-301 Investigators. Budesonide Oral Suspension Improves Outcomes in Patients with Eosinophilic Esophagitis: Results from a Phase 3 Trial. Clin Gastroenterol Hepatol. 2022 Mar;20(3):525-534.e10.

45. Mukkada VA, Gupta SK, Gold BD, Dellon ES, Collins MH, Katzka DA, Falk GW, Williams J, Zhang W, Boules M, Hirano I, Desai NK. Pooled Phase 2 and 3 Efficacy and Safety Data on Budesonide Oral Suspension in Adolescents with Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. 2023 Dec 1;77(6):760-768.

46. Dellon ES, Rothenberg ME, Collins MH, et al. Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis. NEJM. 2022;387(25).

47. Rothenberg ME, Dellon ES, Collins MH, et al. Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebocontrolled, phase 3 trial. The Lancet Gastroenterology & Hepatology. 2023.

48. Lucendo AJ & Molina-Infante J. Esophageal dilation in eosinophilic esophagitis: risks, benefits, and when to do it. Curr Opin Gastroenterol. 2018; 34(4):226-32.

49. Dellon ES, Gonsalves N, Hirano I, et al. ACG Clinical Guideline: Evidenced Based Approach to the Diagnosis and Management of Esophageal Eosinophilia and Eosinophilic Esophagitis (EoE). Am J Gastroenterol. 2013;108(5):679-692.

50. Dougherty M, Runge TM, Eluri S, Dellon ES. Esophageal dilation with either bougie or balloon technique as a treatment for eosinophilic esophagitis: a systematic review and metaanalysis. Gastrointest Endosc. 2017;86(4):581-591.

51. Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s
disease. Clin Gastroenterol Hepatol. 2015;13(6):1042-1050.

52. Hirano I, Furuta GT. Approaches and challenges to management of pediatric and adult patients with eosinophilic esophagitis. Gastro. 2020;158(4):840-851.

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Nutrition Reviews in Gastroenterology, SERIES #17

Diet-Based Treatments of Gastroparesis with a Special Focus on Small Particle Size

September 2024 • Volume XLVIII, Issue 9
Emily Rubin,Nicholas Noverati,Stephanie Moleski

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Gastroparesis presents a significant clinical challenge due to delayed gastric emptying, often without mechanical obstruction, causing symptoms impacting patients’ quality of life. Current therapies for gastroparesis include smaller, low-fat, and low-fiber meals, aiming to alleviate symptoms while ensuring adequate nutrition. These conventional methods have limitations, driving the exploration of innovative and less restrictive dietary approaches. Recent research suggests that modifying dietary consistency to a smaller particle size with blended, mashed, minced, and chopped foods can improve gastric emptying and symptom relief. Investigational foods like soy germ pasta, Pistacia atlantica kurdica gum, and modified consistency test diets show promise in enhancing gastric function. Dietary interventions remain pivotal in management, with emerging evidence favoring small particle size diets. A multidisciplinary team is also essential to provide tailored nutrition guidance and address nutrient deficiencies, while screening for eating disorders to optimize patient outcomes. 

Introduction 

Gastroparesis (GP) is the slowing of the stomach’s ability to empty food contents in the absence of mechanical obstruction. It is a diagnosis encountered and treated across many subspecialities of medicine, including gastroenterology, endocrinology, and primary care. The etiology of GP in 90% of patients is from an idiopathic, diabetic, or postsurgical source.1 Common symptoms of GP include nausea, vomiting, postprandial bloating, and early fullness. The severity of symptoms vary from person to person. The gold standard for diagnosis of GP is gastric scintigraphy using radiolabeled solid food (as the gastric emptying rate of solids and liquids differ).1 Furthermore, there are a few directed medical therapies with supportive evidence available.2 

GP has a significant burden of disease, with an estimated increased healthcare cost of 1,026% from 1997 to 2013.3 The increase is indicative of the rising number of hospital admissions and the increasing costs associated with treatment. Current limited treatment options include pharmacologic therapies with prokinetics and antiemetics, surgical/endoscopic treatments such as pyloromyotomy and pyloric botulinum toxin injection, implantable devices to provide gastric electrical stimulation, dietary interventions, and a wide array of alternative approaches ranging from acupuncture to herbal therapies.4-6 Diet interventions remain the first line of treatment, supported by the American College of Gastroenterology (ACG) guidelines.6

Understanding the principles of dietary guidelines for GP can be a helpful tool in the management of adult patients with this diagnosis, especially in settings where referral to a registered dietitian (RD) is either unavailable or impractical. This review aims to offer an overview of the current evidence to support dietary approaches for the management of GP, updates and applications of the small particle size diet, and additional data for investigational foods. 

Current Role of Diet in Gastroparesis

The diet management of GP aims to not only alleviate symptoms, but also to address fluid and electrolyte imbalances, and other potential nutrient deficiencies.7 Malnutrition and dehydration are common in patients with moderate to severe gastroparesis as they often consume diets that are not nutrient rich. Also, given that food intake can be a significant symptom trigger for patients, some may inadvertently restrict their caloric intake by consuming smaller portions, heightening the risk for malnutrition. For example, one study found that 64% of patients with either diabetic or idiopathic gastroparesis consumed less than 60% of their daily energy requirement.8 Common deficiencies include iron, vitamin B12, vitamin D, and calcium.9 Another study compared healthy controls to those with GP and found a number of micronutrient deficiencies (such as folate, niacin, riboflavin, thiamine, calcium, copper) in addition to consuming less calories in those with GP.10 Therefore, the goal of diet therapy is to identify nutrient-dense food options that can aid in alleviating a patient’s symptoms without compromising adequate nutrition. Tolerance can vary from person to person.

In diabetic gastroparesis, diet can help achieve glycemic control that is crucial for improving gastric emptying. Not only should their diet help them achieve better overall glycemic control, but also avoid acute hyperglycemia. For example, foods with a higher glycemic index can contribute to post-prandial hyperglycemia that disrupts the emptying of both solid and liquid foods.11 

As previously noted by Parrish and McCray in 2011, the traditional dietary approach for GP involves consuming smaller meals that are lower in both fat and fiber.9,12 This is corroborated by recent systematic reviews,13,14 that showed lower fat foods decrease symptoms of GP and another study that showed higher fat content has the opposite effect.15 The same is true for low-fiber diets which might also decrease GP-like symptoms in other disease processes.13 Small meals can also generally reduce the sensation of fullness and thus alleviate GP symptoms.16 

If patients are unable to tolerate small solid meals, they may need to use oral nutrition supplements (ONS).17 These are especially useful as liquids empty faster than solids.17 Though there is no direct evidence supporting their use, dietitians and other clinicians alike have found them to be a helpful option to support nutrition in the patient with severe gastroparesis. If a patient cannot tolerate solids, nor ONS, and there is significant concern for ongoing weight loss and malnutrition, enteral nutrition may be needed. Typically, this is given either through a gastrojejunostomy tube (PEG-J), or direct jejunostomy tube to bypass the stomach. Dietitians can assist in selecting the type of enteral formula used (standard, semi-elemental or elemental) and in developing a regimen.17 Enteral formulas containing fiber are usually not recommended due to potential risk of worsening symptoms. Further, if a patient is not able to tolerate enteral nutrition to any extent, or there is some other contraindication to using enteral nutrition, parenteral nutrition may be necessary. Consumption of foods and beverages should continue as tolerated.

The Small Particle Size Diet 

In more recent years, the focus of diet for GP has shifted to smaller meal size and modified consistency for smaller particle size, which includes foods that can easily be broken down through blending, grinding, mashing, mincing, and chopping to optimize tolerance (see Table 1).

Small Particle Foods 
Cooking methods: mashed, puree, pate, timbale, sauces, ground, minced, lean cooking methods – limit added fats – baked, broiled, boiled, steamed  Fruits/vegetables: mashed turnips, mixed beetroot, pickled beets, asparagus tips, green pea puree, corn pate (cooked and mixed), bean pate (cooked and mixed), Brussels sprout pate (cooked and mixed), mushroom paste, fine mixed onion, dried powdered onion, tomato paste, mashed avocado, puree of fruit or berry, ripe pears without skin, canned peaches, gooseberries, mixed: blueberries, currants, lingonberries, yellow-brown banana, kiwi, watermelon, flour of fruits or almonds Starches: mashed potatoes, pressed potatoes, creamed potatoes, brown crisp, rye crisp Protein/cheeses: mashed-boiled eggs, French omelet, baked omelet Swedish style, baked egg, mixed minced or ground dishes including beef, chicken, turkey, baked flatfish, boiled fish loaf dishes, fish pudding, fish souffle, fish balls, fish pate, fish gratin, herring terrine, mixed shrimp, crab, clams, cottage cheese, Greek yogurt, ricotta cheese, spreadable cheese
Medium Particle Foods
Cooking methods: boiled, steamed, roasted, baked Fruits/vegetables: cooked carrots, cooked turnips, cooked parsnips, cooked cauliflower, broccoli flower, mushrooms, mixed leeks, canned crushed tomatoes, pepper without skin, cooked and canned fruit or berry, ripe pears without skin, raspberries, strawberries, yellow banana, kiwi, mango, papaya  Starches: boiled potatoes, baked potatoes, whole grain cereal, bread baked on coarse flour Protein/cheeses: scrambled eggs, cooked, canned, roasted, baked meat (beef, turkey, chicken) dishes, jellied veal, extra thin slices of ham, baked salmon, baked mackerel, baked cod fish
Large Particle Foods
Cooking methods: raw, wok, fried in a pan, deep fried, coating with egg and breadcrumbs, high fat cooking methods Vegetables: raw carrots, raw turnips, raw parsnips, cooked cauliflower and broccoli stems, asparagus stalk, green pea, boiled corn, cooked beans, cooked Brussels sprouts, raw and cooked cabbage, raw, boiled and fried onion, cooked leeks, rhubarb, salad, cucumber and tomatoes, pepper with skin, and avocado Fruit: fresh fruit, skin and membrane of citrus: orange, clementine, grapefruit, pineapple, blueberries, currants, lingonberries, blackberry, cloudberries, green and green-yellow banana, netted melon Starches: fried potatoes, French potatoes, rice, pasta, parboiled rice and brown rice, non-parboiled rice, bulgur, couscous, porridge, bread, pancakes, white fresh bread, bread with seeds, whole grains Protein/cheeses: high fat cheese, ripened cheese, hard-boiled eggs, soft-boiled eggs, whole meat, cured and smoked salmon, raw spiced salmon, shrimp, crab, clams, tails
Table 1. Common Foods of Differing Particle Size (Adapted from Olausson et al.)19

The  ACG guidelines now formally recommend small particle size diets, supported by the findings of two main studies.6,18,19 The initial study to support the use of this diet investigated gastric emptying time and postprandial blood glucose levels in patients with Type 1 diabetes mellitus (T1DM) and GP compared to healthy controls. The subjects consumed meals of the same nutrient composition, but with varying particle sizes – one with large particles, and another with small particles.18 Both meals contained identical macronutrient profiles, each providing 375 kcal, 26g protein, 13g fat (25-30% of total energy intake), 38g carbohydrates, and 4.8g fiber. The meal components included 100g of meat, 40g of pasta, 150g of carrots, and 5g of oil. The diet in large particle size consisted of slices of roast beef, pasta boiled for 14 minutes, raw carrots, and canola oil. In contrast, the diet in small particle size included minced and baked beef, pasta, and carrots boiled and mixed in a food processor, along with canola oil.18 For patients with GP, the small particle size meal significantly accelerated gastric emptying compared to the large particle meal. Additionally, the study suggested that small particle size could contribute to improved glycemic control for diabetic patients.18 

The second study, a randomized control trial, compared the effects of dietitian-directed meals of small particle size compared to a standard diabetic diet on gastric emptying. Secondary outcomes included the effects of diet on body weight, nutritional intake, metabolic control, mental health, and quality of life. Three different diets were included in the study: one group received a reduced particle size meal (food already processed into small particles), another group received foods that can be easily broken down into small particles (but not pre-prepared for them), and a control group received a diabetic diet that contained normal-sized particles. For all 3 diets, the recommended fat content was 25-30% of total energy, and fiber content was 15g/1000 kcal with 3 meals and 3 snacks or 4-6 small meals per day based on tolerance. Foods that could easily be broken down into small particles were defined as “food [that] should be [easily]…mashed with a fork into small particle size, e.g. mealy potatoes.”19 Therefore, this diet excluded foods with the following characteristics: foods with husks/peels (e.g. corn, peas), membranes (e.g. orange, lemons), stringy foods (e.g. rhubarb, asparagus, leeks, stalks of broccoli), seeds and grains (e.g. nuts and almonds, bread with whole grains), compact, poorly digestible particles (such as pasta, rice) and white fresh bread.19 The control diabetic group used large particle size foods such as whole meat, seafood, cheese slices, almonds and nuts and low glycemic index pasta, rice, grated vegetables, raw vegetable salad, wok vegetables, fresh fruit and bread with whole grain and/or sourdough.19 The results of this study support that smaller particle size diets improve gastric emptying as well as symptoms. The emptying percent at 120 minutes was improved compared to control, as were symptoms such as nausea/vomiting, postprandial fullness, bloating, lower abdominal pain, and heartburn. Also, after 20 weeks on the diet, nutrient intake and glycemic controls stayed the same compared with a typical DM diet.19 This study was limited in that it did not include patients that have other types of GP (such as idiopathic).19 

The modified consistency test diet (MD) (which also refers to foods that are chopped, ground, or pureed), is similar to the principles of the small particle size diet. Research has shown that the MD, combined with rapid-acting insulin, can lead to better postprandial glycemic control and thus even more beneficial to those with diabetic GP. 19 In 2022, in a study by Betônico et al., a MD meal was compared to a consistency standard meal which included: rice, beans, grilled chicken, tomato, cooked carrot, and an apple.20 The MD meal consisted of pasty rice, only bean broth, shredded chicken with tomato sauce, overcooked-mashed carrot, and apple puree. The two meals were similar regarding caloric value and macronutrients distribution, approximately 465.14 kcal, 26% lipids (13.9g), 24% protein (28.1g) and 50% carbohydrate (58.3g).20 Results of the study showed that those on the MD had a smaller increase in post-prandial (2 hours after eating) glucose levels. Patients on this diet also had a lower symptom score and complained less of symptoms such as “not able to finish meal” or “stomach or belly feels larger.”20 Similar to the studies supporting the small particle size diets, this was also limited in that it only included those with diabetic gastroparesis. 

Updates on Investigational Foods 

Soy Germ Pasta

One method that has been explored to expand the dietary options for patients with Type 2 diabetes and gastroparesis is the inclusion of soy germ pasta alongside a diabetic diet. Soy germ is noted for its isoflavones, which have a pro-motility effect on the stomach.21 Unlike conventional pasta, including soybean pasta, only soy germ pasta contains these beneficial isoflavones. In one study, soy germ pasta (containing 2% soy germ and delivering 31–33mg of isoflavones per serving) was tested to liberalize the gastroparesis diet for patients with Type 2 diabetes.21 Patients were randomized into two groups; one group consumed one serving per day of soy germ–enriched pasta (80g) followed by conventional pasta for 8 weeks, while the other group consumed these pastas in reverse sequence.21 The soy germ-enriched pasta contained 33mg of total isoflavones per serving (80g). Compared to conventional pasta, soy germ pasta significantly increased gastric emptying time (i.e., it improved gastric emptying). Glucose and insulin concentrations were not affected by soy germ pasta.21 These findings suggest that soy germ pasta may offer a simple dietary approach for managing Type 2 diabetes. However, soy germ pasta is currently unavailable for purchase. Other high-isoflavone options, equivalent to 33 grams of isoflavones per serving, include foods such as tofu, tempeh, soy protein and soy flour. These alternatives have not been studied in the same context but offer similar isoflavone content22 and, since this was a small pilot study, more data is needed before confidently recommending this option to improve gastroparesis symptoms.

Pistacia atlantica kurdica Gum

Pistacia atlantica is a species of pistachio tree which contains resin, used as chewing gum. The essential oil of this species is said to have pro-motility effects on the stomach.23 To test its effectiveness on symptoms of GP, a study investigated the daily consumption of Pistacia atlantica kurdica chewing gum for one month in patients with diabetic gastroparesis.23 The intervention group chewed 2-grams of Pistacia atlantica kurdica gum twice daily and a placebo group chewed sugar free gum containing industrial plastic polymers twice a day. At the conclusion of the study, the intervention group experienced significant reductions in symptoms, including nausea/vomiting, postprandial fullness/early satiety, and bloating, versus placebo. The experimental group also saw significant decreases in systolic blood pressure and HbA1c.23 This study provides valuable insights into the potential benefits of Pistacia atlantica kurdica gum for managing GP in patients with diabetes, although the gum is also not available for purchase.

Risk of Eating Disorders with Gastroparesis 

Patients with GP often discover or adopt restrictive diets to manage their symptoms and may be vulnerable to developing or exacerbating an underlying eating disorder. One study indicated that a GP diagnosis typically precedes the onset of avoidant/restrictive behaviors.10 Another study of patients referred for symptoms indicative of GP revealed that 55% of these patients exhibited signs of a feeding and eating disorder known as Avoidant/Restrictive Food Intake Disorder (ARFID). ARFID is characterized by feeding and eating disturbances that result in failure to meet nutritional needs leading to low weight, nutritional deficiency, dependence on supplemental feedings, and/or psychosocial impairment.24 Common symptoms of ARFID include restricted range and amount of food, avoidance of certain food textures, fears of choking or vomiting, lack of interest in food, as well as gastrointestinal symptoms at mealtimes including early satiety, constipation, abdominal pain, stomach cramps, or an upset stomach related to food consumption.25 These studies support the notion that individuals with GP are at risk of developing eating disorders.12,24 Therefore, it is crucial to take this into consideration when working with patients diagnosed with GP. Screening can be performed with a quick, validated questionnaire such as the Nine Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS).26

• Comprehensive nutritional assessment (patient history, anthropometrics, physical examination focused on nutrition, laboratory tests and diagnostic procedure, food and nutrition history, functional status)
• Identifying and preventing patients at risk of malnutrition
• Ability to address nutritional deficiencies and promote optimal nutritional status
• Restoration of fluids and electrolytes
• Provide nutrition counseling and individualized diet recommendations  
• Recommend nutrition support via oral nutrition supplements, post-pyloric feeding tube or parenteral route
• Improve glycemic control in diabetic gastroparesis
• Screen for eating disorders – Avoidant/Restrictive Food Intake Disorder 
• Addressing patients’ individual and mental well-being and quality of life 

GI Dietitian Database Websites: 
International Foundation
for Gastrointestinal Disorders
(IFFGD) iffgd.org
American Gastroenterological Association
(AGA) gastro.org
Table 2.
Indications to Refer Patients to a GI Registered Dietitian  

The Role of the Registered Dietitian

The RD plays an important part in the treatment and management of GI disorders, including GP. Dietitians are integral members of a multidisciplinary team and are uniquely qualified in the assessment and management of nutritional status. They are skilled at identifying patients at risk of and with confirmed malnutrition. Patients with GP should be referred to a RD for a comprehensive nutrition assessment to assess the patient’s nutritional status and formulate a personalized nutrition intervention plan.17 The nutrition plan may encompass educating the patient about gastroparesis-specific nutrition, providing counseling for effective implementation, and adjusting dietary strategies to address any emerging challenges.17 In patients with diabetic gastroparesis in particular, research has shown that incorporating nutrition intervention by a RD can lead to improved glycemic control, reduced risk of complications, and improved quality of life.27 When available, it can be important to recognize when it can be important to refer someone to a RD for further recommendations and management in their disease course (see Table 2). 

Conclusion 

Nutritional strategies for managing GP encompass practices of consuming smaller, more frequent meals, while limiting foods high in fiber and fats (see Table 3). Dietary approaches for people with GP aim to mitigate symptoms and improve digestion while ensuring caloric goals are met and micronutrient deficiencies are prevented. Specific dietary interventions hold the potential to ameliorate symptoms and enhance gastric emptying in adult patients, with diets of small particle size being a prime example. This approach, which includes foods in a consistency of blended, mashed, minced, and chopped, has demonstrated a significant reduction in the severity of symptoms of GP such as nausea/vomiting, postprandial fullness, and bloating. Optimizing nutrition is a multidisciplinary approach for patients with GP and should also include considering screening for eating disorders. More research is needed regarding the use of investigational foods in treatment for GP. 

Consider a GP diet that alters meal – volume, consistency, composition, amount of fat, and fiber
Foods in small particle size through small meals throughout the day   Fat content (25–30% of total energy)16 Fiber content (15g/1000kcal)16 4-6 small meals per day based on tolerance  Limit foods of large particle size  Liquid meals and/or high energy/protein oral nutritional supplement (ONS) if appropriate Modify meal timing, form of carbohydrates (simple, complex), according to diabetes treatment regimen Diet must be personalized as tolerance can vary from person to person depending on severity of symptoms.
Table 3.
Summary of Diet Recommendations for Gastroparesis 

References

1. Rao SSC, Camilleri M, Hasler WL, et al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterology & Motility. 2011;23(1):8-23. 

2. Bonetto S, Gruden G, Beccuti G, Ferro A, Saracco GM, Pellicano R. Management of dyspepsia and gastroparesis in patients with diabetes. a clinical point of view in the year 2021. Journal of Clinical Medicine. 2021;10(6):1313. 

3. Wadhwa V, Mehta D, Jobanputra Y, Lopez R, Thota PN, Sanaka MR. Healthcare utilization and costs associated with gastroparesis. World Journal of Gastroenterology. 2017;23(24):4428. 

4. Gupta E, Lee LA. Diet and complementary medicine for chronic unexplained nausea and vomiting and gastroparesis. Current treatment options in gastroenterology. 2016;14:401-409. 

5. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1592-1622. 

6. Camilleri M, Kuo B, Nguyen L, et al. ACG Clinical Guideline: Gastroparesis. The American Journal of Gastroenterology. 2022;117(8):1197-1220. 

7. Aguilar A, Malagelada C, Serra J. Nutritional challenges in patients with gastroparesis. Current Opinion in Clinical Nutrition & Metabolic Care. 2022;25(5):360-363. 

8. Parkman HP, Yates KP, Hasler WL, et al. Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. Gastroenterology. 2011;141(2):486-498. e7. 

9. Parrish CR, McCray S. Gastroparesis and nutrition: The art. Pract Gastroenterol. 2011;99(4):26-41. 

10. Ogorek CP, Davidson L, Fisher RS, Krevsky B. Idiopathic gastroparesis is associated with a multiplicity of severe dietary deficiencies. American Journal of Gastroenterology (Springer Nature). 1991;86(4)

11. Halland M, Bharucha AE. Relationship between control of glycemia and gastric emptying disturbances in diabetes mellitus. Clinical Gastroenterology and Hepatology. 2016;14(7):929-936. 

12. Wytiaz V, Homko C, Duffy F, Schey R, Parkman HP. Foods provoking and alleviating symptoms in gastroparesis: patient experiences. Digestive Diseases and Sciences. 2015;60:1052-1058. 

13. Lehmann S, Ferrie S, Carey S. Nutrition management in patients with chronic gastrointestinal motility disorders: a systematic literature review. Nutrition in Clinical Practice. 2020;35(2):219-230. 

14. Eseonu D, Su T, Lee K, Chumpitazi BP, Shulman RJ, Hernaez R. Dietary interventions for gastroparesis: a systematic review. Advances in Nutrition. 2022;13(5):1715-1724. 

15. Homko C, Duffy F, Friedenberg F, Boden G, Parkman H. Effect of dietary fat and food consistency on gastroparesis symptoms in patients with gastroparesis. Neurogastroenterology & Motility. 2015;27(4):501-508. 

16. Barrett AC, Johnson KP, Halabi ME, Parkman HP. Meal-eating characteristics among patients with symptoms of gastroparesis: Relationships to delays in gastric emptying. Neurogastroenterology & Motility. 2023;35(11):e14661. 

17. Limketkai BN, LeBrett W, Lin L, Shah ND. Nutritional approaches for gastroparesis. The Lancet Gastroenterology & Hepatology. 2020;5(11):1017-1026. 

18. Olausson EA, Alpsten M, Larsson A, Mattsson H, Andersson H, Attvall S. Small particle size of a solid meal increases gastric emptying and late postprandial glycaemic response in diabetic subjects with gastroparesis. Diabetes Research and Clinical Practice. 2008;80(2):231-237. 

19. Olausson EA, Störsrud S, Grundin H, Isaksson M, Attvall S, Simrén M. A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized controlled trial. Official Journal of the American College of Gastroenterology| ACG. 2014;109(3):375-385. 

20. Betônico CC, Cobello AV, Santos-Bezerra DP, et al. Diet consistency modification improves postprandial glycemic and gastroparesis symptoms. Journal of Diabetes & Metabolic Disorders. 2022;21(2):1661-1667. 

21. Setchell KD, Nardi E, Battezzati P-M, et al. Novel soy germ pasta enriched in isoflavones ameliorates gastroparesis in type 2 diabetes: a pilot study. Diabetes Care. 2013;36(11):3495-3497. 

22. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutrition and Cancer. 2006;55(1):1-12. 

23. Mahjoub F, Salari R, Yousefi M, Mohebbi M, Saki A, Rezayat KA. Effect of Pistacia atlantica kurdica gum on diabetic gastroparesis symptoms: a randomized, triple-blind placebo-controlled clinical trial. Electronic Physician. 2018;10(7):6997. 

24. Murray HB, Bailey AP, Keshishian AC, et al. Prevalence and characteristics of avoidant/restrictive food intake disorder in adult neurogastroenterology patients. Clinical Gastroenterology and Hepatology. 2020;18(9):1995-2002. e1. 

25. Ridgeway L, McNicholas F. Clinical management of avoidant restrictive food intake disorder (ARFID). Irish Medical Journal. 2021;114(4):331. 

26. Zickgraf HF, Ellis JM. Initial validation of the Nine Item Avoidant/Restrictive Food Intake disorder screen (NIAS): A measure of three restrictive eating patterns. Appetite. 2018;123:32-42. 

27. Moore M, Evert AB, Evert AB, Franz MJ. Nutrition Therapy for Diabetic Gastroparesis. American Diabetes Association Guide to Nutrition Therapy for Diabetes. American Diabetes Association; 2017:0.

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From the Pediatric Literature

The Pediatric Microbiome in Patients with Ulcerative Colitis and Primary Sclerosing Cholangitis

September 2024 • Volume XLVIII, Issue 9

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Adult and pediatric patients with primary sclerosing cholangitis (PSC) often have associated ulcerative colitis (UC), and it has been hypothesized that gut microbiome changes may be the cause of this UC and PSC disease connection. Minimal data regarding such changes are present in the pediatric population, and the authors of this study attempted to describe diversification in both the bacterial and fungal microbiome in patients with UC and PSC compared to patients with UC alone.

This prospective study occurred at 2 pediatric hospitals in Italy in which patients with UC and PSC, patients with UC alone, and control patients all aged between 2 and 19 years old were recruited. Patients were diagnosed with PSC using standard physical examination and laboratory findings with the addition of characteristic findings on endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, or liver biopsy. Patients with secondary sclerosing cholangitis were excluded. Patients were diagnosed with UC using Porto criteria and Montreal classification. Stool samples were collected from all patients, and these samples underwent both bacterial and fungal metagenomic analysis. Linear discriminant analysis effect sizes were used to determine taxa abundance.

A total of 26 patients with UC and PSC, 27 patients with UC alone, and 26 control patients were evaluated. Age, gender, body mass index, and endoscopic findings were not different between the two groups. Patients with UC and PSC were statistically more likely to be on azathioprine and ursodeoxycholic acid. As expected, patients with UC and PSC had significantly higher serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT). Many microbiome differences between groups were noted. 

Patients with UC and PSC and patients with UC alone had decreased bacterial alpha diversity (less bacterial diversity) and decreased beta diversity (less diversity between groups) compared to control patients. Bacterial analysis demonstrated increased Verrucomicrobia and Bacteroidetes in control patients while patients with UC alone had an increase in proteobacteria. Increased Klebsiella, Haemophilus, Enterococcus,and Collinsella were present in patients with UC alone while patients with UC and PSC had increased Streptococcus.  Control patients had increased Akkermansia, Bacteroides, Dialister, Parabacteroides,and Oscillospira compared to both patients with UC and PSC and patients with UC alone.

Fungal analysis showed no real difference in either alpha or beta diversity. Statistically significant increases of Ascomycota were present in patients with UC and PSC and of Basidiomycota in control patients. Patients with UC and PSC had increased amounts of Saccharomyces, Sporobolomyces, Tilletiopsis, and Debaryomyces. Patients with UC alone had increased amounts of Piptoporus, Candida, and Hypodontia. Patients with UC and PSC and patients with UC alone had decreased amounts of Meyerozyma and Malassezia.

More positive bacterial correlations were noted compared to fungal correlations regarding serum AST, ALT, GGT, and body mass index. Some negative bacterial and fungal correlations were seen regarding Montreal scoring of ulcerative colitis. Linear discriminant function analysis demonstrated that patients with UC alone had a correlation with Collinsella and Dorea in fecal samples whilepatients with UC and PSC had a correlation with Bacteroides and Saccharomyces in fecal samples. Finally, patients with UC and PSC, patients with UC alone, and control patients appeared to have different bacterial metabolic profiles.

This study provides intriguing information about the microbiome of pediatric patients with UC and PSC compared to those pediatric patients with UC alone. Perhaps the results of this study can help in determining the risk of PSC occurring in pediatric patients with UC while also providing information about potential therapeutics in the setting of microbiome differences and changes in these patient populations. 

Del Chierico F, Cardile S, Baldelli V, Alterio T, Reddel S, Bramuzzo M, Knafelz D, Lega S, Bracci F, Torre G, Maggiore G, Putignani L.  Characterization of the Gut Microbiota and Mycobiota in Italian Pediatric Patients with Primary Sclerosing Cholangitis and Ulcerative Colitis.  Inflamm Bowel Dis 2024; 30: 529-537.

The Association of Meals and Chronic Abdominal Pain in Children

Many children with chronic abdominal pain are diagnosed with functional dyspepsia or irritable bowel syndrome. Functional dyspepsia can be further characterized as postprandial distress syndrome (early satiety and postprandial fullness) and epigastric pain syndrome (epigastric pain before or after meals). Adult studies have found an association between postprandial distress syndrome and psychological disorders suggesting an alteration of the brain-gut axis.

The authors of this study performed a retrospective study of pediatric patients presenting with chronic abdominal pain for at least 8 weeks. All patients underwent a Rome IV criteria questionnaire, Sleep Disturbances Scale for Children (SDSC) to assess for sleep disorders, and a Behavior Assessment System for Children – Third Edition (BASC-3) to assess for emotional functioning. All included patients were followed for 2 years.

A total of 226 patients were evaluated in this study (mean age 13.9 ± 2.7 years; 72% female). At least one gastrointestinal (GI) symptom was reported in 87.6% of patients. There were significantly more females with abdominal pain associated with eating as well as increased nausea with eating compared to males, and adolescents (patients ≥ 13 years old) were significantly more likely to have nausea with eating compared to children (patients ˂ 13 years old). Symptoms of increased abdominal pain with eating, increased nausea with eating, early satiety, and postprandial bloating were all related to one another significantly. BASC-3 indicators for anxiety and depression were statistically associated with increased nausea with eating, early satiety, and postprandial bloating in adolescent patients. SDSC scores demonstrated a significant correlation between a potential disorder in initiating and maintaining sleep in adolescents with increased nausea with eating as well as a significant correlation between excessive daytime somnolence and early satiety and postprandial bloating.

This study demonstrates that functional dyspepsia associated with postprandial distress correlates with potential anxiety and depression in adolescent patients. There appears to be some degree of correlation of such GI symptoms with disorders of sleep, and further research on improving sleep quality in pediatric patients with chronic abdominal pain is needed.  

Benegal A, Friesen H, Schurman J, Colombo J, Friesen C.  Meal Related Symptoms in Youth with Chronic Abdominal Pain: Relationship to Anxiety, Depression, and Sleep Dysfunction.  J Pediatr Gastroenterol Nutr 2024; 78: 1091-1097.

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