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, Escherichiacoli 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
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.13Malassezia 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.13Staphylococcus 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 Met
Additional Criteria
Positive catheter tip culture
None required
Positive catheter blood culture and percutaneous culture with identical microorganisms
The 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.
Topic
Teaching 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
1. Fojtová A, Norek B, Gazdíková K. The importance of home parenteral nutrition in clinical practice – own experience from our workplace. Gastroenterol Hepatol. 2022;76(1):60-66.
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.
4. Bond A, Chadwick P, Smith TR, Nightingale JMD, Lal S. Diagnosis and management of catheter-related bloodstream infections in patients on home parenteral nutrition. Frontline Gastroenterol. 2020;11(1):48-54.
5. Dibb M, Lal S. Home Parenteral Nutrition: Vascular Access and Related Complications. Nutr Clin Pract. 2017;32(6):769-776.
6. Donaldson E, Taylor M, Abraham A, et al. Improving quality in a national intestinal failure unit: greater efficiency, improved access and reduced mortality. Frontline Gastroenterol. 2015;6(3):182-193.
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.
8. Bonnes SL, Salonen BR, Hurt RT, McMahon MT, Mundi MS. Parenteral and Enteral Nutrition—From Hospital to Home: Will It Be Covered? Nutr Clin Pract. 2017;32(6):730-738.
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.
55. Gorski LA. A Look at 2021 Infusion Therapy Standards of Practice. Home Health Now. 2021;39(2):62-71.
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
References
1. Yadav D, Whitcomb DC. The role of alcohol and smoking in pancreatitis. Nature reviews Gastroenterology & hepatology. 2010;7(3):131-45.
2. Dumonceau JM, Delhaye M, Tringali A, Arvanitakis M, Sanchez-Yague A, Vaysse T, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Updated August 2018. Endoscopy. 2019;51(2):179-93.
3. Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol. 2011;106(12):2192-9.
4. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252-61.
5. Ewald N, Bretzel RG. Diabetes mellitus secondary to pancreatic diseases (Type 3c)–are we neglecting an important disease? Eur J Intern Med. 2013;24(3):203-6.
6. Bradley EL, 3rd. Pancreatic duct pressure in chronic pancreatitis. Am J Surg. 1982;144(3):313-6.
7. Dumonceau JM, Deviere J, Le Moine O, Delhaye M, Vandermeeren A, Baize M, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-term results. Gastrointestinal endoscopy. 1996;43(6):547-55.
8. Binmoeller KF, Jue P, Seifert H, Nam WC, Izbicki J, Soehendra N. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results. Endoscopy. 1995;27(9):638-44.
9. Smits ME, Badiga SM, Rauws EA, Tytgat GN, Huibregtse K. Long-term results of pancreatic stents in chronic pancreatitis. Gastrointestinal endoscopy. 1995;42(5):461-7.
10. Siddiqui UD, Jamidar PA. Endoscopic therapy for the treatment of pain in chronic pancreatitis: a success story in tropical pancreatitis. Gastrointestinal endoscopy. 2007;66(1):76-8.
11. Seza K, Yamaguchi T, Ishihara T, Tadenema H, Tawada K, Saisho H, et al. A long-term controlled trial of endoscopic pancreatic stenting for treatment of main pancreatic duct stricture in chronic pancreatitis. Hepatogastroenterology. 2011;58(112):2128-31.
12. Romagnuolo J, Talluri J, Kennard E, Sandhu BS, Sherman S, Cote GA, et al. Clinical Profile, Etiology, and Treatment of Chronic Pancreatitis in North American Women: Analysis of a Large Multicenter Cohort. Pancreas. 2016;45(7):934-40.
13. Rosch T, Daniel S, Scholz M, Huibregtse K, Smits M, Schneider T, et al. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy. 2002;34(10):765-71.
14. Hu LH, Ye B, Yang YG, Ji JT, Zou WB, Du TT, et al. Extracorporeal Shock Wave Lithotripsy for Chinese Patients With Pancreatic Stones: A Prospective Study of 214 Cases. Pancreas. 2016;45(2):298-305.
15. Korpela T, Udd M, Tenca A, Lindström O, Halttunen J, Myrskysalo S, et al. Long-term results of combined ESWL and ERCP treatment of chronic calcific pancreatitis. Scand J Gastroenterol. 2016;51(7):866-71.
16. Sherman S, Freeman ML, Tarnasky PR, Wilcox CM, Kulkarni A, Aisen AM, et al. Administration of secretin (RG1068) increases the sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis. Gastroenterology. 2014;147(3):646-54.e2.
17. Fritscher-Ravens A, Brand L, Knöfel WT, Bobrowski C, Topalidis T, Thonke F, et al. Comparison of endoscopic ultrasound-guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis. Am J Gastroenterol. 2002;97(11):2768-75.
18. Buxbaum J. Contrast EUS of the pancreas: top tips for advanced endoscopy (with videos). Gastrointest Endosc. 2022;95(5):996-1000.
19. Gabbrielli A, Mutignani M, Pandolfi M, Perri V, Costamagna G. Endotherapy of early onset idiopathic chronic pancreatitis: results with long-term follow-up. Gastrointestinal endoscopy. 2002;55(4):488-93.
20. Ell C, Rabenstein T, Schneider HT, Ruppert T, Nicklas M, Bulling D. Safety and efficacy of pancreatic sphincterotomy in chronic pancreatitis. Gastrointestinal endoscopy. 1998;48(3):244-9.
21. Kim MH, Myung SJ, Kim YS, Kim HJ, Seo DW, Nam SW, et al. Routine biliary sphincterotomy may not be indispensable for endoscopic pancreatic sphincterotomy. Endoscopy. 1998;30(8):697-701.
22. Varadarajulu S, Wilcox CM. Randomized trial comparing needle-knife and pull-sphincterotome techniques for pancreatic sphincterotomy in high-risk patients. Gastrointestinal endoscopy. 2006;64(5):716-22.
23. Hookey LC, RioTinto R, Delhaye M, Baize M, Le Moine O, Deviere J. Risk factors for pancreatitis after pancreatic sphincterotomy: a review of 572 cases. Endoscopy. 2006;38(7):670-6.
24. Kozarek RA, Ball TJ, Patterson DJ, Brandabur JJ, Traverso LW, Raltz S. Endoscopic pancreatic duct sphincterotomy: indications, technique, and analysis of results. Gastrointestinal endoscopy. 1994;40(5):592-8.
25. Lehman GA, Sherman S, Nisi R, Hawes RH. Pancreas divisum: results of minor papilla sphincterotomy. Gastrointestinal endoscopy. 1993;39(1):1-8.
26. Vitale GC, Vitale M, Vitale DS, Binford JC, Hill B. Long-term follow-up of endoscopic stenting in patients with chronic pancreatitis secondary to pancreas divisum. Surgical endoscopy. 2007;21(12):2199-202.
27. Yamamoto N, Isayama H, Sasahira N, Tsujino T, Nakai Y, Miyabayashi K, et al. Endoscopic minor papilla balloon dilation for the treatment of symptomatic pancreas divisum. Pancreas. 2014;43(6):927-30.
28. Farnbacher MJ, Schoen C, Rabenstein T, Benninger J, Hahn EG, Schneider HT. Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and success. Gastrointestinal endoscopy. 2002;56(4):501-6.
29. Dumonceau JM, Costamagna G, Tringali A, Vahedi K, Delhaye M, Hittelet A, et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial. Gut. 2007;56(4):545-52.
30. Ohara H, Hoshino M, Hayakawa T, Kamiya Y, Miyaji M, Takeuchi T, et al. Single application extracorporeal shock wave lithotripsy is the first choice for patients with pancreatic duct stones. The American journal of gastroenterology. 1996;91(7):1388-94.
31. Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the management of chronic calcific pancreatitis: a meta-analysis. JOP : Journal of the pancreas. 2005;6(1):6-12.
32. Nguyen-Tang T, Dumonceau JM. Endoscopic treatment in chronic pancreatitis, timing, duration and type of intervention. Best practice & research Clinical gastroenterology. 2010;24(3):281-98.
33. Moole H, Jaeger A, Bechtold ML, Forcione D, Taneja D, Puli SR. Success of Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management: A Meta-Analysis and Systematic Review. Pancreas. 2016;45(5):651-8.
34. Lawrence C, Siddiqi MF, Hamilton JN, Keane TE, Romagnuolo J, Hawes RH, et al. Chronic calcific pancreatitis: combination ERCP and extracorporeal shock wave lithotripsy for pancreatic duct stones. Southern medical journal. 2010;103(6):505-8.
35. Lehman GA. Role of ERCP and other endoscopic modalities in chronic pancreatitis. Gastrointestinal endoscopy. 2002;56(6 Suppl):S237-40.
36. Seven G, Schreiner MA, Ross AS, Lin OS, Gluck M, Gan SI, et al. Long-term outcomes associated with pancreatic extracorporeal shock wave lithotripsy for chronic calcific pancreatitis. Gastrointestinal endoscopy. 2012;75(5):997-1004.e1.
37. Tandan M, Reddy DN, Talukdar R, Vinod K, Santosh D, Lakhtakia S, et al. Long-term clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific pancreatitis. Gastrointestinal endoscopy. 2013;78(5):726-33.
38. Tandan M, Reddy DN. Extracorporeal shock wave lithotripsy for pancreatic and large common bile duct stones. World journal of gastroenterology : WJG. 2011;17(39):4365-71.
39. Choi EK, McHenry L, Watkins JL, Sherman S, Fogel EL, Cote GA, et al. Use of intravenous secretin during extracorporeal shock wave lithotripsy to facilitate endoscopic clearance of pancreatic duct stones. Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al]. 2012;12(3):272-5.
40. Saghir SM, Mashiana HS, Mohan BP, Dhindsa BS, Dhaliwal A, Chandan S, et al. Efficacy of pancreatoscopy for pancreatic duct stones: A systematic review and meta-analysis. World J Gastroenterol. 2020;26(34):5207-19.
41. Arvanitakis M, Van Laethem JL, Parma J, De Maertelaer V, Delhaye M, Deviere J. Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with K-ras gene mutation. Endoscopy. 2004;36(6):535-42.
42. Muniraj T, Chari ST. Diabetes and pancreatic cancer. Minerva gastroenterologica e dietologica. 2012;58(4):331-45.
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.
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.
References
1. Dobbins JW, Sheahan DG, Behar J. Eosinophilic gastroenteritis with esophageal involvement. Gastroenterology. 1977; 72:1312–6.
2. Landres RT, Kuster GG, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology. 1978; 74:1298–1301.
3. Attwood SE, Smyrk TC, Demeester TR, Jones JB. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci. 1993; 38:109–16.
4. Straumann A, Spichtin HP, Bernoulli R, Loosli J, Vogtlin J. Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopicfindings. Schweiz Med Wochenschr. 1994; 124:1419–29.
5. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acidbased formula. Gastroenterology. 1995; 109:1503–12.
6. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342–1363.
7. Benninger MS, Strohl M, Holy CE, Hanick AL, Bryson PC. Prevalence of atopic disease in patients with eosinophilic esophagitis. Int Forum Allergy Rhinol. 2017;7(8):757-762.
8. Arias A, Perez-Martinez I, Tenias JM, Lucendo AJ. Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in populationbased studies. Aliment Pharmacol Ther. 2015. 43(1):3-15.
9. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al.14 Years of Eosinophilic Esophagitis: Clinical Features and Prognosis. J Pediatr Gastroenterol Nutr. 2009; 48(1):30-6.
10. Kottyan LC, Parameswaran S, Weirauch MT, Rothenberg ME, Martin LJ. The genetic etiology of eosinophilic esophagitis. J Allergy Clin Immunol. 2020. 145(1):9-15.
11. Alexander ES, Martin LJ, Collins MH, et al. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J Allergy Clin Immunol. 2014; 134(5).
12. Noti M, Wojno EDT, Kim BS, et al. Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat Med. 2013;19(8):1005-1013.
13. Aceves SS, Chen D, Newbury RO, Dohil R, Bastian JF, Broide DH. Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction. J Allergy Clin Immunol. 2010;126.
14. O’Shea KM, Aceves SS, Dellon ES, et al. Pathophysiology of eosinophilic esophagitis. Gastroenterology. 2018;154:333-345.
15. Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 2005;3(12):1198-206.
16. Baxi et al. Clinical presentation of patients with eosinophilic inflammation of the esophagus. Clin Endosc. 2012;64(4):473-478.
17. Straumann A, Bussmann C, Zuber M, Vannini S, Simon HU, Schoepfer A. Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients. Clin Gastroenterol Hepatol. 2008;6(5):598-600.
18. Schoepfer AM, Safroneeva E, Bussmann C, et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology. 2013;145(6):1230-6.
19. Dellon ES, Liacouras CA, Molina-Infante J, et al. Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology. 2018;155:1022–1033.
21. Prasad GA, Alexander JA, Schleck CD, et al. Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol. 2009;7:1055–1061.
22. Muller S, Puhl S, Vieth M, et al. Analysis of symptoms and endoscopic findings in 117 patients with histological diagnoses of eosinophilic esophagitis. Endoscopy. 2007;39:339–344.
23. Dellon ES 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.
24. Henderson C.J. Abonia J.P. King E.C. Putnam P.E. Collins M.H. Franciosi J.P., et al. Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2012; 129: 1570-1578
25. Kagalwalla A.F. Shah A. Li B.U. Sentongo T.A. Ritz S. Manuel-Rubio M., et al. Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet. J Pediatr Gastroenterol Nutr. 2011; 53: 145-149.
26. Gonsalves N. Yang G.Y. Doerfler B. Ritz S. Ditto A.M. Hirano I. Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology. 2012; 142: 1451-1455
27. Lucendo A.J. Arias A. Gonzalez-Cervera J. Yagüe-Compadre J.L. Guagnozzi D. Angueira T., et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease. J Allergy Clin Immunol. 2013; 131: 797-804
28. Molina-Infante J, Lucendo A. Dietary therapy for eosinophilic esophagitis. J Allergy Clin Immunol. 2019. 142(1): 41-47.
29. Kliewer et al. One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trial. Lancet Gastroenterol Hepatol. 2023 May;8(5):408-421.
30. Spergel JM et al. Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet. J Allergy Clin Immunol. 2012;130(2):461.
31. Henderson CJ et al. Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2012;129(6):1570.
32. Wolf WA, Jerath MR, Sperry SLW, Shaheen NJ, Dellon ES. Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2014;12(8):1272.
33. Eckmann JD, Ravi K, Katzka DA, et al. Efficacy of Atopy Patch Testing in Directed Dietary Therapy of Eosinophilic Esophagitis: A Pilot Study. Dig Dis Sci. 2018;63(3):694.
34. Molina-Infante J, Martin-Noguerol E, Alvarado-Arenas M, et al. Selective elimination diet based on skin testing has suboptimal efficacy for adult eosinophilic esophagitis. J Allergy Clin Immunol. 2012;130(5):1200-2.
35. Arias A, Gonzalez-Cervera J, Tenias JM, Lucendo AJ. Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology. 2014;146:1639-1648.
36. Dellon ES, Speck O, Woodward K, et al. Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol. 2013;108(12):1854-1860.
37. Cheng E, Zhang X, Huo X, et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut. 2013;62(6):824-832.
38. Rank MA, Sharaf RN, Furuta GT, et al. Technical review on the management of eosinophilic esophagitis: a report from the AGA Institute and the Joint Task Force on Allergy- Immunology Practice Parameters. Gastroenterology. 2020;158(6):1789-1810.
39. Lucendo AJ, Arias Á, Molina-Infante J. Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14(1):13-22.
40. Laserna-Mendieta EJ, Casabona S, Guagnozzi D, et al; EUREOS EoE CONNECT research group. Efficacy of proton pump inhibitor therapy for eosinophilic oesophagitis in 630 patients: results from the EoE connect registry. Aliment Pharmacol Ther. 2020;52(5):798-807.
41. O’Donnell S & O’Morain CA. Therapeutic benefits of budesonide in gastroenterology. Ther Adv Chronic Dis. 2010;1(4): 177–186.
42. Murali AR, Gupta A, Attar BM, Ravi V, Koduru P. Topical steroids in eosinophilic esophagitis: Systematic review and meta-analysis of placebo-controlled randomized clinical trials. J Gastroenterol Hepatol. 2016;31(6):1111-9.
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.
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 atlanticakurdica chewing gum for one month in patients with diabetic gastroparesis.23 The intervention group chewed 2-grams of Pistacia atlanticakurdica 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 atlanticakurdica 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.
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.
Biliary strictures are one of the most common pathologic processes encountered by therapeutic endoscopists. Understanding the etiology and endoscopic management of biliary strictures is critical. Biliary strictures vary widely in clinical presentation; their location in the biliary tree; and span benign, malignant, and indeterminate etiologies (Table 1). Although biliary strictures can be managed endoscopically, percutaneously, or surgically, the scope of this article will focus on endoscopic management via endoscopic retrograde cholangiopancreatography (ERCP). When an obstruction is identified, initiating a prompt evaluation to determine the cause, relieve the obstruction, and manage the underlying pathology are key steps. Here, we aim to review the ERCP technique and treatment paradigms used to manage a variety of biliary strictures based on location and etiology.
Clinical History, Symptoms, Laboratory Features, and Non-Invasive Imaging of a Biliary Stricture
While biliary strictures can result in a constellation of signs and symptoms, a thorough patient history often provides significant insight into the etiology of the stricture. For instance, a history of painless jaundice and weight loss in an elderly patient, suggests a malignant etiology. Alternatively, a history of inflammatory bowel disease may suggest primary sclerosing cholangitis (PSC). Other critical information includes a thorough family history, tobacco usage, and personal history of new-onset diabetes or pancreatitis, especially when malignancy is suspected. Additionally, understanding the chronicity of symptoms can, in some cases, help elucidate the cause of a stricture. A chronic presentation >3 months may indicate a benign/fibrotic stricture that has developed over time. If symptoms are rapidly progressive and without a predisposing event, a malignancy should be suspected.1 An acute presentation with a predisposing factor such as recent biliary surgery or liver transplant suggests a benign etiology such as an anastomotic stricture or post-operative ischemic stricture. Some benign biliary strictures, such as those related to IgG4-related disease or chronic pancreatitis, are inflammatory and may have fluctuating symptoms over time.1
Signs and symptoms that may be related to a biliary obstruction are non-specific and can include jaundice (most commonly), scleral icterus, pruritus, weight loss, anorexia, abdominal discomfort, nausea and vomiting.2 In certain cases, with advanced malignancies, patients may present with iron-deficiency anemia due to luminal bleeding. When evaluating liver function tests, biliary obstruction leads to an elevation in alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and ultimately conjugated hyperbilirubinemia. Chronic biliary obstruction can lead to vitamin K malabsorption and a prolonged prothrombin time.3 Although non-specific, and typically used for prognostic purposes, other indicators of biliary obstruction include elevated tumor markers carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). Neither CA19-9 nor CEA are sensitive or specific tests to be used for diagnosis alone and can be elevated in both benign and malignant biliary obstruction.4,5 However, marked elevations in CA19-9 >1000 IU are typically only seen in cancer or severe cholangitis.6 There may be elevations in other liver function tests including aspartate transaminase (AST) and alanine transaminase (ALT). Although non-specific, the R-factor can be used to differentiate hepatocellular from cholestatic liver injury. An R-factor <2 may indicate a cholestatic liver injury related to a biliary stricture.7 When determining the etiology of a stricture, in the appropriate clinical setting, the immunoglobulin G subfraction four level (IgG4) may be elevated. IgG4 elevations may be seen in autoimmune pancreatitis and IgG4-related cholangiopathy.
When initially faced with a jaundiced patient with elevated liver function tests, the recommended first imaging modality is typically a transabdominal ultrasound (US). Although US is highly sensitive for bile duct dilation and cholelithiasis, it is not ideal for identifying the specific etiology of a stricture. After US has demonstrated duct dilation, the next step in noninvasive imaging typically depends on clinical judgement. In some situations, the next imaging modality is computed tomography (CT) of the abdomen. CT, although useful for identifying and staging mass lesions as well as inflammatory processes, is not as sensitive as magnetic resonance cholangiopancreatography (MRCP).8 MRCP is the ideal non-invasive imaging modality to define stricture extent and location. MRCP is an excellent diagnostic tool, especially if tissue acquisition or direct invasive therapy is not needed. It provides the cross-sectional detail of CT plus sensitive cholangiographic images as a non-invasive and low-risk modality. Both CT and MRI can play roles in establishing surgical resectability, provide a vascular evaluation, and establish the best modality for tissue sampling and stenting.9 Studies have shown that the sensitivity and specificity of MRCP for the diagnosis of malignant strictures may even approach that of ERCP.10 For instance, MRCP has a sensitivity of 77%-86% and a specificity of 63%-98% for the diagnosis of malignant biliary obstruction caused by cholangiocarcinoma.10,11 Furthermore, MRCP often serves as a guide for future ERCP with stenting for intrahepatic and hilar strictures as well.9
Benign Strictures
Malignant Strictures
Post-Surgical/Iatrogenic Strictures: Post-Cholecystectomy Post-liver transplant or resection (anastomotic)
Metastatic Disease: Gastric Cancer Colon Cancer Breast Cancer Others
Chronic Pancreatitis
Lymphoma
Primary Sclerosing Cholangitis
Malignant Lymphadenopathy
IgG4-related Cholangiopathy
Various Rare Causes: Vasculitis Mrizzi syndrome Infectious (Tuberculosis, HIV cholangiopathy, parasitic) Radiation therapy Abdominal trauma Post-Radiofrequency Ablation
Table 1. Etiologies of Biliary Strictures
Benign Biliary Strictures
Overview and Role of ERCP
ERCP plays a key role in the management of benign biliary strictures (BBS). The most common cause of these strictures is typically post-surgical, usually after cholecystectomy or anastomotic strictures after liver transplant. Other common causes of benign biliary strictures include chronic pancreatitis, IgG4-related cholangiopathy, PSC, in addition to a variety of other rare etiologies. The scope of this section will focus on the endoscopic management of the most common causes of benign strictures due to iatrogenic surgical injury, anastomotic strictures, chronic pancreatitis, and IgG4-related disease. PSC-related strictures will be discussed in a separate section.
Therapeutic management of a benign stricture via stenting involves (1) traversing the stricture with a guidewire, (2) dilating the stricture in certain situations (Image 1), and finally (3) placing one or more biliary stents across the stricture (Image 2). After biliary cannulation, a cholangiogram is necessary to determine the length and location of the stricture. A complete sphincterotomy can be helpful as it allows for easy endoscopic access to the biliary tree, needed for instrument exchanges during the index ERCP and future endoscopic stent exchanges in the management of a BBS.16 It should be noted that not all patients require sphincterotomy for stricture management.
Studies have shown that although balloon dilation is immediately effective, either in single or multiple sessions, this modality alone is insufficient for durable duct patency and associated with a high rate of re-stenosis up to 47%.17-19 Therefore, stent placement is imperative to allow for stricture patency for a prolonged period to allow scar remodeling.20 A single plastic stent has not been shown to provide durable patency over the long term, although many go this route at the initial ERCP for expediency and this is within the standard of care.21 For refractory benign biliary strictures, studies have shown an effective method for long-term duct patency is the gradual placement of up-sized temporary plastic stents, with exchanges every 3-4 months, over the period of a year. Although this “multi-stenting strategy” requires multiple procedures, it is highly effective for benign biliary strictures, especially post-operative strictures.16,22 Recently, fully covered self-expandable metal stents (FCSEMS) have emerged as an excellent alternative to the “multi-stenting strategy,” potentially accomplishing dilation with a fewer number of ERCP for stent exchanges. A critical point is that uncovered stents should not be placed for benign strictures as tissue in-growth makes these stents irretrievable. Secondly, placing fully covered metal stents across the hilum can potentially obstruct or jail one side of the liver and should be avoided.22
Biliary Strictures after Liver Transplantation (LT)
Post-LT strictures can be anastomotic, occurring at the duct-to-duct connection between the donor duct and recipient duct, or non-anastomotic with an overall incidence of 5-32%.23-25 Anastomotic strictures comprise 80% of all post-LT biliary strictures.26 ERCP is first-line for the management of anastomotic biliary strictures and can also play a role in non-anastomotic strictures.
Prior to endoscopic intervention and when a biliary complication is suspected, cross-sectional imaging and hepatologic workup should be performed to rule out vascular complications (i.e., hepatic artery stenosis) or organ rejection. In patients with an anastomotic stricture (Image 3), standard ERCP treatment includes the multi-stenting strategy as described above with stricture dilation and multiple stent exchanges every 3-4 months. Studies have shown success rates of 70-80% in cases of orthotopic liver transplant and 60% in living-donor liver transplant with this strategy.27-31 Despite successful response to ERCP, the rate of cholestasis recurrence has been shown to be approximately 18%.32 The alternative approach is the placement of a single FCSEMS across the stricture, which has shown to be effective and shorten the duration of endoscopic treatment in patients with BBS.33-35 The stent is removed 3-6 months after placement. Although safe and feasible, disadvantages include the risk of stent migration and a stricture recurrence of 9-47% over 5 years of follow-up.36-38
Non-anastomotic strictures typically occur as a consequence of ischemia and, less commonly, a recurrence of the underlying hepatic dysfunction, such as PSC.39 Strictures in this scenario can be unifocal or multiple strictures can develop anywhere along the biliary tree. The role of ERCP is to preserve biliary patency until definitive treatment can be performed, such as re-transplantation. Several studies have shown the multi-stenting strategy can be useful with plastic stents, but have low success rates ranging from 50-75%.40
Post-Cholecystectomy Benign Biliary Strictures
There are numerous anatomic, vascular, inflammatory, and surgical causes that lead to benign biliary strictures after cholecystectomy, the incidence of which as increased with the transition to a laparoscopic approach.41 ERCP has replaced surgery due to its safety and high success rate in the management of these strictures as compared to surgery.42 Similar to the management of other benign strictures, the multi-stenting strategy with replacement of plastic stents every 3-4 months with possible dilation and up-sizing of stents has been the gold-standard, with increasing use of FCSEMs as well given their ease of use and excellent outcomes. Stent exchanges and dilations should continue until there is no fluoroscopic evidence of stricture. Long term success ranges from 80-100% with long-term durability.22 Although data with FCSEMS in this population is less robust, several studies33,35 have shown the efficacy of metal stents for BBS due to various etiologies.
Benign Biliary Strictures in Chronic Pancreatitis
In patients with advanced chronic pancreatitis (CP), up to 33% develop a biliary stricture but surprisingly overt jaundice is only seen in a minority of patients.43,44 There is no clear relationship between the degree of biliary obstruction with the severity or duration of chronic pancreatitis.44 Biliary compression caused by edema from ongoing inflammation or mass-effect by a pseudocyst typically improves with treatment of the underlying CP, but obstruction from a fibrotic stricture requires endoscopic intervention.
A multi-stenting strategy in chronic pancreatitis has a success rate of 44-92%.45-47 This success rate is lower than post-surgical biliary strictures due to the ongoing inflammation, calcification, and fibrosis associated with CP, particularly in the head of the pancreas.45-47 However, as opposed to post-cholecystectomy strictures, the data for FCSEMS is quite robust and these strictures may be particularly well-suited to FCEMS because CP-related strictures typically develop in the intrapancreatic portion of the common bile duct, which is easy to span with a short FCSEMS. Success rates of FCSEMS range from 43-77%.48,49 Anti-migration flaps were developed to these FCSEMS to overcome this disadvantage and these stents are now available commercially.50
IgG4-Related Autoimmune Cholangiopathy
Autoimmune, or IgG4-related cholangiopathy, can result in a BBS anywhere along the biliary tree mimicking hilar cholangiocarcinoma, pancreatic ductal adenocarcinoma, or even PSC. This entity is associated with autoimmune pancreatitis. Although it can be associated with an elevation in IgG4, serum levels can be normal as well,51making the diagnosis quite challenging. Oftentimes, the diagnosis is made in retrospect after a high-clinic suspicion and empiric steroid administration improves the biliary obstruction and imaging findings. When endoscopic intervention is needed, tissue acquisition by the methods described earlier followed by histologic staining for IgG4 plasma cells clinches the diagnosis.51 Temporary biliary stenting can also be useful to relieve the jaundice prior to initiation of steroid therapy.52
Malignant Biliary Strictures
Overview and Role of ERCP
Malignant strictures of the biliary tree are another common pathologic process encountered by therapeutic endoscopists. The most common presenting symptom is jaundice, and the most common underlying etiology is pancreatic adenocarcinoma. However, other etiologies include ampullary carcinoma, cholangiocarcinoma, gallbladder carcinoma, and metastatic disease (gastric, colon, malignant lymphadenopathy, melanoma, among others). The management of distal and hilar/intrahepatic biliary strictures vary in several key areas. The scope of this section is to discuss the various endoscopic techniques via ERCP and outcomes to provide diagnostic and therapeutic solutions to biliary strictures. As reviewed in the section on benign biliary strictures, the role of ERCP in malignant strictures also includes tissue acquisition and palliative stenting.
Distal Malignant Biliary Obstruction: Tissue Acquisition and Endoscopic Therapy
The most common cause of a distal or mid-bile duct malignant biliary obstruction (Image 4) is pancreatic adenocarcinoma, accounting for more than 90% of cases.53 Other causes include, ampullary carcinoma, cholangiocarcinoma, gallbladder carcinoma, and metastatic disease.
When faced with a malignant distal biliary obstruction, the first step is to establish a diagnosis and stage the malignancy. As described previously, CT and MRI can provide valuable data about vascular involvement, location and extent of the primary tumor, and distant metastasis (Image 5). While there are multiple modalities for tissue acquisition including percutaneous biopsy, and ERCP with brush cytology or cholangioscopy, EUS-guided biopsy has taken on a dominant role given its very high diagnostic success rate and low risk.
Beyond the potential role of cytology brushings, the primary role of therapeutic ERCP is palliative via biliary stent placement for obstructive jaundice. This can oftentimes be done simultaneously at the time of EUS FNA/B. ERCP is definitively indicated for non-surgical candidates with advanced malignancy causing biliary obstruction and has been shown to improve quality of life in this patient population.54 Patients with malignancy presenting with cholangitis should also undergo endoscopic stenting. Stenting is indicated in jaundiced patients prior to the initiation of potentially hepatotoxic chemotherapeutic agents or neoadjuvant chemoradiation.55 However, in potential surgical candidates with biliary obstruction, biliary stenting is controversial, particularly if surgery is to occur within a short term (weeks). There are some studies showing a benefit of pre-surgical drainage, whereas others demonstrate a higher rate of significant complications up to 4 months post-surgery (74% in stenting group [notably, only plastic stents used] vs. 39% in early surgery group).56,57 Currently, if surgery is planned within 1-2 weeks in an asymptomatic but jaundiced patient, biliary drainage may not be indicated. However, if the patient develops symptomatic obstruction or surgical intervention is planned for >3 weeks, a stent should be placed.58 In modern clinical practice, most patients with pancreatic cancer undergo neoadjuvant therapy and pre-operative stent placement is the norm.
Initially, the placement of a temporary, removable plastic stent is an effective and inexpensive first step. The stent should traverse about 1cm above the stricture proximally and about 1cm into the duodenum. As smaller diameter stents can get occluded or migrate, larger caliber stents (typically 10 French) are used for biliary patency and can be exchanged every 3-4 months.59 The primary disadvantages of plastic stents include stent occlusion (median 3-6 months) by the development of a bacterial biofilm60 requiring frequent exchanges and stent migration (in 10% of patients).61 Finally, once a plastic stent has been placed, we favor a scheduled stent exchange as it has shown to decrease the rate of adverse events as compared to as-needed stent exchange.62
SEMS are an excellent long-term option for the stenting of distal malignant strictures. As they are delivered in a sheath and expand after deployment, they can be delivered through the working channel of the duodenoscope and provide a diameter 3-4 times larger than plastic stents. This larger diameter stent results in a much more prolonged duration of stent patency compared to plastic stents, with a median of 9-12 months.63 Currently, SEMS are available as uncovered, partially covered, and fully covered designs. Although, there is no definitive data favoring one type of SEMS over another,64,65 they are superior to plastic stents for malignant biliary strictures,66 especially when longer-term pre-operative biliary drainage is required.67 When placed, SEMS seem more likely to cause post-ERCP pancreatitis than plastic stents, but no difference was seen between FCSEMS and uncovered SEMS.68 Adverse events related to SEMS include occlusion and migration. More specifically to FCSEMS, occlusion of the cystic duct and pancreatic duct can lead to cholecystitis and pancreatitis, respectively. Although FCSEMS tend to migrate more frequently than uncovered SEMS, two potential advantages of FCSEMS is that they are less likely to become occluded by tissue in-growth and they are easy to remove/exchange, if necessary.69 Uncovered SEMS become occluded via tumor in-growth and mucosal hyperplasia. This makes uncovered metal stents very difficult to remove and can lead to duct injury if the stent is pulled with mucosal/tumor in-growth.
When deciding which type of stent to place, there are pros and cons between covered SEMS, uncovered SEMS, and plastic stents. Although there are a multitude of individual variables including endoscopist preference, stent efficacy/durability, cost considerations, potential need for re-intervention, stricture location, and patient factors such as life expectancy that go into this decision, we aim to provide broad guidance. Foremost, SEMS provide long term patency as compared to plastic stents.70,71 One meta-analysis showed that although SEMS showed longer patency, there was no difference between metal and plastic stents when it came to therapeutic success, technical success, adverse events, and 30-day mortality.72 In the current financial climate, it must be noted that despite their longer patency, SEMS are significantly more expensive than plastic stents, however recent randomized controlled trials have demonstrated the cost-effectiveness of SEMS regardless of patient survival.72,73 When comparing covered versus uncovered SEMS for a distal biliary stricture, FCSEMS demonstrated longer patency but was found to have higher rates of stent migration and sludge formation.72,74 In general, most patients with malignant strictures will ultimately receive a SEMS of some type.
Although hilar and intrahepatic cholangiocarcinoma (CCA) will be discussed in the next section, for distal CCA survival is quite poor and surgical resection in patients without metastatic spread is the only curative option. If the patient is a poor surgical candidate, ERCP can be utilized for palliative relief of biliary obstruction with plastic or metal stents.75
Hilar and Intrahepatic Malignant Biliary Obstruction: Tissue Acquisition and Endoscopic Therapy
Cholangiocarcinoma is the most common cause of malignant biliary obstruction of the hilum and intrahepatic ducts. Cholangiocarcinoma can be divided into proximal (intrahepatic; incidence: 5-10% of CCAs), hilar (Klatskin tumors; incidence: 60-70% of CCAs), and distal (extrahepatic; incidence: 20-30%) subsets.76 Hilar CCA is classified according to the Bismuth-Corlette classification (Table 2) as described later in this section. As discussed in the next section, the most important risk factor for CCA is PSC.
Type
Malignant Strictures
I
Involving the common hepatic duct distal to the confluence
II
Involving the common hepatic duct confluence
IIIa
Involving the common hepatic duct confluence and right hepatic duct
IIIb
Involving the common hepatic duct confluence and left hepatic duct
IV
Involving the common hepatic duct confluence, right hepatic duct, and left hepatic duct
Table 2. Bismuth-Corlette Classification for Hilar Tumors
Other etiologies of hilar and intrahepatic malignant strictures include gallbladder carcinoma, primary liver tumors, portal lymphadenopathy, and metastatic disease. ERCP plays a key role in relieving malignant biliary stenosis of the hilum and survival has been shown to correlate with the percentage of liver segments drained.77 When evaluating and endoscopically treating tumors of the intrahepatic ducts or hilum, it is important to understand the segmental liver anatomy, the Bismuth-Corlette classification of hilar tumors, and normal variants.
In the liver, segments II, III, and IV make up the left hepatic lobe and ERCP typically drains segment II and III of the liver (large left intrahepatic duct). The right hepatic lobe, divided into the right anterior and right posterior intrahepatic ducts, is divided into segments V-VIII. The caudate lobe (segment I) is not typically drained by ERCP.78 Cancers in the perihilar region are classified by the Bismuth-Corlette classification which can help guide ERCP-guided palliative stent placement. The Bismuth classification has four types; Type 1 (tumors below the confluence of the left and right hepatic ducts), type 2 (tumors reaching the confluence of the right and left hepatic ducts), type 3 (tumors occluding the common hepatic duct and either the first radicals on the right [type 3a] or left [type 3b – Image 6] intrahepatic ducts), and type 4 (tumors that involve the major ducts and radicals of the both right and left intrahepatic ducts).79
As discussed previously, once typical symptoms and lab values indicate biliary obstruction, the next step is non-invasive radiographic imaging. MRCP is the ideal imaging modality for most hilar and intrahepatic malignancies. MRCP can recreate a three-dimensional view of the biliary system and note the location/extent of structuring to direct stent placement during ERCP.80 The next step is tissue acquisition.
When used as a diagnostic tool, ERCP-guided cytology brushings have been shown to have sensitivity of 35% to 69% and a specificity of 90%.13 These are widely employed given their very low cost to obtain. Given the suboptimal yield of brush cytology, newer tests to assess DNA proliferation have been developed. These include fluorescence in-situ hybridization (FISH), digital image analysis, and molecular profiling (MP) by flow cytometry. The combination of all 3 tests (cytology, FISH, and MP) had the highest sensitivity for malignancy (66%) and all three individually have been shown to improve the specificity of cytology.81-83 FISH is the test most commonly incorporated advanced analytic test with biliary brushings to enhance sensitivity. FISH uses fluorescent probes to label certain areas of chromosomes to determine cellular ploidy. Detection of more than five cells with polysomy is considered evidence of malignancy. These tests are further discussed in the section on indeterminate strictures. Obtaining direct tissue from the stricture can be accomplished via direct visualization with cholangioscopy or fluoroscopic-guided sampling with biopsy forceps. Although stricture biopsies can increase the diagnostic yield to 63%,14 directly visualized biopsy samples via cholangioscopy are better than those without cholangioscopy.84 Cholangioscopy is the most frequently utilized method for direct biopsy of hilar strictures and has demonstrated improved diagnostic accuracy.85 Visual impression accuracy with single-operator cholangioscopy for diagnosing malignancy has been reported to be as high as 95.1% (with 100% sensitivity and 89.5% specificity). Cholangioscope-guided biopsy accuracy was 80.5% (63.6% sensitivity and 100% specificity).86 Finally, studies have shown that cholangioscopy for evaluating intraductal spread in potentially resectable perihilar CCA can detect more extensive disease and change surgical management.86
Other methods of endoscopic sampling include endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Although EUS-FNA is commonly used for distal pancreatobiliary masses/strictures, EUS-FNA for hilar/intrahepatic lesions raises the concern for potential peritoneal tumor seeding from the needle tract.87 This is a particular concern for patients who are candidates for curative surgical resection or liver transplantation. In general, EUS-FNA sampling of a hilar stricture should not be performed due to this risk of seeding. However, EUS-guided lymph node biopsy can change management if positive for metastasis. Intraductal ultrasonography (IDUS) has fallen out of favor in recent years with improvements in cholangioscopy. These probes can be passed over a wire into the biliary system. IDUS can determine longitudinal tumor extent and vascular involvement.88 Finally, confocal laser endomicroscopy (CLE) probe can be advanced through a cholangioscope. CLE allows for in-vivo microscopic, subcellular evaluation of the biliary mucosa through the utilization of a lower-power laser detecting reflected fluorescent light from tissue. One study found significantly higher accuracy with CLE plus ERCP brushings versus ERCP brushings and tissue acquisition (90% vs. 73%).89 The learning curve and specialized equipment required for CLE have limited its utility.
Surgery (resection or liver transplantation) is the only curative option for hilar cholangiocarcinoma. Preoperative biliary drainage in a jaundiced patient with hilar cholangiocarcinoma has remained controversial as it may delay surgery and increase the risk of adverse events. One large study found no difference in mortality and a higher rate of adverse events/infection. However, in practice, pre-operative biliary drainage is often performed at the discretion of the surgeon.90
In nonoperative candidates with symptomatic biliary obstruction or to lower the bilirubin for chemotherapy, ERCP plays a role in palliative drainage. To resolve jaundice, only ~50% of the liver parenchyma needs to be drained.91 When preparing for ERCP for hilar/intrahepatic strictures, several important factors should be noted throughout the steps of the procedure. First, non-invasive imaging can help provide a roadmap for drainage and scans should be reviewed. Next, a sphincterotomy is important during the sentinel procedure to allow room for multiple stents, simplify endoscopic instrument exchanges, and make subsequent cannulations easier. When the stricture is encountered and there is a suspicion for malignancy, tissue sampling should be performed, ideally with more than one modality, but at minimum with cytology brushings. Antibiotics should be given at the time of procedure and possibly post-procedurally, at the discretion of the endoscopist. If possible, stricture dilation due to the methods described earlier in this article should be pursued followed by stent placement. Finally, it is critical to note that only viable segments of the hepatic parenchyma with dilated ducts should be drained with stenting. Stenting should not be attempted in diminutive, atrophic, or occluded ducts and contrast used judiciously in segments that cannot be drained.75,92
Stent choice for hilar and intrahepatic duct malignancy has been an extensively studied topic. First, in non-operative candidates, SEMS should be used over plastic stents. In patients where pre-operative stenting is pursued, plastic stents should be pursued.93 Similar to the advantages discussed earlier for SEMS, in hilar malignancies, SEMS have been shown to have longer patency, decreased risk of cholangitis, and higher success rates.66,94 Finally, as discussed previously, uncovered SEMS should be used when crossing the hilum due to the risk of covered stents obstructing adjacent biliary ducts. The placement of multiple stents can often be accomplished via a multiple guidewire technique wherein a wire is left in each segment to be drained followed by sequential stent placement. Several studies have evaluated bilateral versus unilateral stenting. When unilateral plastic, bilateral plastic, unilateral metal, and bilateral metal stenting was compared for malignant hilar strictures, Hu et al. found that, if technically possible, dual metal stent placement is a preferred palliation strategy, and unilateral metal stent placement is the second option.95 Alternatively, a recent systematic review and meta-analysis has demonstrated that unilateral and bilateral SEMS stenting techniques are comparable in terms of efficacy and safety for unresectable hilar malignancies.96 Overall, due to this mixed data of unilateral versus bilateral stenting (SEMS favored over plastic stents), endoscopist discretion in regard to the technical feasibility, resource availability, and patient prognosis often dictates which option is pursued.
In patients with unresectable cholangiocarcinoma, ERCP-guided tumor ablation therapies have been developed to improve the quality of life by tumor debulking and improving stent patency. Although the data is mixed and cost is significant, these two therapies include wire-guided radiofrequency ablation (RFA) and photodynamic therapy. RFA, although commonly used for Barrett’s esophagus, provides local heat therapy to CCA via endobiliary probes. Endobiliary RFA can be used for tumor debulking within the biliary tree97 and to open up occluded uncovered SEMS.98 Recent data suggests they may even improve survival prior to stent placement.97 Although, the heat applied by RFA leads to adverse events and limits its use, newer temperature-controlled RFA devices are being studied.99 Photodynamic therapy (PDT) is another ablation therapy which utilizes the administration of a photosensitizing agent activated by light to kill cancer cells. Although it had promising data with longer survival times, improved biliary drainage, and improved quality of life on initial studies100 or as neoadjuvant therapy for unresectable CCA,101 its use is limited due to adverse effects such as severe light sensitivity, which significantly impacted quality of life.
Biliary Strictures in Special Populations
Indeterminate Biliary Strictures
A crucial point when evaluating a biliary stricture is to determine whether it is benign or malignant as the treatment paradigms and prognosis differ significantly based on the underlying etiology. As described previously, the immediate next steps include obtaining an accurate history, laboratory testing, non-invasive imaging, tissue sampling, and ultimately relief of the obstruction. Although each of these steps can be accomplished in a variety of ways, ERCP plays a crucial role in tissue acquisition and the relief of obstruction.
As described earlier, there are certain signs and symptoms indicating biliary obstruction, most common of which is jaundice. Laboratory markers, specifically elevated total bilirubin and alkaline phosphatase further suggest obstruction. Serologic markers such as CA19-9, although non-specific, can contribute to characterization of an indeterminate stricture as benign or malignant. Non-invasive imaging again provides a roadmap for further, more invasive investigation. Ultimately, ERCP is the gold-standard for the characterization of biliary strictures, particularly extrahepatic strictures. Optimal evaluation of a stricture requires expert use of contrast to opacify the length and duct involvement strictures using pressure cholangiograms, a rotatable C-arm, and wire manipulation. Of note, cholangiographic interpretation during ERCP is inadequate to determine malignancy and strictures often interpreted to be benign are actually malignant.102 Cholangiographic predictors of malignancy include stricture length greater than 14mm, progressive structuring over time, abrupt “shelf-like” strictures, and intrahepatic duct dilation.102,103 After wire-guided access and stricture dilation, tissue acquisition can be pursued. As mentioned before, a combination of multiple modalities has been shown to improve yield. These methods have been discussed previously including brush cytology (at minimum), intraductal forceps biopsy, and confocal laser endomicroscopy. Flow cytometry, FISH, and digital image analysis (DIA) are additional methods of tissue evaluation. DIA uses a computerized assessment to identify and analyze the DNA content of cells. Although data is mixed104 and the analysis costly, recent data demonstrates that DIA provides a higher sensitivity identifying malignancy than standard cytology.105 Studies have demonstrated that FISH provides higher sensitivity (42.9% vs. 20.1%) than routine cytology with equivalent specificity.106,107 IDUS has also been extensively studied. Data has demonstrated its superior sensitivity and accuracy compared to cytology and biopsy sampling.108 However, IDUS has significant limitations including an inability to acquire tissue, its steep learning curve/difficult interpretation, and inability to evaluate distant disease hindering its routine use. Finally, as extensively discussed previously, direct sampling techniques with cholangioscopy provides an additional method of sampling.
Primary Sclerosing Cholangitis (PSC)
Primary sclerosing cholangitis (PSC) is a chronic inflammatory condition of the biliary tree characterized by structuring and dilation of the bile ducts with biliary obstruction. Over time PSC leads to chronic cholestasis and biliary cirrhosis, making liver transplantation the only cure. PSC also carries a risk of developing cholangiocarcinoma in 10-20% of patients.109 PSC is most commonly diagnosed by MRCP (Image 7) due to its excellent safety profile, high sensitivity, and specificity.110 The role of ERCP in PSC largely consists of tissue sampling and biliary intervention including stricture dilation and stenting. ERCP is largely indicated in PSC when there is evidence of symptomatic cholestasis, cholangitis, and to distinguish a dominant stricture from cholangiocarcinoma.
Certain critical points should be considered when treating a patient with PSC and a dominant stricture endoscopically. Data has shown that repeat endoscopy to maintain biliary patency may improve the survival of patients with PSC.111 A dominant stricture has been defined as a stricture >1.5mm diameter in the common bile duct, or >1mm in the left or right main hepatic ducts, but this definition is not universally accepted and others exist.112 About 36-57% of PSC patients that undergo ERCP have dominant strictures and patients can have multiple dominant strictures.113 Patients with a dominant stricture have poorer survival compared those without and the stricture may harbor CCA.113,114 Therefore, ERCP plays a key role in treating the stricture and ruling out malignancy. As always, biliary access is key via sphincterotomy and wire-placement. Prophylactic antibiotics are recommended at the time of the procedure and a few days post-procedurally.112 Rectal indomethacin should also be considered in PSC patients without contraindications to avoid post-ERCP pancreatitis.112
Dominant strictures should always be sampled at each ERCP procedure to rule out malignancy prior to endoscopic intervention. In patients with PSC with dominant strictures, malignancy is more likely if the stricture is greater than 1cm in length, located at the hilum, and have irregular borders.115 As discussed previously, numerous methods have been utilized to diagnose CCA in PSC including tumor markers (CA19-9, CEA), brush cytology, fine-needle aspiration, and forceps biopsy. These all carry a poor sensitivity despite a high specificity. Therefore, FISH is most commonly added to brush cytology specimens and increased specificity for CCA.116 In PSC, FISH has been shown to be superior to DIA and cytology for indeterminate strictures.106 Studies report that FISH combined with cytology can improve the sensitivity for malignant lesions to 45-59%, while keeping the specificity near 100%.117 One meta-analysis of the utility of FISH in PSC encompassing 8 studies noted sensitivity and specificity of 68% and 70%, respectively.118
Finally, numerous studies have evaluated stricture dilation versus stenting in PSC and the American Association for the Study of Liver Diseases (AASLD) recommends that biliary stricture dilation be the initial treatment for dominant strictures.119 However, the European Association for the Study of the Liver (EASL) leave the decision to the discretion of the endoscopist.112 Balloon dilation should be performed serially with gradual dilation 1-4 weeks apart. Studies have shown improvement in both biliary obstruction and transplant-free survival.112,120 Stent placement has been reserved for when biliary dilation is inadequate or not durable. Stent placement has been associated with higher rates of adverse events including cholangitis and bile duct perforation in some older studies, but in practice is widely performed.111,121 One study comparing dilation versus dilation plus stenting demonstrated no benefit to stenting after dilation, an increased need for procedures, and a higher adverse event rate in the stent group.122 Finally, the multicenter, randomized DILSTENT trial demonstrated that short-term stents were not superior to balloon dilation and associated with a significantly higher occurrence of complications.123 When stenting is indicated (Image 8), some authors have advocated for short-term stent duration of 1-2 weeks with either a 10-French stent for an extrahepatic duct stricture or two 7-French stents for hilar strictures.112,124 No benefit has been shown for longer duration stenting in some studies, but in practice many PSC patients do become stent dependent and require long term stenting to good effect.113
Conclusion
ERCP has been used to manage biliary pathology since the 1970s. However, over the last 20 years, the diagnosis and treatment of benign, malignant, and indeterminate biliary strictures has evolved significantly. There has been a refinement of techniques and novel treatments developed. ERCP provides a minimally invasive, safe, and feasible treatment option for the management of biliary strictures, one of the most common pathologic processes encountered by therapeutic endoscopists. The paradigm shifts in management that have occurred over this time frame parallel advances in endoscopic technology and tools. The improvements made in biliary wires, adjunct devices such as cytology brushes and dilating balloons, cholangioscopy, and stent development have made ERCP a first-line treatment for the diagnosis and treatment of biliary strictures. As endoscopic technology evolves with the impending arrival of biodegradable stents, artificial intelligence, and endoscopic robotics, the management of biliary strictures will continue to progress. Continued efforts in training highly skilled and capable endoscopists are key to ensure that our patients receive the highest-quality care.
References
1. Peterson sBret T. Indeterminate Biliary Strictures. In: Baron TH, Kozarek RA, Carr-Locke DL, ed. ERCP: Third Edition. Philadelphia, PA: Elsevier; 2019:394-404.
2. Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol. 2005;7(5):189-197.
3. Papadopoulos V, Filippou D, Manolis E, Mimidis K. Haemostasis impairment in patients with obstructive jaundice. J Gastrointestin Liver Dis. 2007;16(2):177-186.
4. Viterbo D, Gausman V, Gonda T. Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy. World J Gastrointest Endosc. 2016;8(3):128-142.
5. Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology. 2005;128(6):1655-1667.
6. Grunnet M, Mau-Sørensen M. Serum tumor markers in bile duct cancer–a review. Biomarkers. 2014;19(6):437-443.
7. Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272-276.
8. Jhaveri KS, Hosseini-Nik H. MRI of cholangiocarcinoma. J Magn Reson Imaging. 2015;42(5):1165-1179.
9. Freeman ML, Overby C. Selective MRCP and CT-targeted drainage of malignant hilar biliary obstruction with self-expanding metallic stents. Gastrointest Endosc. 2003;58(1):41-49.
10. Rösch T, Meining A, Frühmorgen S, et al. A prospective comparison of the diagnostic accuracy of ERCP, MRCP, CT, and EUS in biliary strictures. Gastrointest Endosc. 2002;55(7):870-876.
11. Guibaud L, Bret PM, Reinhold C, et al. Bile duct obstruction and choledocholithiasis: diagnosis with MR cholangiography. Radiology 1995;197:109-15.
12. Tabibian JH, Macura SI, O’Hara SP, et al. Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography. Lab Invest. 2013;93(6):733-743.
13. de Bellis M, Sherman S, Fogel EL, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (Part 2). Gastrointest Endosc. 2002;56(5):720-730.
14. Ponchon T, Gagnon P, Berger F, et al. Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc. 1995;42(6):565-572.
15. Navaneethan U, Hasan MK, Kommaraju K, et al. Digital, single-operator cholangiopancreatoscopy in the diagnosis and management of pancreatobiliary disorders: a multicenter clinical experience (with video). Gastrointest Endosc 2016;84:649–55.
16. Costamagna G, Boskoski I, Familiari P. Benign Biliary Strictures. In: Baron TH, Kozarek RA, Carr-Locke DL, ed. ERCP: Third Edition. Philadelphia, PA: Elsevier; 2019:417-421.
17. P Draganov, B Hoffman, W Marsh, et al.: Long-term outcome in patients with benign biliary strictures treated endoscopically with multiple stents. Gastrointest Endosc. 55:680-686 2002
18. PG Foutch, MV Sivak Jr: Therapeutic endoscopic balloon dilatation of the extrahepatic biliary ducts. Am J Gastroenterol. 80:575-580 1985
19. MT Smith, S Sherman, GA Lehman: Endoscopic management of benign strictures of the biliary tree. Endoscopy. 27:253-266 1995
20. C Berkelhammer, P Kortan, GB Haber: Endoscopic biliary prostheses as treatment for benign postoperative bile duct strictures. Gastrointest Endosc. 35:95-101 1989
21. PG van Boeckel, FP Vleggaar, PD Siersema: Plastic or metal stents for benign extrahepatic biliary strictures: a systematic review. BMC Gastroenterol. 9:96-111 2009
22. G Costamagna, A Tringali, M Mutignani, et al.: Endotherapy of postoperative biliary strictures with multiple stents: results after more than 10 years of follow-up. Gastrointest Endosc. 72:551-557 2010
23. A Maheshwari, W Maley, Li Z, et al.: Biliary complications and outcomes of liver transplantation from donors after cardiac death. Liver Transpl. 13:1645-1653 2007 18044778
24. S Sharma, A Gurakar, N Jabbour: Biliary strictures following liver transplantation: past, present and preventive strategies. Liver Transpl. 14:759- 769 2008 18508368
25. JH Tabibian, M Girotra, HC Yeh, et al.: Sirolimus based immunosuppression is associated with need for early repeat therapeutic ERCP in liver transplant patients with anastomotic biliary stricture. Ann Hepatol. 12:563- 569 2013 23813134
26. S Thethy, BN Thomson, H Pleass, et al.: Management of biliary tract complications after orthotopic liver transplantation. Clin Transplant. 18:647-653 2004
27. J Fatima, JG Barton, TE Grotz, et al.: Is there a role for endoscopic therapy as a definitive treatment for post-laparoscopic bile duct injuries?. J Am Coll Surg. 211:495-502 2010
28. MT Perera, A Monaco, MA Silva, et al.: Laparoscopic posterior sectoral bile duct injury: the emerging role of nonoperative management with improved long-term results after delayed diagnosis. Surg Endosc. 25:2684- 2691 2011
29. Li J, A Frilling, S Nadalin, et al.: Surgical management of segmental and sectoral bile duct injury after laparoscopic cholecystectomy: a challenging situation. J Gastrointest Surg. 14:344-351 2010
30. T Rustagi, HR Aslanian: Endoscopic management of biliary leaks after laparoscopic cholecystectomy. J Clin Gastroenterol. 48:674-678 2014
31. AJ Kaffes, L Hourigan, N De Luca, et al.: Impact of endoscopic intervention in 100 patients with suspected postcholecystectomy bile leak. Gastrointest Endosc. 61:269 2005
32. WM Alazmi, EL Fogel, JL Watkins, et al.: Recurrence rate of anastomotic biliary strictures in patients who have had previous successful endoscopic therapy for anastomotic narrowing after orthotopic liver transplantation. Endoscopy. 38:571-574 2006
33. GA Coté, A Slivka, P Tarnasky, et al.: Effect of covered metallic stents compared with plastic stents on benign biliary stricture resolution: a randomized clinical trial. JAMA. 315:1250-1257 2016
34. AO Tal, F Finkelmeier, N Filmann, et al.: Multiple plastic stents versus covered metal stent for treatment of anastomotic biliary strictures after liver transplantation: a prospective, randomized, multicenter trial. Gastrointest Endosc.
35. J Devière, D Nageshwar Reddy, A Püspök, et al.: Benign Biliary Stenoses Working Group. Successful management of benign biliary strictures with fully covered self-expanding metal stents. Gastroenterology. 147:385-395 2014
36. U Chaput, O Scatton, B Bichard, et al.: Temporary placement of partially covered self-expandable metal stents for anastomotic biliary strictures after liver transplantation: a prospective, multicenter study. Gastrointest Endosc. 72:1167-1174 2010
37. I Tarantino, M Traina, F Mocciaro, et al.: Fully covered metallic stents in biliary stenosis after orthotopic liver transplantation. Endoscopy. 44:246- 250 2012
38. I Tarantino, L Barresi, G Curcio, et al.: Definitive outcomes of self-expandable metal stents in patients with refractory post-transplant biliary anastomotic stenosis. Dig Liver Dis. 47:562-565 2015
39. CI Buis, RC Verdonk, EJ Van der Jagt, et al.: Nonanastomotic biliary strictures after liver transplantation, part 1: Radiological features and risk factors for early vs. late presentation. Liver Transpl. 13:708-718 2007
40. IW Graziadei, H Schwaighofer, R Koch, et al.: Long-term outcome of endoscopic treatment of biliary strictures after liver transplantation. Liver Transpl. 12:718-725 2006
41. Nuzzo, F Giuliante, I Giovannini, et al.: Bile duct injury during laparoscopic cholecystectomy: results of an Italian national survey on 56 591 cholecystectomies. Arch Surg. 140:986-992 2005
42. G Costamagna, M Pandolfi, M Mutignani, et al.: Long-term results of endoscopic management of postoperative bile duct strictures with increasing numbers of stents. Gastrointest Endosc. 54:162-168 2001
43. G Angelini, D Sgarbi, A Castagnini, et al.: Common bile duct involvement in chronic pancreatitis. Ital J Gastroenterol. 26:79-82 1994 8032082
44. TH Baron Sr, T Davee: Endoscopic management of benign bile duct strictures. Gastrointest Endosc Clin N Am. 23:295-311 2013
45. MF Catalano, JD Linder, S George, et al.: Treatment of symptomatic distal common bile duct stenosis secondary to chronic pancreatitis: comparison of single vs. multiple simultaneous stents. Gastrointest Endosc. 60:945-952 2004
46. J Pozsar, P Sahin, F Laszlo, et al.: Medium-term results of endoscopic treatment of common bile duct strictures in chronic calcifying pancreatitis with increasing numbers of stents. J Clin Gastroenterol. 38:118-123 2004
47. JM Regimbeau, D Fuks, E Bartoli, et al.: A comparative study of surgery and endoscopy for the treatment of bile duct stricture in patients with chronic pancreatitis. Surg Endosc. 26:2902-2908 2012
48. M Kahaleh, B Behm, BW Clarke, et al.: Temporary placement of covered self-expandable metal stents in benign biliary strictures: a new paradigm? (with video). Gastrointest Endosc. 67:446-454 2008
49. V Perri, I Boskoski, A Tringali, et al.: Fully covered self-expandable metal stents in biliary strictures caused by chronic pancreatitis not responding to plastic stenting: a prospective study with 2 years of follow-up. Gastrointest Endosc. 75:1271-1277 2012
50. DH Park, SS Lee, TH Lee, et al.: Anchoring flap versus flared end, fully covered self-expandable metal stents to prevent migration in patients with benign biliary strictures: a multicenter, prospective, comparative pilot study (with videos). Gastrointest Endosc. 73:64-70 2011
51. KV Chathadi, V Chandrasekhara, RD Acosta, et al.: The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 81:795-803 2015
52. T Itoi, T Kamisawa, Y Igarashi, et al.: The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis. J Gastroenterol. 48:504-514 2013
53. M Kitano, Y Yamashita, K Tanaka, et al.: Covered self-expandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreaticcarcinoma: a randomized multicenter trial. Am J Gastroenterol. 108:1713-1722 2013
54. Abraham NS, Barkun JS, Barkun AN. Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life. Gastrointest Endosc. 2002;56(6):835-841.
55. EA Bonin, TH Baron: Preoperative biliary stents in pancreatic cancer. J Hepatobiliary Pancreat Sci. 18:621-629 2011
56. NA van der Gaag, EA Rauws, CH van Eijck, et al.: Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med. 362:129- 137 2010 20071702
57. TH Baron, RA Kozarek: Preoperative biliary stents in pancreatic cancer— proceed with caution. N Engl J Med. 362:170-172 2010
58. JH Lee: Self-expandable metal stents for malignant distal biliary strictures. Gastrointest Endosc Clin N Am. 21:463-480 2011
59. AG Speer, P Cotton, KD MacRea: Endoscopic management of malignant biliary obstruction: stents of 10 French gauge are preferable to stents of 8 French gauge. Gastrointest Endosc. 34:412-417 1988
60. Baron TH. Palliation of malignant obstructive jaundice. Gastroenterol Clin North Am 2006;35:101-12.
61. JF Johanson, MJ Schmalz, JE Geenen: Incidence and risk factors for biliary and pancreatic stent migration. Gastrointest Endosc. 38:341-346 1992
62. F Prat, O Chapat, B Ducot, et al.: A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc. 47:1-7 1998
63. M Kaassis, J Boyer, R Dumas, et al.: Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc. 57:178-182 2003
64. Moole H, Bechtold ML, Cashman M, et al. Covered versus uncovered self-expandable metal stents for malignant biliary strictures: A meta-analysis and systematic review. Indian J Gastroenterol. 2016;35(5):323-330.
65. C Luigiano, F Ferrara, V Cennamo, et al.: A comparison of uncovered metal stents for the palliation of patients with malignant biliary obstruction: nitinol vs. stainless steel. Dig Liver Dis. 44:128-133 2012
66. Sawas T, Al Halabi S, Parsi MA, et al. Self-expandable metal stents versus plastic stents for malignant biliary obstruction: a meta-analysis. Gastrointest Endosc 2015;82:256–67.e7
67. Tol JAMG, van Hooft JE, Timmer R, et alMetal or plastic stents for preoperative biliary drainage in resectable pancreatic cancerGut 2016;65:1981- 1987.
68. GA Cote, N Kumar, M Ansstas, et al.: Risk of post-ERCP pancreatitis with placement of self-expandable metallic stents. Gastrointest Endosc. 72:748-754 2010
69. G Costamagna, M Pandolfi: Endoscopic stenting for biliary and pancreatic malignancies. J Clin Gastroenterol. 38:59-67 2004
70. W Ridtitid, R Rerknimitr, A Janchai, et al.: Outcome of second interventions for occluded metallic stents in patients with malignant biliary obstruction. Surg Endosc. 24:2216-2220 2010
71. Chu D, D Adler: Malignant biliary tract obstruction: evaluation and therapy. J Natl Compr Canc Netw. 8:1033-1044 2010
72. A Saleem, CL Leggett, H Murad, et al.: Meta-analysis of randomized trials comparing the patency of covered and uncovered self-expandable metal stents for palliation of distal malignant bile duct obstruction. Gastrointestinal Endosc. 74:321-327 2011
73. D Walter, PG van Boeckel, MJ Groenen, et al.: Cost efficacy of metal stents for palliation of extrahepatic bile duct obstruction in a randomized controlled trial. Gastroenterology. 149:130-138 2015
74. IS Grimm, TH Baron: Biliary stents for palliation of obstructive jaundice: choosing the superior endoscopic management strategy. Gastroenterology. 149:20-22 2015
75. MA Anderson, V Appalaneni, et al. The role of endoscopy in the evaluation and treatment of patients with biliary neoplasia. Gastrointest Endosc. 2013;77(2):167-174.
76. A Bergquist, E von Seth: Epidemiology of cholangiocarcinoma. Best Pract Res Clin Gastroenterol. 29:221-232 2015
77. Caillol F, Bories E, Zemmour C, et al. Palliative endoscopic drainage of malignant stenosis of biliary confluence: Efficiency of multiple drainage approach to drain a maximum of liver segments. United European Gastroenterol J. 2019;7(1):52-59.
78. LH Blumgart, Y Fong, T Akhurst, et al.: Surgery of the Liver and Biliary Tract. 3rd ed 2000 W.B. Saunders New York
79. H Bismuth, R Nakache, T Diamond: Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. 215:31-38 1992
80. T Hennedige, SK Venkatesh: Imaging of hepatocellular carcinoma: diagnosis, staging and treatment monitoring. Cancer Imaging. 12:530-547 2012
81. Liew ZH, Loh TJ, Lim TKH, et al. Role of fluorescence in situ hybridization in diagnosing cholangiocarcinoma in indeterminate biliary strictures. J Gastroenterol Hepatol. 2018;33(1):315-319.
82. Kushnir VM, Mullady DK, Das K, et al. The Diagnostic Yield of Malignancy Comparing Cytology, FISH, and Molecular Analysis of Cell Free Cytology Brush Supernatant in Patients with Biliary Strictures Undergoing Endoscopic Retrograde Cholangiography (ERC): A Prospective Study. J Clin Gastroenterol. 2019;53(9):686-692.
83. TH Baron, GC Harewood, A Rumalla, et al.: A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2:214-219 2004
84. Y Fukuda, T Tsuyuguchi, Y Sakai, et al.: Diagnostic utility of peroral cholangioscopy for various bile-duct lesions. Gastrointest Endosc. 62:374- 382 2005
85. AA Siddiqui, V Mehendiratta, W Jackson, et al.: Identification of cholangiocarcinoma by using the Spyglass spyscope system for peroral cholangioscopy and biopsy collection. Clin Gastroenterol Hepatol. 10:466-471 2012
86. Pereira P, Santos S, Morais R, et al. Role of Peroral Cholangioscopy for Diagnosis and Staging of Biliary Tumors. Dig Dis. 2020;38(5):431-440.
87. JK Heimbach, W Sanchez, CB Rosen, et al.: Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB. 13:356-360 2011
88. Sun B, Hu B. The role of intraductal ultrasonography in pancreatobiliary diseases. Endosc Ultrasound. 2016;5(5):291-299.
89. A Meining, Chen YK, D Pleskow, et al.: Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc. 74:961-968 2011
90. Liu F, Li Y, Wei Y, et al.: Preoperative biliary drainage before resection for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis Sci. 56:663-672 2011
91. A Schmassmann, E von Gunten, J Knuchel, et al.: Wallstents versus plastic stents in malignant biliary obstruction: effects of stent patency of the first and second stent on patient compliance and survival. Am J Gastroenterol. 91:654-659 1996
92. A Sarkisian, R Sharaiha. Malignant Biliary Obstruction of the Hilum and the Proximal Bile Ducts. In: Baron TH, Kozarek RA, Carr-Locke DL, ed. ERCP: Third Edition. Philadelphia, PA: Elsevier; 2019:385-393
93. RA Kozarek: Malignant hilar strictures: one stent or two? Plastic versus self-expanding metal stents? The role of liver atrophy and volume assessment as a predictor of survival in patients undergoing endoscopic stent placement. Gastrointest Endosc. 72:736-738 2010
94. Hong W, Sun X, Zhu Q: Endoscopic stenting for malignant hilar biliary obstruction: should it be metal or plastic and unilateral or bilateral?. Eur J Gastroenterol Hepatol. 25:1105-1112 2013
95. Xia MX, Cai XB, Pan YL, et al. Optimal stent placement strategy for malignant hilar biliary obstruction: a large multicenter parallel study. Gastrointest Endosc. 2020;91(5):1117-1128.e9.
96. Aghaie Meybodi M, Shakoor D, Nanavati J, et al. Unilateral versus bilateral endoscopic stenting in patients with unresectable malignant hilar obstruction: a systematic review and meta-analysis. Endosc Int Open. 2020;8(3):E281-E290.
97. RZ Sharaiha, N Natov, KS Glockenberg, et al.: Comparison of metal stenting with radiofrequency ablation versus stenting alone for treating malignant biliary strictures: is there an added benefit?. Dig Dis Sci. 59:3099-3102 2014
98. JE Eaton, EG Barr Fritcher, GJ Gores, et al.: Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 110:299-309 2015
99. Lee YN, Jeong S, Choi HJ, et al. The safety of newly developed automatic temperature-controlled endobiliary radiofrequency ablation system for malignant biliary strictures: A prospective multicenter study. J Gastroenterol Hepatol. 2019;34(8):1454-1459.
100. ME Ortner, K Caca, F Berr, et al.: Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 125:1355-1363 2003
101. S Shimizu, T Nakazawa, K Hayashi, et al.: Photodynamic therapy using talaporfin sodium for the recurrence of cholangiocarcinoma after surgical resection. Intern Med. 54:2321-2326 2015
102. VG Bain, N Abraham, GS Jhangri, et al.: Prospective study of biliary strictures to determine the predictors of malignancy. Endoscopy. 14:397- 402 2000
103. RL MacCarty, NF LaRusso, GR May, et al.: Cholangiocarcinoma complicating primary sclerosing cholangitis: cholangiographic appearances. Radiology. 156:43-46 1985
104. TH Baron, GC Harewood, A Rumalla, et al.: A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2:214-219 2004
105. Helmy A, Saad Eldien HM, Seifeldein GS, et al. Digital Image Analysis has an Additive Beneficial Role to Conventional Cytology in Diagnosing the Nature of Biliary Ducts Stricture. J Clin Exp Hepatol. 2021; 11(2):209-218
106. EG Fritcher, BR Kipp, KC Halling: A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures. Gastroenterology. 36:2180-2186 2009
107. M Smoczynski, A Jablonska, A Matyskiel, et al.: Routine brush cytology and fluorescence in situ hybridization for assessment of pancreatobiliary strictures. Gastrointest Endosc. 75:65-73 2012
108. MJ Levy, TH Baron, AC Clayton, et al.: Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol. 103:1263-1273 2008
109. S Rizvi, JE Eaton, GJ Gores: Primary sclerosing cholangitis as a premalignant biliary tract disease: surveillance and management. Clin Gastroenterol Hepatol. 13:2152-2165 2015
110. Moff SL, Kamel IR, Eustace J, et al. Diagnosis of primary sclerosing cholangitis: a blinded comparative study using magnetic resonance cholangiography and endoscopic retrograde cholangiography. Gastrointest Endosc. 2006;64:219–223.
111. M Gluck, NR Cantone, JJ Brandabur, et al.: A twenty-year experience with endoscopic therapy for symptomatic primary sclerosing cholangitis. J Clin Gastroenterol. 42:1032-1039 2008
112. Aabakken L, Karlsen TH, Albert J, et al. Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline. Endoscopy. 2017;49(6):588-608.
113. Tischendorf JJ, Hecker H, Krüger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study. Am J Gastroenterol. 2007;102(1):107-114.
114. Chapman MH, Webster GJ, Bannoo S, Johnson GJ, Wittmann J, Pereira SP. Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience. Eur J Gastroenterol Hepatol. 2012;24(9):1051-1058.
115. JJW Tischendorf, M Kruger, C Trautwein, et al.: Cholangioscopic characterization of dominant bile duct stenosis in patients with primary sclerosing cholangitis. Endoscopy. 38:665-669 2006
116. JE Eaton, EG Barr Fritcher, GJ Gores, et al.: Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 110:299-309 2015
117. Gonda TA, Glick MP, Sethi A, et al. Polysomy and p16 deletion by fluorescence in situ hybridization in the diagnosis of indeterminate biliary strictures. Gastrointest Endosc. 2012;75(1):74-79.
118. U Navaneethan, B Njei, PGK Venkatesh, et al.: Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc. 79:943-950 2014 e3
119. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–678.
120. Gotthardt DN, Rudolph G, Klöters-Plachky P, Kulaksiz H, Stiehl A. Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment. Gastrointest Endosc. 2010;71(3):527- 534.
121. S Singh, JA Talwalkar: Primary sclerosing cholangitis: diagnosis, prognosis, and management. Clin Gastroenterol Hepatol. 11:898-907 2013
122. Kaya M, Petersen BT, Angulo P, et al. Balloon dilation compared to stenting of dominant strictures in primary sclerosing cholangitis. Am J Gastroenterol. 2001;96(4):1059-1066.
123. Ponsioen CY, Arnelo U, Bergquist A, et al. No Superiority of stents vs balloon dilatation for dominant strictures in patients with primary sclerosing cholangitis. Gastroenterology. 2018;155:752–759 (e5).
124. CH Chan, JJ Telford: Endoscopic management of benign biliary strictures. Gastrointest Endosc Clin N Am. 22:511-537 2012
In esophageal cancer, an esophagectomy may be used as curative treatment in early stages or in conjunction with chemotherapy and radiation in more advanced stages of disease. Malnutrition is prevalent before and after an esophagectomy and is associated with increased postoperative complications and decreased survival. Traditionally, postoperative diet advancement after esophagectomy has been delayed for fear of eating with a newly created upper gastrointestinal anastomosis. However, early oral feeding protocols are becoming more commonplace. The placement of an intraoperative jejunostomy feeding tube is often performed to secure a reliable route for nutrition and hydration. Multidisciplinary nutritional care before and after an esophagectomy is important to help prevent and address nutrition concerns that may arise. This review will discuss some of the most important nutritional considerations for patients with esophageal cancer undergoing esophagectomy.
Case-Preoperative Course
A 70-year-old male with clinical stage III esophageal cancer and recent completion of chemoradiation presented to the thoracic surgery clinic for consideration of an esophagectomy. Before and during his initial treatment, he experienced an unintentional weight loss of 45 lbs. from his usual body weight of 185 lbs., which resulted in a nadir of 140 lbs. After completion of his chemoradiation, he achieved a 15 lbs. weight gain to reach 155 lbs. The patient was admitted for surgery and underwent an Ivor Lewis esophagectomy (ILE) with intraoperative placement of a jejunostomy feeding tube (J-tube).
Introduction
Esophageal cancer accounts for 1.1% of new cancer cases annually in the United States.1 The majority of malignant esophageal neoplasms stem from the histological type of adenocarcinoma or squamous cell carcinoma and treatment regimens may include chemotherapy, radiation, and/or surgery.1 Due to the nature of the pathologies necessitating esophageal resection, patients undergoing surgical resection with an esophagectomy have a complex array of nutritional needs and considerations. These patients are often malnourished at the time of diagnosis and the duration of this malnutrition is frequently chronic. The perioperative and long-term nutritional needs for these patients present unique challenges, underscoring the need for a good partnership between the surgeon and registered dietitian (RD). Using a case-based approach, this review will discuss the esophagectomy procedure, potential nutrition and surgical complications, and nutritional interventions for these complex patients.
Fundamentals of the Esophagectomy Procedure
Esophagectomy is the surgical resection of the esophagus by removing the distal esophagus and the proximal stomach.2 Gastrointestinal (GI) reconstruction requires repurposing the remaining stomach to act as the new “esophagus” or “conduit,” which is then connected to the proximal esophagus (See Figure 1). Most esophagectomies are performed for malignancies at the esophagus and gastroesophageal junction. However, occasionally the procedure is performed for benign conditions such as end-stage achalasia, caustic injury, and trauma. In most cases, immediate reconstruction is performed to reestablish continuity of the GI tract, but occasionally in the acute setting for caustic and other traumatic injuries, delayed reconstruction is performed.
The method of esophagectomy can be broadly divided into transthoracic or transhiatal surgical approaches, the main difference being whether the chest is entered during surgery (transthoracic) or not (transhiatal).3 The decision regarding what approach to undergo largely depends on the disease process, tumor location and surgeon preference. There is no consensus for the best approach and typically the surgeon uses clinical judgment based on the individual needs of the patient.
The stomach is the preferred reconstructive conduit to replace the esophagus in most cases, as a gastric conduit is easy to create, is generally less susceptible to ischemia, and requires only one surgical anastomosis. In cases where the stomach is not available for a conduit, such as prior injury or surgery, other conduit options include the colon or jejunum.4 Colonic or jejunal conduits are more prone to ischemia, however.
Preoperative Nutrition Evaluation
Poor nutritional status due to arising symptoms, such as dysphagia often caused by obstruction of the esophageal lumen by tumor, is associated with an increase in postoperative complications as well as decreased tolerance of chemotherapy.5,6 Compared to other cancers, patients with esophageal cancer are at a higher risk of weight loss on presentation, with the majority (>60%) presenting with severe malnutrition and an average weight loss of 10-15% from baseline.7,8 A significant reduction in overall survival has been reported in patients with esophageal cancer who have lost ³10% of their baseline weight by the time of surgery.9
Oral intake in patients presenting to the clinic with an esophageal mass for consideration of surgery is often found to have been suboptimal for weeks to months. Early nutritional assessment of patient tolerance to oral intake (solids vs. soft foods vs. liquids), extent of weight loss, presence of dysphagia, current appetite, with utilization of physical assessment of fat and muscle wasting helps guide nutritional therapy. The RD can work with the patient to improve oral intake by using oral nutrition supplements (ONS), modifying the consistency of food, and educating on increased caloric intake. However, in patients with signs of malnutrition or unable to make changes in diet, it is likely advantageous to establish enteral access preoperatively for supplemental feeding.10
It is important to consider if a patient is undergoing chemoradiation treatment before surgical restaging, as these treatments could make oral intake more problematic, especially until the esophageal mass decreases in size or in cases where the patient develops significant radiation esophagitis. Preoperative jejunostomy (J-tube) or gastrostomy (G-tube) could be used as appropriate enteral access. These decisions are often best done with a specialized RD in the clinic, which has been shown to improve patient outcomes.11 In our own clinic, having a dedicated RD in clinic resulted in improved preservation of weight postoperatively as well as for earlier J- tube removal, with a trend toward decreased readmissions.12 Many patients with esophageal malignancies will receive induction chemoradiation or chemotherapy before surgery. Close nutrition monitoring during treatment with ongoing re-evaluation for enteral nutrition (EN) should take place.
Postoperative Feeding Modalities
Traditionally, enteral feeding access is established in patients undergoing esophagectomy and enteral nutrition begins within a day of surgery.13 Jejunal feeding may be needed to supplement oral intake anywhere from a few weeks to a few months, depending on how quickly the patient rebounds postoperatively.12 More recently, with increased minimally invasive robotic and laparoscopic approaches and the development of Enhanced Recovery after Surgery (ERAS) pathways, some surgeons are omitting the practice of routine jejunostomy tube placement.13,14 This could become problematic in the case of the patient that has postoperative complications preventing oral intake and occasionally enteral access must later be established. The timing and resumption of oral intake after esophagectomy also varies by practice, with some centers allowing oral intake within days of surgery and others may delay oral diet for weeks postoperatively.
In 2019, ERAS guidelines for esophagectomy surgery were published, and although they provide some strong nutritional perioperative recommendations, their postoperative nutritional advancement recommendation remained vague.14 See Table 1 for a summary of the guidelines.Davies et al. examined the effect of perioperative nutrition support and weight loss to outcomes, with their protocol safely implementing earlier diet advancement to a pureed diet by postoperative day 5.15 Another group published three studies investigating early feeding after minimally invasive ILE, including high volume centers in the Netherlands (N=114), international centers (N=148), and a single Netherlands center in attempts for a more controlled surgical technique (N=196). All studies here compared limited liquids on post operative day (POD) 1 that progressed to 1500mL liquids by POD 5, the centers allowed solid foods on various later post op days, also evaluating using or not using supplemental EN. In aggregate, these studies demonstrated the safety of various early feeding protocols after esophagectomy.16–18
Table 1. ERAS Society Recommendations for Perioperative Nutritional Care in Esophagectomy Surgery 14
Element
Recommendation
Recommendation Grade*
Preoperative Nutritional Assessment and Treatment
Nutritional assessment should be undertaken in all patients to detect malnutrition (risk) and optimize nutritional status prior to surgery
Strong
Preoperative Nutritional Intervention
In high-risk cases enteral support is indicated using the GI tract with selective use of feeding tubes
Strong
Routine Use of Enteric Feeding Tubes
Early enteral feeding (should be strongly considered). Either feeding jejunostomy or nasojejunal/nasoduodenal tubes may be used
Moderate
Preoperative Fasting
Prolonged fasting should be avoided, and clear liquids should be allowed until 2 hours prior to surgery
Strong
Postoperative Early Nutrition: oral vs jejunostomy
Introduction of early enteral nutrition is beneficial in patients undergoing surgery for esophageal cancer
Strong
*Strength of recommendations based on Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.36
Due to the high prevalence of either surgical or nutritional tolerance complications causing patients to be unable to abide by early feeding protocols, consideration should be given to placement of a J-tube at the time of surgery. J-tubes are generally safe, and while complications do occur, including displacement, clogging, leaking around the tube, and infections, major complications remain low at 1.5%.6 Due to the low complication rate of J-tubes, they should be considered for all patients status post esophagectomy who are at nutritional risk, as these patients may need to continue feeding after discharge.19,20 The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend consideration for intraoperative placement of an enteral tube for patients who are estimated to meet less than half of their nutritional needs in the first week after surgery, those who are malnourished at the time of surgery, and those undergoing major GI surgery for cancer.6
Complications of Esophagectomy and Nutritional Consequences
Complications following esophagectomy are frequent and can be separated into short- and long-term complications, many of which impact the nutrition of the patient. One study found that 59% of patients did not remain on their postoperative early oral nutrition advancement pathway.21 The main cause of deviation was postoperative complications specifically, anastomotic leak, chyle leak, and acute respiratory distress. Additionally, 58% of patients complained of feeding intolerances such as nausea, vomiting, early satiety, and dysphagia, which was found to be most common in patients with a cervical anastomosis.21 Common surgical complications include pneumonia (14.6%), arrhythmias (14.5%), other infections such as wound infections and sepsis (14.2%), delayed conduit emptying (6.7%) and thoracic wound dehiscence (1.5%). Anastomotic leaks are a frequent occurrence after an esophagectomy, reported to occur in 11.4% of patients.22 Conduit ischemia or necrosis are rarer events, occurring in approximately 1.3% of patients. Chyle leaks, which have unique surgical and nutritional considerations, occur at a rate of 4.7%.22
These complications can take a toll on nutritional status. A systematic review of 18 studies found over half of esophagectomy patients were malnourished at 6 and 12 months postoperatively (defined as losing >10% of their body weight), and noted many patients were unable to return to their preoperative weight over time.23 Weight loss has an impact on survival and has been associated with increased mortality at 90-days and one year after esophagectomy, underscoring the importance of pre- and post-operative nutrition interventions.15
Anastomotic leaks – managing an anastomotic leak depends on the location and size of the leak as well as the overall condition of the patient. After a leak has been identified or suspected, an upper endoscopy is usually performed to evaluate the location and extent of the leak and evaluate the conduit for signs of ischemia. The chest tube remains in place as a drain for the leak, and feeding should be administered via the distally placed J-tube when one has been placed. If a patient lacks enteral access, then parenteral nutrition (PN) would be considered. Small anastomotic leaks can usually be managed endoscopically with either placement of a covered self-expanding stent, which is removed after several weeks, or an intraluminal wound vac placement via a nasoenteric approach (endoscopic vacuum therapy or EVT).24,25 In the case of stenting, oral intake can sometimes be resumed if exclusion of the leak can be confirmed radiographically. A post-stent diet includes soft foods and liquids, to avoid stent migration. If the anastomotic leak is large, the anastomosis has dehisced, or the conduit shows evidence of ischemic necrosis, a re-operative approach is usually mandatory. If the conduit has extensive necrosis or the anastomosis cannot be salvaged, a diverting cervical esophagostomy (spit fistula) is constructed, and the stomach brought back down into the abdominal cavity until the appropriate time of reoperation to restore gastrointestinal continuity. In these settings, patients are dependent on EN until continuity can be reestablished.
Chyle leaks – can arise due to direct injury to the thoracic duct, which courses near the esophagus inside the chest, from smaller branches of the thoracic duct, or more rarely from lymph node removal.26 In patients who are consuming an oral diet or receiving EN, a common sign is a milky appearance of the chest tube output, high in volume. However, occasionally chyle leaks do not demonstrate a milky appearance of the pleural drainage, especially when fats have not been reintroduced into the diet, and high volume of chest tube output may be the only sign. In fact, Maldonado et al. found milky drainage was not a sensitive marker for chyle leak.27 Laboratory confirmation of a chyle leak can be done by sending the chest tube output for chylomicrons or triglycerides. A triglyceride level of >110mg/dL is indicative of a chyle leak and anywhere from 500-1000mL/day is considered “high output”. 26,28 Urgent intervention is important when a chyle leak is identified, as delayed treatment leads to significant dehydration, compounds the already present malnutrition, and has effects on immune function and wound healing. Chyle leaks of <1000mL/day can often be managed by decreasing oral or enteral intake of long chain triglycerides (LCT) which are broken down into chylomicrons and enter the circulation via lymphatics. If a patient is maintained on an oral diet, it is imperative to counsel the patient to maximize calories while restricting fat.29 If the patient is receiving EN, the enteral formula most often utilized is Vivonex RTF by Nestle, which only contains 6.5g of LCT per liter of formula; other formulas with comparable lipid profiles could be tried as well.30 Use of medium chain triglycerides (MCTs) may help increase calories in this patient population. MCTs are absorbed directly into the portal vascular system, unlike long-chain fatty acids, and do not add to the chyle load of the lymphatic system. However, MCTs do not supply essential fatty acids and a patient can develop EFA deficiency in as little as 2-4 weeks unless 2-4% of total calories are supplied from linoleic acid.29 PN should be reserved for cases when low-LCT EN has failed, as macronutrients are supplied directly to the bloodstream, which can include IV lipids which provides EFA, and completely bypass the lymphatic system.
Case-Postoperative Course
Postoperatively, a standard polymeric EN formula was initiated via his J-tube while he was kept nil per os (NPO). On POD 4, the volume of his chest tube output increased to > 500mL in 24 hours and became milky in color, concerning for a chyle leak. A triglyceride level was obtained from his pleural fluid, which was elevated at 707 mg/dL. At this time, his EN was changed to a very low-fat elemental formula. Unfortunately, the volume of output from his drain continued to increase and rose to 1200mL/day. Therefore, EN was stopped, and PN was initiated due to history of malnutrition and prolonged NPO status.
Table 2. Nutrition Recommendations Status Post Esophagectomy 10,13,29
Complication
Nutrition Recommendations
Dysphagia or Food Feeling “Stuck”
• Chew all foods well • Take small bites • Soft/moist foods are best tolerated • Evaluate for strictures or delayed emptying from the conduit
Chyle Leak
• If oral intake-requires very low-fat diet • If on enteral feeding – adjust feeding to very low-fat elemental feeding • If chyle leak refractory to fat restriction, PN may be indicated • If prolonged >2-4 weeks, may require supplemental LCT to avoid EFAD as well as water soluble forms of Vitamins A, D, E, K • Ensure adequate protein intake
Dumping Syndrome
• Avoid simple sugars in foods • Drink sugar free beverages and diluted juices • Separate fluids from solids during meals to slow intestinal transit • Limit foods rich in simple sugars and eat slowly
Early Satiety
• Consume small portions consumed frequently • Choose high calorie, nutrient dense foods • Liquids (ONS or blenderized smoothies) empty more easily from the stomach and may be better tolerated • Sit upright while eating and for an hour afterwards; take a short walk after eating • Limit carbonation, initially • Evaluate for prokinetic therapy to enhance conduit emptying
Reflux
• Ensure foods are well chewed • Take small bites and eat slowly – allow time for the sensation of fullness • Start with smaller amounts of foods consumed at one time. Advance as tolerated. • Sit upright while eating and for an hour afterwards; take a short walk after eating • Limit carbonation, initially • Avoid constipation Block gastric acid with PPI or H2 blocker
Anastomotic strictures – are generally ischemic in nature or are associated with a previous anastomotic leak. Upper endoscopy is an important part of the diagnosis and treatment; to visualize the stricture, rule out recurrence of cancer, and perform a dilation. Often several dilations are needed, repeated at intervals, to improve oral intake. When strictures occur, the RD must ensure the patient receives adequate nourishment via liquids and soft foods until a durable solution is achieved.
Dumping syndrome – may occur with rapid emptying of gastric conduit contents into the small bowel, causing diarrhea, flushing, and discomfort.31 This can occur within 3 months postoperatively and may resolve within a year. Two forms of dumping have been observed: early and late dumping. Early dumping occurs immediately after a meal and include bloating, nausea, diarrhea, flushing, fatigue, and hypotension.31 Late dumping occurs up to 3 hours after a meal, and mainly includes vasomotor symptoms such as perspiration, weakness, hunger, shakiness, and hypoglycemia.32 Sun et al. found that emptying of liquids from the gastric conduit can be accelerated postoperatively compared to preoperative emptying rates.33
Table 3. Studies on Early Diet Advancement Post Esophagectomy 33,37-43
Study
Surgery Characteristics
Early Diet Advance Protocol
Results of Earlier Feeding
Li (2012)
Mix of MI & open ILE, thoracoabdominal transabdominal, 3 field
POD 3-4 – sips of liquids POD 5 – clear liquids POD 6 – soft foods (as part of an ERAS program)
Decreased LOS, no difference in rate of complications/ readmission
Ford (2014)
Two stage IL esophagectogastrectomy
POD 6 – full liquid diet (if approved by RD) Trophic jejunal feeding POD 0 Discharged on tube feeding (as part of an ERAS program)
Decreased LOS, no difference in post op complications or 30-day readmissions
Sun (2015)
Thoracolaparoscopic esophagectomy
POD 1- full liquid diet – Gastric emptying of liquids WNL per study on POD 1 -No reports of n/v or fullness If liquids were tolerated, patients were advanced to soft food diet
Faster return to bowel function and decreased LOS, no increase in post op complications
Weijs (2016)
MI ILE
POD 0 – clear liquids POD 1 – any liquids POD 7- solids Supplemental EN if PO intake <50% at POD 5
No difference in complications with early feeding * 38% of patients unable to take po orally d/t post op complications
Giacopuzzi (2017)
Mix of MI & Open McKeown and ILE or a modification per surgeon preference
Early: POD 1-3 – clear liquids POD 4 – soft foods Standard: POD 6 – clears post swallow POD 8 – soft foods EN POD 1 if access in place (PN POD 1-3 if no EN access)
No difference in post op complications
Sun (2018)
McKeown MIE
Initially sips of clears to assess for aspiration POD 1- full liquid diet POD 2- soft diet
Shorter return to bowel function and decreased LOS
Liao (2020)
MI ILE
Oral liquid diet POD 4 vs POD 7 Both groups maintained on EN
Decreased LOS in early fed group, no differences in complications
Li (2021)
Mix of MI & Open McKeown and ILE
Oral liquid (& PN) by 48 hours, semifluid POD 4, PN stopped POD 6-8
No differences in complications, earlier return of bowel function
MI: Minimally invasive; ILE: Ivor Lewis Esophagectomy; POD: post op day; LOS: length of stay; RD Registered Dietitian; WNL: within normal limits; ASGS: Accordion Severity Grading System; PO: oral intake; ERAS Enhanced Recovery After Surgery; EN: enteral nutrition; PN: parenteral nutrition
Other concerns –reflux may occur frequently with the lack of a gastroesophageal sphincter. Early satiety can be related to the narrower dimensions of the conduit compared to the native stomach. Early satiety is the primary nutritional factor hindering adequate intake and advancement. Delayed conduit emptying can occur and present early, causing early satiety and nausea. Delayed conduit emptying warrants an evaluation including fluoroscopic swallow study, CT scan and/or upper endoscopy which can treat this with dilation. Other attempted treatments for the above include prokinetic agents. Malabsorption is a potential long-term consequence of esophagectomy. This can occur from poor mixing of pancreatic enzymes with nutrients in the intestinal lumen, causing a functional exocrine pancreatic insufficiency (EPI). This has been reported in both esophagectomy and total gastrectomy patients.34 Small bowel bacterial overgrowth and bile acid malabsorption has also been reported in this patient population.35 Clinicians following these patients long-term should be aware of these potential complications. See Table 2 for further nutritional interventions post esophagectomy.
Case Completion
Once the patient’s chest tube output started declining, the surgical team approved re-initiation of a very low-fat elemental EN formula. The patient’s EN was started, and the volume of drain output was monitored closely. The EN resulted in no increased output with gradual decreases in volume. From there, the EN was advanced to goal rate and PN was discontinued. The chyle leak resolved, the chest tube was removed, and the patient was discharged 14 days after surgery on a clear liquid diet and EN. Within two weeks of discharge, his weight was stable, a regular solid food diet had been resumed, and his EN was decreased to 50% of his needs, cycled overnight. He tolerated his diet well thus his J-tube was removed a few weeks later.
Conclusion
Esophagectomy is a complicated surgery performed in patients with esophageal cancer. Multiple studies have now shown the safety of early oral advancement postoperatively in patients who are status post esophagectomy. See Table 3 for further studies. Even then, a high rate of preoperative malnutrition and postoperative complications delaying oral intake may require alternative and/or supplemental nutrition. Therefore, J-tubes placed during surgery continue to be an effective way to improve nutrition in this population. As more early oral feeding studies are conducted, there may be potential for selective J-tube placement at the time of surgery. Most importantly, strong collaboration between the surgical team and the RD is imperative to achieve optimal outcomes.
References
1. National Cancer Institute. Cancer Stat Facts: Esophageal Cancer https://seer.cancer.gov/statfacts/html/esoph.html Accessed 7/15/2024
2. Bonavina L, Asti E, Sironi A, et al. Hybrid and total minimally invasive esophagectomy: how I do it. J Thorac Dis. 2017;9(Suppl 8):S761-S772.
3. Noordman BJ, Wijnhoven BPL, van Lanschot JJB. Optimal surgical approach for esophageal cancer in the era of minimally invasive esophagectomy and neoadjuvant therapy. Dis Esophagus. 2016;29(7):773-779.
4. Kumar R, Wei B. The Difficult Esophageal Conduit. Surg Clin North Am. 2019;99(3):471-478.
5. Bozzetti F. Nutritional interventions in elderly gastrointestinal cancer patients: the evidence from randomized controlled trials. Support Care Cancer. 2019;27(3):721-727.
6. Weimann A, Braga M, Carli F, et al. ESPEN practical guideline: Clinical nutrition in surgery. Clin Nutr. 2021;40(7):4745-4761.
7. Bozzetti F, SCRINIO Working Group. Screening the nutritional status in oncology: a preliminary report on 1,000 outpatients. Support Care Cancer. 2009;17(3):279-284.
8. Bozzetti F, Mariani L, Lo Vullo S, et al. The nutritional risk in oncology: a study of 1,453 cancer outpatients. Support Care Cancer. 2012;20(8):1919-1928.
9. van der Schaaf MK, Tilanus HW, van Lanschot JJ, et al. The influence of preoperative weight loss on the postoperative course after esophageal cancer resection. J Thorac Cardiovasc Surg. 2014;147(1): 490-495
10. Jordan T, Mastnak DM, Palamar N, Kozjek NR. Nutritional Therapy for Patients with Esophageal Cancer. Nutr Cancer. 2018;70(1):23-29.
11. Deftereos I, Yeung JMC, Arslan J, et al. Preoperative Nutrition Intervention in Patients Undergoing Resection for Upper Gastrointestinal Cancer: Results from the Multi-Centre NOURISH Point Prevalence Study. Nutrients. 2021;13(9):3205.
12. Berry, A, Lepecha ,L, Martin,L. Routine Registered Dietitian intervention in esophagectomy patients improves weight maintenance, readmissions and time to jejunal tube removal. Unpublished; Abstract Presentation ASPEN Nutrition and Science Practice Conference, 2023.
13. Johnson S, Ziegler J, August DA. Timing of oral intake after esophagectomy: A narrative review of the literature and case report. Nutr Clin Pract. 2022;37(3):536-554.
14. Low DE, Allum W, De Manzoni G, et al. Guidelines for Perioperative Care in Esophagectomy: Enhanced Recovery After Surgery (ERAS®) Society Recommendations. World J Surg. 2019;43(2):299-330.
15. Davies SJ, West MA, Rahman SA, et al. Oesophageal cancer: The effect of early nutrition support on clinical outcomes. Clin Nutr ESPEN. 2021;42:117-123.
16. Fransen LFC, Janssen THJB, Aarnoudse M, et al. Direct Oral Feeding After a Minimally Invasive Esophagectomy: A Single-Center Prospective Cohort Study. Ann Surg. 2022;275(5):919-923.
17. Berkelmans GHK, Fransen LFC, Dolmans-Zwartjes ACP, et al. Direct Oral Feeding Following Minimally Invasive Esophagectomy (NUTRIENT II trial): An International, Multicenter, Open-label Randomized Controlled Trial. Ann Surg. 2020;271(1):41-47.
18. Berkelmans GHK, Fransen L, Weijs TJ, et al. The long-term effects of early oral feeding following minimal invasive esophagectomy. Dis Esophagus. 2018;31(1):1-8.
19. Lorimer PD, Motz BM, Watson M, et al. Enteral Feeding Access Has an Impact on Outcomes for Patients with Esophageal Cancer Undergoing Esophagectomy: An Analysis of SEER-Medicare. Ann Surg Oncol. 2019;26(5):1311-1319.
20. Baker ML, Halliday V, Robinson P, et al. Nutrient intake and contribution of home enteral nutrition to meeting nutritional requirements after oesophagectomy and total gastrectomy. Eur J Clin Nutr. 2017;71(9):1121-1128.
21. Berkelmans GHK, Kingma BF, Fransen LFC, et al. Feeding protocol deviation after esophagectomy: A retrospective multicenter study. Clin Nutr. 2020;39(4):1258-1263.
22. Low DE, Kuppusamy MK, Alderson D, et al. Benchmarking Complications Associated with Esophagectomy. Ann Surg. 2019;269(2):291-298.
23. Baker M, Halliday V, Williams RN, et al. A systematic review of the nutritional consequences of esophagectomy. Clin Nutr. 2016;35(5):987-994.
24. Berlth F, Bludau M, Plum PS, et al. Self-Expanding Metal Stents Versus Endoscopic Vacuum Therapy in Anastomotic Leak Treatment After Oncologic Gastroesophageal Surgery. J Gastrointest Surg. 2019;23(1):67-75.
25. Mandarino FV, Barchi A, Fanti L, et al. Endoscopic vacuum therapy for post-esophagectomy anastomotic dehiscence as rescue treatment: a single center case series. Esophagus. 2022;19(3):417-425.
26. Mahmodlou R, Yousefiazar A. Incidence of chylothorax over nineteen years of transhiatal esophagectomy: A case series and review study. Turk J Surg. 2022;38(4):401-408.
27. Maldonado, F, Hawkins, FJ, Daniels, CE. Pleural fluid characteristics of chylothorax. Mayo Clin Proc. 2009;84(2):129-133.
28. Duletzke, N, Kiraly,L, Martindale, R. Chylothorax and chylous ascites: Overview, management, and nutrition. Nutr Clin Pract. 2023;38:557-563.
29. McCray, S, Parrish, C. Nutritional Management of Chyle Leaks. Pract Gastroenterol. 2011;35(4):12-32.
30. Smoke A, Delegge MH. Chyle leaks: consensus on management? Nutr Clin Pract. 2008;23(5):529-532.
31. Rogers C. Postgastrectomy nutrition. Nutr Clin Pract. 2011;26(2):126-136.
32. Ukleja A. Dumping syndrome: pathophysiology and treatment. Nutr Clin Pract 2005;20(5):517-525.
33. Sun H bo, Liu X ben, Zhang R xiang, et al. Early oral feeding following thoracolaparoscopic oesophagectomy for oesophageal cancer. Eur J Cardiothorac Surg. 2015;47(2):227-233.
34. Heneghan HM, Zaborowski A, Fanning M, et al. Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery. Ann Surg. 2015;262(5):803-807
35. Khaw RA, Nevins EJ, Phillips AW. Incidence, Diagnosis and Management of Malabsorption following Oesophagectomy: a systematic review. J Gastrointest Surg. 2022;26(8):1781-1790.
36. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926.
37. Li C, Ferri LE, Mulder DS, et al. An enhanced recovery pathway decreases duration of stay after esophagectomy. Surgery. 2012;152(4):606-614; discussion 614-616.
38. Ford SJ, Adams D, Dudnikov S, et al. The implementation and effectiveness of an enhanced recovery programme after oesophago-gastrectomy: a prospective cohort study. Int J Surg. 2014;12(4):320-324.
39. Weijs TJ, Berkelmans GH, Nieuwenhuijzen GA, et al. Immediate Postoperative Oral Nutrition Following Esophagectomy: A Multicenter Clinical Trial. Ann Thorac Surg. 2016;102(4): 1141-1148.
40. Giacopuzzi S, Weindelmayer J, Treppiedi E, et al. Enhanced recovery after surgery protocol in patients undergoing esophagectomy for cancer: a single center experience. Dis Esophagus. 2017;30(4):1-6.
41. Sun HB, Li Y, Liu XB, et al. Early Oral Feeding Following McKeown Minimally Invasive Esophagectomy: An Open-label, Randomized, Controlled, Noninferiority Trial. Ann Surg. 2018;267(3):435-442.
42. Liao M, Xia Z, Huang P, et al. Early enteral feeding on esophageal cancer patients after esophageal resection and reconstruction. Ann Palliat Med. 2020;9(3):816-823.
43. Li Y, Liu Z, Liu G, et al. Impact on Short-Term Complications of Early Oral Feeding in Patients with Esophageal Cancer After Esophagectomy. Nutr Cancer. 2021;73(4):609-616.
PHATHOM PHARMACEUTICALS ANNOUNCES FDA APPROVAL OF VOQUEZNA® (VONOPRAZAN) TABLETS FOR THE RELIEF OF HEARTBURN ASSOCIATED WITH NON-EROSIVE GERD IN ADULTS
VOQUEZNA is now approved and available to treat the largest category of Gastroesophageal Reflux Disease (GERD)
VOQUEZNA met its primary endpoint in its Phase 3 pivotal trial by demonstrating a significant and rapid reduction of heartburn with daily treatment
VOQUEZNA represents the first major innovation in GERD treatment in over 30 years and the only FDA-approved treatment of its kind available in the U.S.
FLORHAM PARK, N.J., July 18, 2024 (GLOBE NEWSWIRE) – Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal (GI) diseases, announced the U.S. Food and Drug Administration (FDA) has approved VOQUEZNA® (vonoprazan) 10 mg tablets for the relief of heartburn associated with Non-Erosive Gastroesophageal Reflux Disease (Non-Erosive GERD) in adults. Non-Erosive GERD represents a substantial segment of the U.S. GERD population, affecting millions of individuals suffering from frequent heartburn. This is the third FDA approval for VOQUEZNA, which is also approved to treat all severities of Erosive Esophagitis (EE), also referred to as Erosive GERD, and in combination with antibiotics for the eradication of Helicobacter pylori (H. pylori) infection.
“Today marks a significant milestone for millions of GERD patients as we proudly announce the approval of VOQUEZNA for the treatment of Non-Erosive GERD,” said Terrie Curran, President, and Chief Executive Officer at Phathom. “For decades GERD sufferers had no new class of treatment to turn to in the U.S. This approval provides patients and healthcare providers with immediate access to the first and only FDA-approved treatment of its kind, from a new class of acid suppression therapy, and the power to help provide complete 24-hour heartburn-free days and nights. We are very excited to introduce VOQUEZNA to the broader GERD community and look forward to its potential to help change the way this disease is treated.”
Non-Erosive GERD is the largest category of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. An estimated 45 million U.S. adults living with Non-Erosive GERD, and approximately 15 million are treated with a prescription medicine annually. Despite longstanding treatment options, many patients remain dissatisfied with such therapies and continue to suffer from heartburn symptoms which may impact overall quality of life with episodic heartburn, occurring during the day and at night.
“Millions of patients with Non-Erosive GERD continue to suffer from heartburn despite current treatment options,” said Colin W. Howden, M.D., Professor Emeritus, University of Tennessee College of Medicine. “The pivotal study that led to this approval showed that VOQUEZNA significantly reduced heartburn episodes in patients with Non-Erosive GERD along with an established safety profile. Today’s approval of VOQUEZNA provides physicians with a novel, first-in-class treatment that can quickly and significantly reduce heartburn for many adult patients.”
This approval is supported by the positive results from the PHALCON-NERD-301 study (NCT05195528), a Phase 3 randomized, placebo-controlled, double-blind, multi-site U.S. study evaluating the efficacy and safety of VOQUEZNA for the daily treatment of adults with Non-Erosive GERD. The trial enrolled 772 adult patients with Non-Erosive GERD who experienced four or more days of heartburn per week, with the majority having six to seven days of heartburn per week, and compared patients treated with VOQUEZNA 10 mg to placebo in the relief of heartburn over four weeks. The trial also included a 20-week extension period where all patients received VOQUEZNA to evaluate long-term treatment.
In the pivotal trial, VOQUEZNA quickly and significantly reduced heartburn with daily treatment through week 4. VOQUEZNA demonstrated the power of more complete all-day and all-night heartburn-free days with significantly more 24-hour heartburn-free days through week 4 versus placebo, the primary endpoint. The mean percentage of heartburn-free days for patients taking VOQUEZNA was 45% versus 28% for placebo (p<0.001), and the median percentage of 24-hour heartburn-free days was 48% versus 17%, respectively. Improvements for those taking VOQUEZNA were also seen in the percentage of each of heartburn-free days and nights, in addition to the percentage of days without rescue antacid use. Results from the pivotal study were previously presented at Digestive Disease Week® (DDW) 2024 and also published in Clinical Gastroenterology and Hepatology.
The most common adverse reactions (≥2%) reported in patients treated with VOQUEZNA during the four-week placebo-controlled trial include abdominal pain, constipation, diarrhea, nausea, and urinary tract infection. Upper respiratory tract infection and sinusitis were also reported in patients who received VOQUEZNA in the 20-week extension phase of the trial.
Phathom offers savings programs for eligible patients who face coverage or affordability issues, including co-pay assistance for patients with commercial insurance. For more information, please visit: voquezna.com/savings.
VOQUEZNA is marketed exclusively by Phathom Pharmaceuticals, Inc. and is currently available via prescription. To learn more about VOQUEZNA, please visit: voquezna.com.
About PHALCON-NERD-301 Study
PHALCON-NERD-301 was a phase 3, randomized, double-blind, multicenter, 4-week study conducted in U.S. patients with heartburn related to Non-Erosive GERD. The primary endpoint was the percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days) over the 4-week placebo-controlled treatment period. The trial also included a 20-week long-term extension period to further evaluate the treatment of VOQUEZNA. A total of 776 patients with Non-Erosive GERD who experienced four or more days of heartburn per week, with the majority having six to seven days of heartburn per week, were enrolled and randomized in the multisite U.S. trial.
About Non-Erosive Gastroesophageal Reflux Disease
Non-Erosive GERD is the largest category of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. There are over 65 million U.S. patients living with GERD, and it is estimated that approximately 70% of this population have Non-Erosive GERD. Symptoms of Non-Erosive GERD may impact overall quality of life and can include episodic heartburn, especially at night, regurgitation, problems swallowing, and chest pain.
About VOQUEZNA®
VOQUEZNA® (vonoprazan) tablets contain vonoprazan, an oral small molecule potassium-competitive acid blocker (PCAB). PCABs are a novel class of medicines that block acid secretion in the stomach. VOQUEZNA is approved in the U.S. for the treatment of adults with Erosive Esophagitis, also known as Erosive GERD, the relief of heartburn associated with Erosive GERD, the relief of heartburn associated with Non-Erosive GERD, and for the treatment of H. pylori infection in combination with either amoxicillin or amoxicillin and clarithromycin. Phathom in-licensed the U.S. rights to vonoprazan from Takeda, which markets the product in Japan and numerous other countries in Asia and Latin America.
About Phathom Pharmaceuticals, Inc.
Phathom Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel treatments for gastrointestinal diseases. Phathom has in-licensed the exclusive rights to vonoprazan, a first-in-class potassium-competitive acid blocker (PCAB) that is currently marketed in the United States as VOQUEZNA® (vonoprazan) tablets for the treatment of heartburn associated with Non-Erosive GERD in adults, the healing and maintenance of healing of Erosive GERD in adults and associated heartburn, in addition to VOQUEZNA® TRIPLE PAK® (vonoprazan tablets, amoxicillin capsules, clarithromycin tablets) and VOQUEZNA® DUAL PAK® (vonoprazan tablets, amoxicillin capsules) for the treatment of H. pylori infection in adults. For more information about Phathom, visit the company’s website at www.phathompharma.com and follow on LinkedIn and X.
REDHILL BIOPHARMA R&D UPDATE
Newly Published Positive Phase 3 Data Demonstrates 64% Increased Efficacy with RedHill’s RHB-104 in Crohn’s Disease
RedHill Biopharma (Nasdaq: RDHL) announced the new publication of ground-breaking positive data from its Phase 3 Crohn’s disease study with RHB-104, showing that RHB-104 plus standard of care (SoC), targeting Mycobacterium avium subspecies paratuberculosis (MAP), was 64% more effective than SoC alone in the study, supporting the hypothesis of a Mycobacterial basis to the disease.
Newly published in the peer-reviewed journal Antibiotics, the 331-patient Phase 3 Crohn’s disease study data shows the primary endpoint of clinical remission at week 26 was achieved, with high statistical significance, in 36.7% (61/166) of orally administered RHB-104 plus standard of care (SoC) patients, compared to 22.4% (37/165) of placebo plus SoC patients (p=0.0048); Safety profile similar to placebo. Study conducted across more than 100 sites.
The advanced stage clinical data demonstrating the potential efficacy of oral RHB-104 triple antimicrobial therapy targeting Mycobacterium avium subspecies paratuberculosis (MAP,) supports the paradigm-changing hypothesis of a Mycobacterial basis to Crohn’s disease, where high unmet medical need exists.
“This ground-breaking data shows that RHB-104, which contains antimicrobial therapy directed against Mycobacterium paratuberculosis, or MAP, which typically infects cattle, appears to be effective for the treatment of Crohn’s disease – potentially opening a new avenue of therapy directed against its possible cause,” said Dr. David Y. Graham, Professor of Medicine and Molecular Virology and Microbiology at Baylor College of Medicine, the lead investigator of the study. Dr. Graham added: “It is particularly important to note that RHB-104 proved beneficial to patients receiving anti-TNF agents, corticosteroids or immunosuppressive agents, and may also have a role as an add-on therapy for patients not responding to their current treatment.”
The Crohn’s disease market was valued at more than $13 billion in 2023. Commonly used therapies in the treatment of Crohn’s include: Abbvie’s Humira® (adalimumab), Janssen’s Remicade® (infliximab) and Stelara® (ustekinumab), BMS’s Zeposia® (ozanimod) and Pfizer’s Xeljanz® (tofacitinib).
“This study was designed based on the hypothesis that infection with MAP is the primary cause of Crohn’s disease and that antimicrobial therapy designed to treat MAP would favorably influence the outcome of Crohn’s disease,” said study lead investigator, Dr. David Y. Graham, Professor of Medicine and Molecular Virology and Microbiology at Baylor College of Medicine and the Michael E. DeBakey Veterans Administration Hospital in Houston, Texas, USA. “We believe that this data shows that treatment with RedHill’s RHB-104 appears to be effective for the treatment of Crohn’s disease – this is important as an effective and safe oral therapy for Crohn’s could be highly beneficial to the patients and treating community. A unique feature of this Phase 3 study was that patients were permitted concomitant treatment with infliximab, adalimumab and/or corticosteroids at study entry. To our knowledge, no other similar Crohn’s trial has allowed tumor necrosis factor (TNF) agents to be continued throughout the treatment period. It is therefore also important to note that RedHill’s RHB-104 proved beneficial to patients receiving corticosteroids, immunosuppressive agents, or anti-TNF agents and may also have a role as an add-on therapy for patients not responding to their current treatment.”
“Crohn’s disease causes immense suffering to millions of patients globally and sometimes leads to death due to various complications. Recognizing this, RedHill is firmly committed to the RHB-104 potential paradigm-changing Phase 3-stage program. It has been more than 100 years since Scottish surgeon, Dalziel, first sowed the seeds of a possible link between MAP and Crohn’s. Evidence has grown of MAP involvement in the etiology of Crohn’s, being associated with immune signaling dysregulation and being identified in over 50% of Crohn’s patients,” said Dror Ben-Asher, RedHill’s Chief Executive Officer. “This makes the new peer-reviewed publication of these data highly exciting as Crohn’s is a terrible disease that remains steadfastly resistant to the search for a cure – despite the enormous research efforts made in the field of immunosuppression. We have a long-held conviction in the MAP approach – vindicated by this compelling data. Planning ahead, the advent of an accurate and reliable MAP diagnostic, allied to this proven triple antimicrobial therapeutic strategy, has the potential to change the treatment paradigm in inflammatory bowel disease (IBD). Accordingly, we have been pursuing creative partnership models to advance the development of RHB-104 and intend to update the market in due course.”
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States (US). Screening can help reduce CRC incidence and mortality but only 59% of adults are up to date to current screening recommendations. To achieve our national goal of screening 80% of the average-risk population, we must embrace non-invasive screening options for CRC. Our review aims to summarize the performance of currently available and emerging stool and blood-based CRC screening tests. Among the stool-based tests, fecal immunochemical testing (FIT) is the most widely used screening test. Multi target stool DNA is more sensitive than FIT for CRC, however, has a decreased specificity. Emerging stool-based tests include next generation multi-target stool DNA and multi-target stool RNA. Cell-free DNA blood-based screening tests are an appealing avenue to increase screening participation, but they will need better performance characteristics before they are widely adopted.
Introduction
Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the United States (US).1 In 2024, it is estimated that over 150,000 individuals will be diagnosed with CRC and over 50,000 will die from this disease.1 Equally concerning is the rising incidence of CRC among adults less than 50 years of age, which currently accounts for 1 out of 10 CRCs diagnosed in the US.2
Randomized trials have shown that screening reduces CRC incidence and CRC-related mortality,3 primarily through the early detection of cancer and removal of precancerous lesions. Current guidelines recommend several CRC screening modalities for average-risk adults ≥45 years of age including: 1) colonoscopy; 2) sigmoidoscopy; 3) computed tomography (CT) colonography; and 4) stool-based tests.3 However, despite the availability of these screening options, only 59% of eligible adults are up to date with CRC screening4 and rates are even lower among minority races and the underinsured.5 The COVID-19 pandemic further exacerbated sub-par screening rates as shelter-in-place orders led to fewer screening tests being performed, followed by a heightened demand that exceeded capacity as the pandemic waned.6 However, even before the pandemic, CRC screening in the US fell short of the national goal of 80% up to date with screening.
In the US, colonoscopy is the most widely used screening modality because of its ability to detect and remove pre-cancerous lesions and accurately identify CRC. However, the test is invasive and inconvenient (e.g., requires taking a bowel preparation, obtaining help with transportation, taking time off from work, etc.).7 Given these barriers to colonoscopy completion, there is a huge need for convenient non-invasive tests to improve screening uptake. In this review, we highlight current and emerging stool and blood-based CRC screening tests for average-risk adults.
Stool-Based Tests
Table 1. Performance characteristics of stool- and blood-based screening tests for colorectal cancer
Sensitivity CRC
Sensitivity AA
Specificity
Stool-Based Tests
High sensitivity guaiac-based fecal occult blood test
50-75%
6-17%
96-98%
Fecal immunochemical test (FIT)
74-79%
23%
94%
Multitarget stool DNA (Cologuard)
92%
42%
87%
Next generation multitarget stool DNA
94%
43%
91%
Multitarget stool RNA (Colosense)
94%
46%
96%
Blood-Based Tests
Septin 9, mSEPT9 (Epi Procolon, ColoVantage)
48%
11%
92%
Cell free DNA (Shield)
83%
13%
90%
CRC: colorectal cancer; AA: advanced adenoma
High Sensitivity Guaiac-based Fecal Occult Blood Test (HS-gFOBT)
The high sensitivity guaiac-based fecal occult blood test (HS-gFOBT) detects colorectal neoplasia through a chemical oxidation reaction. When stool containing heme is spread onto guaiac paper, alpha-guaiaconic acid on the testing card is oxidized by the hydrogen peroxide reagent, which creates a blue color.8 To perform the test, the patient uses an applicator stick to obtain a sample of stool on three separate occasions and then applies it to the Hemoccult slide.9 Like all non-invasive stool or blood-based screening tests, a colonoscopy is required as a follow-up to a positive test.3
Multiple pragmatic randomized trials of screening with gFOBT have shown a reduction in CRC mortality when compared to no screening.10–12 A 2021 systematic review by the United States Preventative Services Task Force (USPSTF) reported the following characteristics for the Hemoccult SENSA version of the test (Table 1): CRC sensitivity of 50.0%-75.0% (95% confidence interval [CI], 9.0-100) and specificity of 96.0%-98.0% (95% CI, 95.0-99.0); and advanced adenoma (AA) sensitivity of 6.0%-17.0% (95% CI 2.0-23.0) and specificity of 96.0%-99.0% (95% CI, 96.0-99.0).13
The benefits of HS-gFOBT-based screening are that it is non-invasive, inexpensive, and can be performed at home. Limitations include the need for dietary restrictions (no red meat, raw beets, carrots, etc.) and medication restrictions (no NSAIDs, iron, blood thinners, etc.) for two days prior to testing as they can cause false positive results.14 While the USPSTF currently recommends annual screening with this test, HS-gFOBT screening has largely been replaced by fecal immunochemical test (FIT) screening.
Fecal Immunochemical Test (FIT)
The fecal immunochemical test (FIT) uses an antibody against the globin moiety of heme to evaluate for the presence of occult blood in a stool sample.15 FIT screening requires patients to test only one stool sample (as opposed to 3 samples with Hs-gFOBT) and the test does not require dietary or medication restrictions.
Most FITs are qualitative tests, meaning they visually indicate when hemoglobin is detected in stool above a predetermined threshold. However, there are also quantitative tests in which the amount of hemoglobin in stool is measured and reported as positive if greater than a prespecified threshold. The current FDA-approved threshold for a positive test is 20 micrograms of hemoglobin per gram of stool (20ug Hb/g feces) and the sensitivity and specificity for CRC and AA will vary if the threshold is changed.16
In a systematic review evaluating FIT screening at a threshold of 20ug Hb/g feces, the pooled sensitivity for detecting CRC was 75.0% (95% CI, 61.0-86.0) and the specificity was 95.0% (95% CI, 92.0-96.0).17 For AA, the pooled sensitivity was 25.0% (95% CI, 20.0-31.0) and the specificity was 95.0% (95% CI, 93.0-96.0).17 When the FIT threshold was lowered to 10ug/g feces, the pooled sensitivity for CRC increased to 91.0% (95% CI, 84.0-95.0) and the specificity decreased to 90% (95% CI, 86.0-93.0), and similarly for AA the sensitivity increased to 40.0% (95% CI, 33-47) with a decreased specificity of 90.0% (95% CI, 87.0-93.0).17
Multiple randomized trials have evaluated participation with FIT versus colonoscopy screening, either head-to-head or as a sequential choice. These studies have demonstrated that more people participate in FIT screening when offered compared to colonoscopy screening.18–22
FIT screening has demonstrated a higher sensitivity for CRC and AAs with similar specificity compared to HS-gFOBT screening. Although there is a lack of prospective randomized data, FIT’s benefit is inferred from prior gFOBT data, given its superior performance characteristics.13 One large prospective observational study in Taiwan (n=5,417,699) has evaluated the impact of FIT screening on CRC incidence and mortality.23 This study found that 1 to 3 rounds of screening with biennial FIT was associated with a 34% reduction in advanced stage CRC and 40% reduction in death from CRC at 6 years.23 There are currently three ongoing clinical trials evaluating the effectiveness of colonoscopy versus FIT for CRC incidence and mortality.13
Multi-Target Stool DNA Test (MT-sDNA)
The multi-target stool DNA test (MT-sDNA, commercially known as Cologuard, Exact Sciences) combines fecal hemoglobin detection via the FIT with additional biomarkers including mutant KRAS, aberrant NDRG4 and BMP3 methylation, and B-actin. In a prospective study involving 10,023 average-risk individuals, MT-sDNA-based screening demonstrated a superior sensitivity for CRC (92.3%; 95% CI, 83.0-97.5) and AA (42.4%; 95% CI, 32.6-52.8) but lower specificity for CRC or AA (86.6%; 95% CI, 85.9-87.2) compared to FIT [sensitivity of FIT for CRC: 73.8% (95% CI, 61.5-84.0), sensitivity of FIT for AA: 23.9% (95% CI, 20.8-27.0) specificity of FIT: 94.9% (95% CI, 94.4-95.3)].24
The MT-sDNA was approved for CRC screening by the FDA in 2014 and current guidelines recommend the test be performed every three years. However, despite the test’s improved sensitivity for CRC and AA compared to FIT screening, there have been several barriers to widespread adoption of the test in the US and for its use in population-based screening. First, the MT-sDNA itself is much more costly than the FIT. Second, stool collection and sampling are more complex than for the FIT. In one prospective study, 6% of participants were unable to collect or send an adequate sample compared to 0.6% for the FIT.18 Third, the test has a higher false positive rate compared to the FIT (due to a lower specificity for CRC) which results in more unnecessary colonoscopies. Fourth, a positive MT-sDNA followed by a negative colonoscopy raises the question of whether neoplasia was missed at colonoscopy given the test detects tumor DNA. This could potentially lead to over testing and anxiety among patients, although Cotter et al. reported that patients with a false-positive MT-sDNA result did not have a higher subsequent incidence of gastrointestinal and other cancers compared to those with negative test results.25
Recently, a next generation MT-sDNA was evaluated among 20,176 average-risk adults 40 years of age and older in a prospective study.26 In this study, the next generation test showed higher sensitivity for CRC and advanced precancerous lesions (defined as advanced conventional adenomas and sessile serrated lesions) than FIT but lower specificity. The sensitivity of the test for CRC and advanced precancerous lesions was 93.9% (95% CI, 87.1-97.7) and 43.4% (95% CI, 41.3-45.6), respectively, while the specificity for advanced neoplasia (defined as CRC or advanced precancerous lesions) was 90.6% (95% CI, 90.1-91.0). In contrast, FIT sensitivity for CRC and advanced precancerous lesions was 67.3% (95% CI, 57.1-76.5) and 23.3% (95% CI, 21.5-25.2) respectively, while specificity for advanced neoplasia was 94.8% (95% CI, 94.4-95.1).26 The main advantage of the next-generation MT-sDNA compared to the current generation test is its improved specificity for advanced neoplasia (i.e., 90.6%), which will decrease the false positive rate and thereby reduce unnecessary colonoscopies. The next generation MT-sDNA is currently awaiting FDA approval.
Multitarget Stool RNA Test (mt-sRNA)
The multitarget stool RNA test (mt-sRNA, commercially known as Colosense, Geneoscopy) is an emerging stool-based test which combines fecal hemoglobin detection via the FIT with additional RNA biomarkers. The performance of mt-sRNA versus FIT-based screening was recently evaluated in a prospective study (CRC-PREVENT) of 8,920 average-risk participants 45 years of age and older. The study showed that the mt-sRNA sensitivity for CRC and AA was 94.4% (95% CI, 81.0-99.0) and 45.9% (95% CI, 42.0-50.0), respectively, and was superior to the FIT. The specificity of the mt-sRNA for all other findings (medium risk adenomas, low risk adenomas, and no findings) was 85.5% (95% CI, 70.0-89.0) and lower compared to the FIT.27 FIT sensitivity for CRC and AA was 77.8% (95% CI, 61-90) and 28.9% (95% CI, 25-33), respectively. Specificity for all other findings (medium risk adenomas, low risk adenomas, and no findings) was 95.7% (95% CI, 88-97). A unique aspect of the CRC-PREVENT study is its inclusion of 45-49 year-olds for which the USPSTF now recommends CRC screening. In this age group, mt-sRNA screening demonstrated 100% sensitivity for CRC and 44.7% sensitivity for AA (95% CI not available). The authors suggested that the high sensitivity and preserved specificity of the mt-sRNA in this younger age group (i.e., 45-49 year-olds) may be attributable to the inclusion of RNA biomarkers which are not subject to age-related methylation patterns that can impact test results across age groups.27 Colosense was recently FDA approved this year.
Blood-Based Tests
In 2021, the Centers for Medicare and Medicaid Services (CMS) provided guidance on how blood-based CRC screening tests can gain approval for potential reimbursement. First, the guidance stated that blood-based tests need to have a 90.0% specificity and 74.0% sensitivity for CRC compared to an accepted standard. Second, blood-based tests must be approved by the Food and Drug Administration (FDA). Third, blood-based tests need to be endorsed by at least one professional society guideline.28 We discuss some of the current and emerging blood-based screening tests below.
Septin 9 or mSEPT9 (Epi proColon, ColoVantage)
In 2016, a blood-based plasma methylated SEPT9 DNA assay (mSEPT9, marketed under the trade names Epi proColon and ColoVantage) was approved by the FDA for CRC screening. The SEPT9 gene plays an important role in the progression of CRC, as methylated SEPT9 DNA has been detected in most CRC tissues.29 In a prospective study of 7,921 average-risk adults 50 years of age and older, mSEPT9 demonstrated a 48.2% (95% CI, 32.4-63.6) sensitivity for CRC, 11.2% (95% CI, 7.2-15.7) sensitivity for AA, and 91.5% (95% CI, 89.7-93.1) specificity for CRC.30 Although the test is FDA approved, neither the USPSTF nor the US Multi-Society Task Force (USMSTF) guidelines advocate for its use for CRC screening given its performance characteristics and lack of studies demonstrating its effectiveness in reducing CRC incidence or CRC-related mortality. However, two studies have demonstrated mSEPT9’s potential role for CRC screening, particularly for individuals who prefer a blood-based screening option that is more convenient and does not require stool sampling. In a randomized trial of 413 average-risk adults who were due for CRC screening in two integrated US health systems, uptake of the mSEPT9 blood test was significantly higher compared to FIT screening; 99.5% of participants in the mSEPT9 arm completed the test within six weeks compared with 88.1% of participants in the FIT arm.31 Additionally, mSEPT9 was shown to improve screening adherence by 7.5% among average-risk individuals who previously declined colonoscopy and FIT screening.32
cfDNA (Shield)
Recently, there has been growing interest in plasma cell free DNA (cfDNA), which is made of DNA molecules released from various tissues in the body, as a potential source for noninvasive diagnostic and cancer screening. Using this technology, Guardant Health developed a blood-based cfDNA test (Shield, Guardant Health) for colorectal screening. In a retrospective case-control study of 699 Korean individuals with stage I-III CRC and 297 colonoscopy negative control subjects, the sensitivity and specificity of the test for CRC was 96% and 94% respectively (95% CI not available).33 It was later studied in a prospective study (ECLIPSE trial) of 7,861 average-risk adults 45 years of age and older, the cfDNA test detected CRC with a sensitivity of 83.1% (95% CI, 72.2-90.3), advanced neoplasia with a specificity of 89.6% (95% CI 88.8-90.3), and advanced precancerous lesions with a sensitivity of 13.2% (95% CI, 11.3-15.3).34 Although cfDNA demonstrated an 83.1% sensitivity for CRC overall and 87.5% sensitivity for stage I-III CRC, which is comparable to most currently available stool-based tests, the relatively low sensitivity for detecting advanced precancerous lesions (13%) is a limitation. Also, the plasma cfDNA assay focuses on markers specific to CRC and it is possible that markers for AAs and sessile serrated lesions may be different, which would likely negatively impact the test’s performance. Shield received FDA approval this year.
Conclusion
CRC is a common cancer worldwide and preventable through screening. Adherence to CRC screening in the US is below the 80% target, likely in part due to the fact that colonoscopy, the most commonly performed screening test, is both invasive and inconvenient. Non-invasive screening options offer the potential to increase CRC screening rates and address the rising incidence of CRC among adults under 50 years of age. Stool-based tests currently available include the HS-gFOBT, FIT, and MT-sDNA. Although the MT-sDNA has a higher sensitivity for detecting CRC compared with other stool-based tests, it is more costly and has a higher false positive rate. Emerging stool-based tests such as the next-generation MT-sDNA and the mt-sRNA have a slightly higher specificity compared to the current MT-sDNA, which may help reduce unnecessary colonoscopies. The FIT remains the preferred screening test for population-based screening due to its low cost, accuracy for detecting CRC, and ease for mailed outreach. The emergence of the blood-based cfDNA test is a promising avenue for non-invasive screening and may help improve screening participation, particularly among individuals who prefer a non-invasive screening test that does not require stool sampling.
References
References
1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
2. Stoffel EM, Murphy CC. Epidemiology and Mechanisms of the Increasing Incidence of Colon and Rectal Cancers in Young Adults. Gastroenterology. 2020;158(2):341-353. doi:10.1053/j.gastro.2019.07.055
3. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2021;325(19):1965. doi:10.1001/jama.2021.6238
4. Sabatino SA. Up-to-Date Breast, Cervical, and Colorectal Cancer Screening Test Use in the United States, 2021. Prev Chronic Dis. 2023;20. doi:10.5888/pcd20.230071
5. Dougherty MK, Brenner AT, Crockett SD, et al. Evaluation of Interventions Intended to Increase Colorectal Cancer Screening Rates in the United States: A Systematic Review and Meta-analysis. JAMA Intern Med. 2018;178(12):1645-1658. doi:10.1001/jamainternmed.2018.4637
6. Worthington et al. – 2023 – Potential global loss of life expected due to COVI.pdf. Accessed March 5, 2024. https://www.thelancet.com/action/showPdf?pii=S2589-5370%2823%2900258-4
7. Restall G, Michaud V, Walker JR, et al. Patient Experiences with Colonoscopy: A Qualitative Study. J Can Assoc Gastroenterol. 2019;3(6):249-256. doi:10.1093/jcag/gwz016
8. Jain S, Maque J, Galoosian A, Osuna-Garcia A, May FP. Optimal Strategies for Colorectal Cancer Screening. Curr Treat Options Oncol. 2022;23(4):474-493. doi:10.1007/s11864-022-00962-4
9. How to Do a Fecal Occult Blood Test (FOBT) | Memorial Sloan Kettering Cancer Center. Accessed March 5, 2024. https://www.mskcc.org/cancer-care/patient-education/fecal-occult-blood-test
10. Faivre J, Dancourt V, Lejeune C, et al. Reduction in colorectal cancer mortality by fecal occult blood screening in a French controlled study1. Gastroenterology. 2004;126(7):1674-1680. doi:10.1053/j.gastro.2004.02.018
11. Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up | Gut. Accessed March 25, 2024. https://gut.bmj.com/content/61/7/1036.long
12. Shaukat A, Mongin SJ, Geisser MS, et al. Long-Term Mortality after Screening for Colorectal Cancer. N Engl J Med. 2013;369(12):1106-1114. doi:10.1056/NEJMoa1300720
13. Lin JS, Perdue LA, Henrikson NB, Bean SI, Blasi PR. Screening for Colorectal Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality (US); 2021. Accessed March 5, 2024. http://www.ncbi.nlm.nih.gov/books/NBK570913/
14. Mathews BK, Ratcliffe T, Sehgal R, Abraham JM, Monash B. Fecal Occult Blood Testing in Hospitalized Patients with Upper Gastrointestinal Bleeding. J Hosp Med. 2017;12(7):567-569. doi:10.12788/jhm.2773
15. Gupta S. Screening for Colorectal Cancer. Hematol Oncol Clin North Am. 2022;36(3):393-414. doi:10.1016/j.hoc.2022.02.001
16. Robertson DJ, Lee JK, Boland CR, et al. Recommendations on Fecal Immunochemical Testing to Screen for Colorectal Neoplasia: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;152(5):1217-1237.e3. doi:10.1053/j.gastro.2016.08.053
17. Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps. doi:10.7326/M18-2390
18. Shaukat A, Levin TR. Current and future colorectal cancer screening strategies. Nat Rev Gastroenterol Hepatol. 2022;19(8):521-531. doi:10.1038/s41575-022-00612-y
19. Gupta S, Halm EA, Rockey DC, et al. Comparative Effectiveness of Fecal Immunochemical Test Outreach, Colonoscopy Outreach, and Usual Care for Boosting Colorectal Cancer Screening Among the Underserved. JAMA Intern Med. 2013;173(18):1725-1732. doi:10.1001/jamainternmed.2013.9294
20. Singal AG, Gupta S, Tiro JA, et al. Outreach invitations for FIT and colonoscopy improve colorectal cancer screening rates: A randomized controlled trial in a safety net health system. Cancer. 2016;122(3):456-463. doi:10.1002/cncr.29770
21. Pilonis ND, Bugajski M, Wieszczy P, et al. Participation in Competing Strategies for Colorectal Cancer Screening: A Randomized Health Services Study (PICCOLINO Study). Gastroenterology. 2021;160(4):1097-1105. doi:10.1053/j.gastro.2020.11.049
22. Inadomi JM MD, Vijan S MD, MS, Janz NK PhD, et al. Adherence to Colorectal Cancer Screening: A Randomized Clinical Trial of Competing Strategies. Arch Intern Med. 2012;172(7):575-582. doi:10.1001/archinternmed.2012.332
23. Chiu HM, Chen SLS, Yen AMF, et al. Effectiveness of fecal immunochemical testing in reducing colorectal cancer mortality from the One Million Taiwanese Screening Program. Cancer. 2015;121(18):3221-3229. doi:10.1002/cncr.29462
24. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget Stool DNA Testing for Colorectal-Cancer Screening. N Engl J Med. 2014;370(14):1287-1297. doi:10.1056/NEJMoa1311194
25. Cotter TG, Burger KN, Devens ME, et al. Long-Term Follow-up of Patients Having False Positive Multi-target Stool DNA Tests after Negative Screening Colonoscopy: The LONG-HAUL Cohort Study. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2017;26(4):614-621. doi:10.1158/1055-9965.EPI-16-0800
26. Imperiale TF, Porter K, Zella J, et al. Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening. N Engl J Med. 2024;390(11):984-993. doi:10.1056/NEJMoa2310336
27. Multitarget Stool RNA Test for Colorectal Cancer Screening | Colorectal Cancer | JAMA | JAMA Network. Accessed March 5, 2024. https://jamanetwork.com/journals/jama/fullarticle/2811133
28. NCD – Colorectal Cancer Screening Tests (210.3). Accessed March 6, 2024. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=281&ncdver=7
29. Lu P, Zhu X, Song Y, et al. Methylated Septin 9 as a Promising Biomarker in the Diagnosis and Recurrence Monitoring of Colorectal Cancer. Belardinilli F, ed. Dis Markers. 2022;2022:1-8. doi:10.1155/2022/7087885
30. Church TR, Wandell M, Lofton-Day C, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63(2):317-325. doi:10.1136/gutjnl-2012-304149
31. Liles EG, Coronado GD, Perrin N, et al. Uptake of a colorectal cancer screening blood test is higher than of a fecal test offered in clinic: A randomized trial. Cancer Treat Res Commun. 2017;10:27-31. doi:10.1016/j.ctarc.2016.12.004
32. Liang PS, Zaman A, Kaminsky A, et al. Blood Test Increases Colorectal Cancer Screening in Persons Who Declined Colonoscopy and Fecal Immunochemical Test: A Randomized Controlled Trial. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2023;21(11):2951-2957.e2. doi:10.1016/j.cgh.2023.03.036
33. Lee J, Kim HC, Kim ST, et al. Multimodal circulating tumor DNA (ctDNA) colorectal neoplasia detection assay for asymptomatic and early-stage colorectal cancer (CRC). J Clin Oncol. 2021;39(15_suppl):3536-3536. doi:10.1200/JCO.2021.39.15_suppl.3536
34. Chung DC, Gray DM, Singh H, et al. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024;390(11):973-983. doi:10.1056/NEJMoa2304714
This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Cookie settingsACCEPT
Privacy & Cookies Policy
Privacy Overview
This website uses cookies to improve your experience while you navigate through the website. Out of these cookies, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these cookies. But opting out of some of these cookies may have an effect on your browsing experience.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.
Thomas M. Strobel
Dawn B. Beaulieu
Yichun Fu
Edwin McDonald
Thiruvengadam Muniraj
Priya Kathpalia
Rena Mei
Emily Rubin
Nicholas Noverati
Stephanie Moleski
Neal A. Mehta
Tyler M. Berzin
Amy Berry
Dustin M. Walters
Pradeep Koripella
Lawrence J. Leung
Jeffrey K. Lee