Page 53 – Practical Gastro

Probiotic is a general term for live, nonpathogenic microorganisms, many of which exist in a symbiotic relationship within the normal human gut flora. Here we discuss their growth in popularity, their use in treating Gastrointestinal (GI) and non-GI medical conditions, and the data demonstrating their effectiveness.

Skylar Steinberg, BS, Health Promotion and Disease Prevention, Research Assistant, Ventura Clinical Trials Sabine Hazan, MD, Gastroenterology/Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Ventura, CA

Probiotics have grown in popularity in recent years, marketed as a healthy dietary supplement and placed in popular foods such as yogurt, kombucha, kimchi and more. In 2014, Sales of probiotics in the United States exceeded more than $1 billion, constituting a $25 billion market worldwide.¹ The media and proclaimed health magazines have been quick to push the consumption of these products into our everyday lifestyle and diet. However, there is some confusion on the background and potential risks involved with an increased intake of probiotics that needs to be addressed. Furthermore, “probiotic,” has become increasingly misused, with many companies exploiting the term’s popularity without meeting the requisite criteria.

Probiotic is a general term for live, nonpathogenic microorganisms, many of which exist in a symbiotic relationship within the normal human gut flora.¹ They have been used to treat Gastrointestinal (GI) and non-GI medical conditions, but data demonstrating their effectiveness has been conflicting. The Federal Drug Administration also views probiotics as a health food, not a drug, and does not regulate these products.¹ One major issue is the fact that selection and dosing vary among products and the specific, beneficial effects of each probiotic strain cannot be generalized.¹ Not all species of probiotics are a part of the normal human gut bacteria and the benefits associated with one strand cannot be generalized to others.¹ Therefore, not all brands should promise equal effectivity and choosing a probiotic can be incredibly confusing and potentially harmful,¹ especially in immunosuppressed individuals or critically ill patients. For example, two cases of Lactobacillus Bacteremia during probiotic treatment of short gut syndrome have been discovered demonstrating that probiotics may not be as benign a treatment as generally thought.² Yet, as a result of media and marketing, most consumers now believe that probiotics are key to helping remedy a variety of health issues, keeping the demand for these products high.¹

Evidence has shown, however, that probiotics have been beneficial for the treatment of acute diarrhea, pouchitis, atopic eczema, and some genitourinary infections.¹ A 2010 analysis of 63 studies, totaling 8014 participants, concluded that probiotics helped decrease the duration and severity of acute infectious diarrhea.³ In fact, Irritable Bowel Syndrome (IBS) is one of the most common reasons that probiotics are consumed in clinical practice and also one of the most commonly studied with over 80 clinical trials of probiotics for IBS. The main reason for use of probiotics for both IBS constipation or IBS diarrhea is lack of pharmacologic treatment options.⁴

There has been no evidence or even weak evidence that probiotics help in conditions of Crohn’s disease or ulcerative colitis.^5,6,7 In fact, Rolfe et. al. in 2006 showed that out of 160 participants with Crohn’s disease, probiotics were not superior to a placebo or aminosalicylates for the maintenance of remission in patients.⁸ In 2007, Lirussi et al. conducted further studies on liver disease that showed no benefit or harm from probiotics in patients with end-stage liver disease.⁹ However, Xu and al. showed probiotics “significantly reduced the development of overt hepatic encephalopathy” in patients with liver cirrhosis.¹⁰

With regards to metabolic diseases, probiotics have shown to significantly decrease plasma glucose and glycosylated hemoglobin. However, there is no agreement that they reduce blood insulin levels in diabetes patients.^{11,12,13,14,15} For patients with cardiovascular and cholesterol conditions, studies found that probiotics decreased LDL, but did not raise HDL. Although Cho and Kim, like several others, emphasized, “both the efficacy of probiotics for cholesterol lowering and safety should be investigated further in well-designed clinical trials.”^16,17,118,19

When looking at the role of probiotics in GI infections like Helicobacter pylori and Clostridium difficile, the data has been controversial. Chao et al. in 2016 showed that probiotics, plus standard therapy, did not improve the eradication rate of H.pylori compared to placebo, however, probiotics did improve the side effects of diarrhea and nausea from the antibiotics.²⁰ When given with antibiotics, probiotics did decrease the risk of developing CDAD by 64%.²¹

There is also inadequate evidence recommending probiotics for respiratory tract infection,²² Bacterial vaginosis,^23,24 UTI,²⁵ or chronic periodontitis.²⁶ Overlooking the literature, it is evident that some effects of probiotics are well-documented, and their use alone or in combination with other therapies can be considered “evidence-based,” such as antibiotic-associated diarrhea, and C. diff-associated diarrhea, and yield positive results. In other conditions, however, further studies are crucial to determine the benefits of probiotics, because the available evidence is insufficient to show the efficacy of probiotics themselves and the studies included a wide swath of participants with varying degrees of ailments. Careful trials are needed to validate the effects of particular strains of probiotics given at specific dosages and for specific durations²⁷ but more importantly, probiotics need to be specific to the individual because, clearly, microbiome profiling has demonstrated species-specific patterns.^28,29

Nutrition Issues In Gastroenterology, Series #180

Conventional, Complementary, and Controversial Approaches to Small Intestinal Bacterial Overgrowth

Amisha Ahuja,

Nitin K. Ahuja

Small intestinal bacterial overgrowth (SIBO), classically understood as an excess of bacteria and their associated byproducts in the small bowel, has become in recent years a progressively credible explanation for a variety of gastrointestinal symptoms. At the same time, clinical presentations associated with this entity are wide-ranging and overlap substantially with other heterogeneous diagnoses like irritable bowel syndrome. This ambiguity is compounded by a lack of standardized testing and treatment modalities, which can be frustrating for providers and patients alike. Herein we outline a contemporary understanding of SIBO pathophysiology, diagnosis, and therapy, with particular attention to their interface with diet and nutrition.

Amisha Ahuja, MD, Resident, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA Nitin K. Ahuja, MD, MS, Assistant Professor of Clinical Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA

Once a highly contested diagnosis, small intestinal bacterial overgrowth (SIBO) has gained traction over the past several years as a reasonable explanation for a variety of gastrointestinal symptoms. This traction is attributable not only to an accumulating foundation of empiric evidence, but also to a growing general interest in the role of gut microbiota in health and illness. At the same time, persistent ambiguities surrounding SIBO with respect to clinical hallmarks, diagnostic testing, and preferred treatment approaches leave providers vulnerable to setting thresholds of suspicion that may be too high or too low. Likewise, patients frustrated by a lack of definitive answers may be prone to perseverating upon this clinical entity given its elusive, protean, and faddish qualities.

Classically, the pathophysiology of SIBO has been understood as an excess of bacteria in the small intestine beyond the conventional cutoff value of 10⁵ colony forming units per milliliter (CFU/mL). This excess of bacteria, along with their associated metabolic processes and byproducts, leads in theory to various forms of maldigestion. More recent refinements in the SIBO disease model suggest that it may also involve the presence of inappropriate microbial species in particular regions of the small intestine. In a healthy state, proximal small intestinal microbiota are comprised primarily of Gram-positive aerobes, whereas the distal small bowel favors mostly facultative anaerobes in a gradient leading toward to the dense and almost exclusively anaerobic population of the colon.¹ Alongside bacterial overgrowth in absolute numbers, then, disturbances in these usual ratios have been suggested as potentially problematic.

Recent work has also focused on delineating qualitative distinctions among the various microbiota that might account for SIBO symptoms in any given individual. Elaborations in breath testing modalities have facilitated scrutiny of organisms producing methane and hydrogen sulfide as metabolic byproducts in response to an oral carbohydrate load, though the quantitative parameters for identifying them are subject to ongoing refinement.² Recognizing that bacteria are not the only microorganisms present in the body, some investigators have suggested that a parallel process of small intestinal fungal overgrowth (SIFO) may account for the persistence of symptoms in patients treated adequately for SIBO.^3,4 While such added layers of detail represent exciting avenues for future research, these distinctions remain difficult to draw clinically and thus, as speculation, can be clarifying and confounding in equal measure.

Clinical Features

Still, amidst these controversies, clinical patterns do exist to guide thinking about SIBO rationally. According to aggregated case series, among patients with SIBO, the most commonly reported symptoms tend to be diarrhea, abdominal pain, and abdominal bloating.⁵ In large individual studies, however, symptom prevalence and severity have been shown to be poor predictors for the presence of SIBO as defined by hydrogen breath testing. Such analyses have considered a wide variety of gastrointestinal symptoms, including heartburn, chest pain, nausea, bloating, belching, flatulence, abdominal pain, constipation, and diarrhea, suggesting that while none is predictive of SIBO, any might in theory be associated with it.⁶ That said, attention to alternative fermentative byproducts has yielded more significant associations. Methane production, for instance, is tied to constipation, perhaps by virtue of delayed gut transit.⁷ Recently presented data on hydrogen sulfide production, meanwhile, suggest an association with diarrhea and abdominal pain.⁸

The overlapping presentations of irritable bowel syndrome (IBS) and SIBO have been scrutinized heavily, and the shifting relationship between these two categories can contribute to uncertainty on the part of both patients and providers. Recognizing that IBS is a diagnosis predicated on clinical criteria, SIBO is likely a mechanism contributing to symptoms in a subset of IBS cases, though not necessary an exclusive explanation. Prevalence data vary widely, with a recent meta-analysis suggesting that approximately one-third of IBS patients tested positive for SIBO by conventional, non-invasive methods.⁹ SIBO has also been hypothesized to contribute to other clinically defined diagnoses, like functional dyspepsia, though experimental data to prove this link are thus far limited.¹⁰

Risk factors for excessive or otherwise altered small bowel microbiota include disturbances of small bowel anatomy or motility, predisposing in turn to bacterial stasis (including diverticula, post-operative adhesions, blind limbs, chronic opiate use, diabetic enteropathy, or underlying connective tissue disease such as systemic sclerosis) and impairments in the normal biochemical clearance mechanisms for bacteria in the small bowel (including hypochlorhydria mediated by proton pump inhibitors, for example, or reduced pancreaticobiliary secretions in the setting of chronic pancreatitis) (Table 1). Incompetence or surgical absence of the ileocecal valve has also been studied as a potential risk factor for SIBO, presumably by virtue of inappropriate reflux of colonic microbiota into the small intestine.¹¹ Given the imperfect nature of available diagnostics, as will be discussed below, recognizing clinical risk factors becomes a valuable means of establishing pre-test probability for SIBO before committing to a potentially protracted series of iterative therapies.

Diagnostic Evaluation

There are multiple modalities available for SIBO testing, though all are subject to important limitations. Quantitative culture of aspirated small bowel fluid is formally considered to be the diagnostic gold standard, though cost, invasiveness, and technical limitations (including variations in bacterial concentration according to the region of small bowel sampled) make it impractical for routine clinical use.¹² By virtue of its relative convenience, breath testing has become a much more widespread surrogate technology for establishing a diagnosis of SIBO, though debate continues to surround basic questions of methodology and interpretation.

Breath tests are performed by asking patients to ingest a pre-specified carbohydrate substrate before quantifying exhaled gases at regular intervals as an indirect measure of small bowel bacterial metabolism. The choice of substrate is an important variable, since glucose is natively absorbed by the small bowel whereas lactulose is not; as such, glucose can be predisposed to more false negative results, while lactulose can lead to more false positives.¹³ A recently published North American consensus document has formalized cutoff values for abnormality with regard to exhaled hydrogen and methane, a helpful frame of reference for an often subjective study.¹⁴ A number of experts explicitly disagree with these values, however, citing conflicting data, flawed assumptions about carbohydrate transit through the small intestine, and the lack of a reliable diagnostic gold standard.¹⁵

Supportive data can be gathered from other laboratory parameters, most of which surround the nutritional implications of SIBO. Severe SIBO is classically associated with reductions in Vitamin B12, due to either competitive bacterial uptake or inhibited absorption, and excesses in folate, a byproduct of bacterial metabolism.¹⁶ While certain bacterial species produce Vitamin B12, the majority are consumers, leading to a functional state of Vitamin B12 malabsorption.¹⁷ In certain circumstances, elevations of methylmalonic acid may be a useful surrogate biomarker of SIBO even when the serum Vitamin B12 level is normal.¹⁸ Fat malabsorption and deficiencies in the fat-soluble vitamins (Vitamins A, D, E, and K) have also been rarely reported, sometimes with clinically significant implications, including reduced bone density, night blindness, neuropathy, and coagulopathy.¹⁹ These metrics are neither sensitive nor specific in isolation, of course, but can be useful points to remember with respect to pattern recognition.

Conventional Therapy

Given the inherent limitations of the tests discussed above, many providers consider empiric treatment for SIBO as a diagnostic modality in its own right. In this context, the most common approach is to utilize a course of antibiotics to reduce bacterial burden and evaluate for symptom improvement thereafter. This strategy errs on the side of overtreatment; however, increasing the number of patients exposed to the potential risks of antibiotic therapy, including medication side effects, precipitation of C. difficile colitis, and the development of resistant organisms.

A variety of antibiotics have been studied with roughly equivalent rates of success, suggesting that targeting specific bacteria may not always be necessary to facilitate the collapse of synergistic, polymicrobial colonies.²⁰ The studied dosages and durations of these antibiotics have also varied. Recent practice has favored the use of rifaximin, a poorly absorbed antibiotic, in part due to its reduced toxicity profile and in part due to a relatively more robust base of evidence, including randomized controlled trial evidence for its utility in IBS with diarrhea, a diagnosis that is often simultaneously entertained.^21,22 For methane-predominant SIBO, certain investigators have advocated using a combination of neomycin and rifaximin, which small data sets suggest is superior in this context to either antibiotic alone.²³

Underlying risk factors for SIBO will predispose to recurrence after a successful course of antibiotic therapy and thus should be mitigated wherever possible. Such maneuvers might include optimizing blood glucose control, withdrawing gut-slowing or acid-suppressing medications, and perhaps even selectively instituting prokinetic drugs.²⁴ Even common risk factors can be potentially significant; some estimates suggest that proton pump inhibitors at daily dosing increase the small intestinal bacterial burden by 50- to 100-fold.²⁵ In situations where risk factors are significant and cannot be reversed, SIBO treatment may obligate the indefinite long-term use of multiple antibiotics in cycling fashion.

Alternative and Nutritional Therapy

A variety of alternative management options for SIBO have been proposed from within and beyond the physician community (Table 2). Among patients with a high threshold of suspicion for SIBO who are intolerant of, or unresponsive to, antibiotic medications, alternative interventions may be seen as attractive options despite a relative paucity of supporting data. Likewise, given the frequent link between food intake and symptom exacerbation, nutrition can be an avenue of native interest for patients with SIBO, though again the available evidence for any individual dietary strategy is sparse. Diets proposed for SIBO tend to focus on reducing or eliminating foods easily fermented by bacteria and leading in turn to gaseous and osmotically active metabolic byproducts. The low FODMAP (fermentable oligo-, di-, monosaccharides and polyols) diet is perhaps the best known of these diets, but it should be noted that its effectiveness has been studied particularly in the context of IBS, not SIBO. Extrapolation regarding the potential benefit of this diet in SIBO rests on the known overlap between these two clinical entities, but to our knowledge, the evidence to support this extrapolation remains largely anecdotal.²⁶ Other popular diets proposed for bacterial overgrowth, under names like “the biphasic diet,” “the fast tract diet,” and “the SIBO specific diet,” among others, are even less driven by published data but seem to function as ad hoc variations on the same basic theme of reducing intake of highly fermentable carbohydrates.

The identification and elimination of dietary triggers may be viewed as a relatively low-harm exercise to the extent that patients with SIBO understand that it represents a short-term and essentially palliative maneuver. Misapprehensions that dietary modification can treat bacterial overgrowth, or that dietary indiscretion can lead to worsening dysbiosis, should be avoided. Symptoms may be mitigated, but the underlying risk factors for SIBO remain. Providers should also counsel patients to keep their exclusions temporary and minimally restrictive, given the risk of developing disordered eating habits (that is, “orthorexia nervosa”) and the potentially deleterious effects of carbohydrate restriction on the gut microbiome overall.^27,28 Registered dietitian involvement can be instrumental in facilitating healthful approaches to dietary optimization, including the identification and repletion of developing micronutrient and macronutrient deficiencies.

Beyond dietary modification, nutritional supplements have also been explored as alternative therapies for SIBO. A recent meta-analysis suggested that probiotics trend toward effectiveness in reducing bacterial burden and symptoms associated with SIBO, though interpretation is limited by heterogeneity in study methodology and the probiotic products under investigation.²⁹ By way of caution and contrast, however, a recent small study suggested that symptomatic SIBO could in fact be provoked by probiotic supplementation.⁴ Herbal compounds for the treatment of SIBO are widely available, and at least one study has suggested comparable efficacy with rifaximin as measured by a negative follow-up breath test.³⁰ Again, however, variations in the composition of these commercial preparations limit the extent to which these findings are clinically actionable.

CONCLUSION

Approaching the question of SIBO responsibly requires acknowledging the persistent ambiguities surrounding the clinician’s standard diagnostic and therapeutic tools. Recognizing clinical patterns can help determine how aggressively to query for SIBO when initial diagnostic and therapeutic modalities are unproductive. Furthermore, literacy with alternative strategies promoted to general audiences can facilitate more meaningful counseling in recognition of patients’ pre-existing health attitudes and behaviors.

Frontiers In Endoscopy, Series #46

A Review of Lithotripsy Applications in Gastroenterology

Praneeth Kudaravalli,

Bilal Aslam,

Moamen Gabr

Lithotripsy has been a principle technique in the field of urology for four decades but was not implemented in the field of gastroenterology until the mid-1980s. In this article we discuss some of the commonly used lithotripsy methods in gastroenterology, such as mechanical lithotripsy, laser lithotripsy, electrohydraulic lithotripsy and extracorporeal shockwave lithotripsy.

Lithotripsy has been a principle technique in the field of urology for four decades but was not implemented in the field of gastroenterology until the mid-1980s. Large in vivo stones are often challenging to extract so lithotripsy is performed to assist in fragmenting or removing stones. Lithotripsy is used for various gastrointestinal conditions like common bile duct stones, pancreatic duct stones, gallstone ileus, Bouveret’s Syndrome, and in the management of some cases of calcified, impacted or occluded stents. Mechanical lithotripsy, laser lithotripsy, electrohydraulic lithotripsy, and extracorporeal shockwave lithotripsy are some of the commonly used lithotripsy methods in gastroenterology.

Praneeth Kudaravalli MD, Department of Internal Medicine, University of Kentucky, Bilal Aslam MD, Department of Digestive Diseases and Nutrition, University of Kentucky, Moamen Gabr MD, MSc, Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY

INTRODUCTION

Lithotripsy is being increasingly used in gastroenterology for fragmentation of stones prior to extraction as large stone removal is technically difficult and failure is associated with increased risk of complications including infection and stone impaction.¹ Surgical techniques are invasive and often associated with significant morbidity and mortality compared to endoscopic procedures. Most stones can be successfully removed by conventional endoscopic techniques alone, however larger stone size, impaction, the location of stone and presence of stricture can limit endoscopic success.^2,3 Lithotripsy in conjunction with conventional endoscopic techniques increases the rate of successful stone removal.

Mechanical lithotripsy for common bile duct (CBD) stones was first described in 1982 by Riemann et al.⁴ and is one of the most commonly used techniques for fragmentation of large CBD stones. Other types of lithotripsy techniques have been developed and used as an alternative to mechanical lithotripsy in patients with refractory stones which include electrohydraulic lithotripsy, laser lithotripsy, and extracorporeal shockwave lithotripsy. In addition to large gallstone management, lithotripsy is employed in other gastrointestinal conditions including chronic calcific pancreatitis caused by pancreatic duct calculi obstructing the main pancreatic duct, gallstone ileus with large stones impacting the duodenum or ileocecal valve, and calcified or occluded pancreatic duct stents.^5-7 This review focuses on endoscopic lithotripsy techniques and their applications in various gastrointestinal conditions.

Lithotripsy Techniques
Mechanical Lithotripsy (ML)

First introduced in 1982, it is one of the most commonly used lithotripsy methods due to cost, simplicity, and availability; and is the initial modality of lithotripsy used for almost all GI lithiasis. ML uses a large, strong basket to capture the stone, and a crank handle (Figure 1.A) to apply tension to the basket wires to crush the stone. ML baskets are of two types: through the scope and a second type called the salvage device. The first uses a 3-piece pre-assembled basket (Figure 1.B) fitted through an inner plastic and outer metal sheath. This apparatus is inserted through the accessory port of the endoscope, and the stone is trapped using the basket and plastic sheath. The metal sheath is then advanced over it and tension is applied to crush the stone using a crank handle (wheel or a caulk gun design). The latter salvage design (LithoCrushV – Olympus America Inc.) is generally used for the emergent treatment of an unexpected broken basket or stone impaction. Hard stones can sometimes break the basket and wires resulting in impaction. A study by Thomas M et al.⁸ with 712 ML cases showed the incidence of trapped/broken basket (N = 18), wire fracture (N = 12), and broken handles (N = 12) for overall biliary and pancreatic procedures. The salvage procedure is performed by removing the endoscope as well as the crank handle from the patient, and then a spiral metal sheath is glided over the bare basket wires with fluoroscopic assistance. The crank handle (Figure 1.C) is then connected, and the stone is crushed. Later both the broken basket and stone are retrieved. Newer techniques now allow passing a smaller sheath through the scope without having to remove the duodenoscope.⁹ A success rate of up to 90% has been reported with this technique.¹⁰ However, this is influenced by several factors including stone composition, size, shape, number, the diameter and tortuosity of the bile duct with or without the presence of stricture, broken lithotripter baskets, stone engagement by lithotripter and impaction.^11-13 Complications like basket impaction, broken handle, bile duct perforation, and pancreatic duct leak are seen with approximately 4% of ML procedures.8 ML is also an acceptable modality of endoscopic treatment for pancreatic duct stones with favorable outcomes.¹⁴ However, rates of complications are three-fold higher than in biliary applications.⁸

Electrohydraulic Lithotripsy (EHL)

After successful animal and corpse experiments, this industrial mining tool was introduced in the late 1970’s by Koch for the management of large bile duct stones in humans.¹⁵ EHL (Northgate Technologies, Inc, Elgin, IL, USA) uses a mother-baby endoscopy system, and a cholangioscope (Figure 2.A) is inserted through the instrument port of a larger duodenoscope. Under direct visualization or fluoroscopic guidance, a bipolar probe connected to a generator (Figure 2.B) is deployed through the instrument channel of the cholangioscope close to the stone, and continuous irrigation is performed to create an aqueous medium. The bipolar probe then creates high-frequency hydraulic pressure waves leading to stone fragmentation.¹⁶ Traditionally, two endoscopists were required to perform this procedure, one to maneuver the duodenoscope and a second to operate the cholangioscope. In addition, older systems had other technical limitations such as fragile scopes and reduced steerability. In 2015, a single-operator cholangiopancreatoscopy system – SpyGlass DS (Legacy and DS; Boston Scientific, Boston, Mass) was introduced with improved operating characteristics and higher image resolution thus overcoming the limitations of older systems.^17,18 EHL has been shown to have a stone fragmentation rate of 96% and final clearance of 90% for gallstones and 83% fragmentation rates for pancreatic duct calculi. Complications are seen in 7-9% of patients with the most common being cholangitis and ductal perforation.¹⁷ A study by Arya N et al.¹⁹ with 111 patients showed complications such as cholangitis (13 patients), hemobilia (1 patient), post-ERCP pancreatitis (1 patient) and biliary leak (1 patient) post-EHL. A multi-center retrospective study of 224 patients by Alder DG et al.²⁰ undergoing a single operator cholangiopancreatoscopy reported adverse events including post ERCP pancreatitis, cholangitis, bleeding and perforation in 3.9%, 1.4%, 1% and 0.7% of cases respectively.

Laser Lithotripsy (LL)

In 1986, endoscopic retrograde laser lithotripsy was used for the first time in the treatment of problematic large bile duct stones.²¹ Numerous types of laser technologies are employed, such as pulsed dye laser lithotripsy, a rhodamine-6G dye laser with an integrated stone-tissue detection system, holmium laser lithotripsy, and Double Pulse Nd: YAG (FREDDY) laser.^22-25 LL (Lumenis Ltd. Israel) (Figure 3.) is performed by direct visualization using a cholangioscope, or under fluoroscopic guidance. A tissue-stone recognition system developed in 1993 identifies gallstones, and the tip of the probe is placed on the surface of the stone using the helium-aiming beam. Laser light initiates plasma formation at the stone surface, and a short, very high-intensity pulse heats the plasma which causes expansion and contraction of the stone leading to fragmentation. Fragments are later extracted with a dormie basket or balloon catheter.²⁴ Alternatively, the stone can first be captured using a double lumen basket, with LL performed subsequently.²⁶ LL is also used for pancreatic duct calculi when conventional methods fail. EUS-guided pancreaticogastrostomy with a self-expanding stent is used to access the main pancreatic duct, and LL is performed on pancreatic duct stones.²⁵ Stone fragmentation rates of 80-90% with a ductal clearance of 64-97% are reported. Adverse events like pancreatitis, hemobilia, and cholangitis have been observed in a trivial number of patients.²⁴

Extracorporeal Shockwave Lithotripsy (ESWL)

This well-established treatment technique for urolithiasis has been extrapolated for the management of gallstones and pancreatic duct stones. It was first used in 1985 to treat difficult gallstones using a kidney lithotripter.²⁶ Stones are targeted with fluoroscopy after injection of contrast medium via nasobiliary catheter or ultrasound guidance, and shock waves are generated by an electromagnetic lithotripter (Delta Compact, Dornier Medtech, Wessling, Germany). These high-pressure shock waves through liquid or tissue medium are then fixated on to a target by elliptical transducers. First generation ESWL required immersion of patients in water and obligated use of general anesthesia. Newer machines do not require immersion and can be used with sedation only.^28,29 Stone clearance rates were as high as 90% for gallstones and 71% for pancreatic duct stones. Complications are seen in about 10-15% of patients, with patients experiencing cardiac arrhythmia, hemobilia, cholangitis, pancreatitis, and hematuria. A prospective study involving 283 patients by Tandan M et al.³⁰ showed complications such as mild hemobilia (12% cases), cholangitis (3.8% cases), and post-ERCP pancreatitis (3.5% cases). Other rare incidents reported include bowel perforation and splenic rupture.^28,31 ESWL is successful and well tolerated by patients, and the equipment is easily available at most institutes as they are the same ones used for renal stones. However, LL has been shown to have better outcomes compared to ESWL in terms of stone-free rates (97% vs. 73%) and number of sessions needed for stone clearance (1.2 vs. 3 respectively).³²

Lithotripsy Applications
Common Bile Duct Stones

Approximately 10% of the US population is diagnosed with gallstones, and 10-20% of these patients develop choledocholithiasis. 35% of patients with gallstones will ultimately become symptomatic and will require cholecystectomy. Of these, 3-10% of patients are found to have CBD stones.³³ CBD stones can vary in size from 1-2 mm to as large as 3 cm or more. CBD stones up to 1.5 cm can be treated with conventional techniques like endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy and basket or balloon extraction. However, conventional endoscopic techniques fail in 10-15% of patients, because the stones are too large or impacted, or due to challenging bile duct access or intrahepatic stones.¹² In such cases, stone fragmentation is required prior to extraction using techniques like lithotripsy. ML technique is very effective in the management of large bile duct stones, but in frail patients or in select high-risk groups, peroral cholangioscopy guided laser or electrohydraulic lithotripsy is safer for fragmentation and ductal clearance.29 EHL has also provided treatment for symptomatic cholelithiasis for high-risk surgical candidates such as patients with end-stage liver disease.³⁴

Chronic Calcific Pancreatitis

Pain in chronic pancreatitis is caused by a wide variety of factors, but the main pancreatic duct obstruction due to stones or strictures resulting in increased duct pressure and pain is well established.³⁵ Stones are observed in as many as 90% of patients with chronic alcoholic pancreatitis. ERCP with sphincterotomy and balloon or basket stone removal after mechanical lithotripsy have been validated with reasonable outcomes. The success of these procedures is limited when the size of the pancreatic duct stone is > 5mm, or in the setting of strictures or impaction. Surgery carries a risk of 5% mortality and has not been shown to achieve long-term pain relief.³¹ Bekkali et al.¹⁷ described ductal clearance for pancreatic duct stone when using SpyGlass-assisted pancreatography with EHL which obviated the need for surgery; similar results have been reproduced by other groups.³⁶ ESWL has been shown to be effective in patients who failed conservative pain management in several retrospective and prospective studies. A study by Tandan et al. showed 84% pain relief at 6 months follow up post ESWL. In a subsequent study, 68.7% of patients at 24-60 months and 60.3% at > 60 months showed the absence of pain after ESWL and ERCP.30,35 A meta-analysis of 27 studies on ESWL showed 52.7% pain relief, quality of life improvement in 88.2% and ductal stone clearance in 70.7% of patients.31 Alternative therapies with LL or EHL for patients who failed ESWL or with hereditary pancreatitis are also available, but experience with these techniques is limited.³⁷

Gallstone Ileus and Bouveret’s Syndrome

Large gallstones can rarely migrate through a cholecystoduodenal or choledochoduodenal fistula and cause obstruction of the gastric outlet, duodenum or ileum.³⁸ Endoscopic treatment with or without lithotripsy is now the first line management for this disorder. A comprehensive review of 61 cases by Dumonceau showed successful treatment by mechanical lithotripsy (40% of cases), EHL (21% of cases), LL (15% of cases), and ESWL (4% of cases).³⁹

Calcified or Occluded Pancreatic Stents

One of the main indications for pancreatic duct stent placement is pain secondary to obstruction from strictures or stones. Several studies have shown a success rate of 75-100% pain relief after stent placement.^40,41 However, the benefit is only short term due to a common phenomenon of stent clogging at 9-12 weeks making regular stent exchange inevitable. ESWL is used effectively to cleanse clogged stents with success in as many as 80% of cases thus increasing exchange intervals.⁷ Stent exchanges can be complicated by calcified stents making them difficult to retrieve by snares or forceps during ERCP; ESWL has been used in such cases where lithotripsy is performed prior to ERCP making stent exchange successful.⁴²

CONCLUSION

In conclusion, given high rates of morbidity and mortality associated with surgical methods, endoscopy with lithotripsy has become the primary modality of treatment in the past few years for difficult to treat gastrointestinal lithiasis. Recent advances in endoscopy techniques with newer ultrathin endoscopes, and single operator cholangioscopes have made these procedures safer and more reliable. In addition, patients prefer alternative non-surgical approaches. Future studies should focus on quality, safety, efficacy and best modalities of lithotripsy for a specific gastrointestinal condition.

Dispatches From The Guild Conference, Series #17

Managing Severe Ulcerative Colitis in the Hospitalized Patient

Edward V. Loftus

Studies tell us that the first year after diagnosis of ulcerative colitis (UC) is associated with the highest colectomy rate and it’s severity can be defined by a combination of clinical and objective parameters. In this article we discuss the management of severe UC in the hospitalized patient.

Esophageal adenocarcinoma is increasing in frequency in the United States. Barrett’s esophagus is the strongest risk factor for esophageal adenocarcinoma making evaluation for Barrett’s esophagus of utmost importance. Currently screening and surveillance are accomplished with regular white light endoscopy; however, new advances in both population screening and surveillance are being developed. This review will cover selecting the appropriate patient population for Barrett’s esophagus screening, available and upcoming technologies for screening and surveillance, and lastly treatment of Barrett’s esophagus.

One of the true “emergencies” in inflammatory bowel disease (IBD) is the management of the patient with acute severe colitis. Natural history studies tell us that the first year after diagnosis of ulcerative colitis (UC) is associated with the highest colectomy rate. Ulcerative colitis severity can be defined by a combination of clinical and objective parameters. The Truelove and Witts Severity Index, developed over 60 years ago, still holds up as a good approximation of disease activity.¹ Patients with severe ulcerative colitis tend to have more than six bowel movements per day, frequent blood in stool, a body temperature >37.5 degrees Celsius, heart rate >90 beats per minute, hemoglobin that is <75% of normal (i.e., <9 g/dL for women, <10 g/dL for men) and erythrocyte sedimentation rate >30 mm per hour.¹

On day one of hospitalization, abdominal film should be obtained to exclude toxic megacolon. Clostridium difficile superinfection should be excluded. The patient should be given intravenous fluids and corticosteroids. Patient expectations should be set. The colorectal surgeon should be consulted. Subcutaneous heparin should be administered for deep venous thrombosis prophylaxis, as patients have an elevated risk due to activation of the coagulation cascade due to systemic inflammation. Narcotics should be avoided as they can further slow gut motility and potentially precipitate toxic megacolon. In anticipation that the patient might require immunosuppression (either infliximab or a calcineurin inhibitor), thiopurine methyltransferase, interferon gamma release assay for tuberculous antigens and hepatitis B virus serologies should be obtained.

Numerous studies have documented the increasing prevalence and severity of Clostridium difficile infection, particularly in patients with inflammatory bowel disease.² These infections can lengthen hospital stay as well as increase in-hospital colectomy rates and mortality. Another superinfection to exclude is cytomegalovirus (CMV) infection, which is diagnosed by flexible sigmoidoscopy and biopsy, asking the pathologist to obtain CMV immunostains (this should be obtained within 48 hours of admission). The density of CMV inclusions in the biopsy fragments will help determine whether the CMV is an “innocent bystander” (generally <5 inclusions per biopsy) or an actual pathogen (generally >5 inclusions per biopsy).³ Multiple studies have demonstrated that antiviral therapy with intravenous (IV) ganciclovir followed by oral valganciclovir can reduce colectomy rates in UC patients who are refractory to intravenous corticosteroids and who have CMV colitis.

Intravenous corticosteroid doses should be equivalent to methylprednisolone 60 mg daily. There is no evidence that steroid doses higher than the equivalent of methylprednisolone 60 mg daily are more efficacious-indeed, a meta-regression of multiple studies correlated colectomy rates with corticosteroid dose and found no reduction in colectomy rates beyond 60 mg daily.⁴ The original “Oxford regimen” for acute severe colitis included not only intravenous fluids, electrolytes and corticosteroids, but also intravenous antibiotics, blood transfusion, bowel rest and corticosteroid enemas.⁵ Although bowel rest is appealing (less antigenic stimulation, less luminal secretion, etc.) there are at least two controlled trials showing that total parenteral nutrition and bowel rest was no more effective in reducing colectomy rates compared to offering the patient a general diet. Therefore, routine bowel rest and total parenteral nutrition for acute severe colitis is not advocated; however, total parenteral nutrition (TPN) may be indicated for severe malnutrition. Similarly, several controlled trials have not demonstrated a benefit for intravenous antibiotics in acute severe colitis, but there may be a role for broad spectrum antibiotics in selected patients with fulminant colitis.

A number of studies have attempted to prognosticate risk of colectomy in patients with acute severe colitis.6,7 The best indices seem to incorporate serum C-reactive protein concentration and stool frequency on the third day of hospitalization. For example, having >8 stools daily, or 3 to 8 stools daily in combination with a CRP >45 mg/L on day three, is approximately 85% predictive of requiring colectomy. Thus, by day three the provider has a good idea as to whether or not salvage therapy with infliximab or a calcineurin inhibitor will need to be implemented at day five.

The best study demonstrating the efficacy of infliximab in the setting of severe ulcerative colitis was a European study by Jarnerot and colleagues.⁸ A total of 45 patients were randomized to infliximab 5 mg/kg versus placebo. Two thirds of the infliximab-treated patients were able to avoid colectomy as compared to only 29% in the placebo-treated group. A subgroup analysis of the Active Ulcerative Colitis Trials (ACT) showed that survival free of colectomy was significantly higher among patients randomized to the infliximab group compared to that of the placebo group.⁹ Adverse events associated with anti-tumor necrosis factor (TNF) alpha agents have been well described over the past 20 years. These events include granulomatous and fungal infections, other serious infections, infusion reactions, drug-induced lupus, demyelination syndromes, congestive heart failure, hepatotoxicity and an increased risk of lymphoma and skin cancer.

The use of infliximab in the acute severe colitis setting is challenging in that infliximab is a protein and severe UC patients generally have a protein-losing colopathy (which in part explains their hypoalbuminemia). It has been shown that patients who are not experiencing clinical or endoscopic response in the acute severe colitis setting have higher levels of fecal infliximab than those responding.¹⁰ Higher doses of infliximab, or an accelerated dosing regimen, might reduce the colectomy rate. However, this has been surprisingly difficult to prove. One retrospective study of 50 hospitalized UC patients who were steroid-refractory received either standard induction dosing or accelerated dosing (three doses within a median interval of 24 days).¹¹ In the short term, patients receiving accelerated dosing were significantly less likely to require colectomy during induction (6.7% versus 40%); however, by two years out, the colectomy rates were not significantly different. The experience with accelerated dosing of infliximab in severe UC by the IBD group at the University of Michigan has been published in preliminary form.¹² They instituted in 2013 a protocol whereby the second dose of infliximab 5 mg/kg was given early if the CRP level had not dropped by 7 mg/L. Surprisingly, the colectomy rate among the accelerated group was significantly higher (47.1%) than among the group receiving standard dosing (12.4%).¹² At this point in time, an accelerated dosing regimen would not be considered “standard of care.”

The landmark trial demonstrating the short-term efficacy of intravenous cyclosporine in the acute severe colitis setting was published in 1994 (82% response rate with cyclosporine vs. 0% placebo, 18% vs. 44% colectomy rate).¹³ Further randomized controlled trials showed that cyclosporine was at least as effective as corticosteroids,¹⁴ and that a 2 mg/kg infusion was as effective as 4 mg/kg.¹⁵ The long-term efficacy remains unclear. This appears to be a good option in a patient na�ve to thiopurines, because one then can use cyclosporine as a bridge to thiopurines. Cyclosporine might make more sense in a patient with marked hypoalbuminemia/protein-losing colopathy. Serious infections including fatal infections (1.4%-2.8%) have been described with the use of cyclosporine.^16-18

A randomized clinical trial comparing cyclosporine to infliximab in 110 patients with acute severe colitis refractory to steroids was performed by the GETAID group.¹⁹ Treatment failure was defined as a composite of no clinical response at day seven, inability to achieve steroid-free remission by day 98, a clinical relapse between days 7 and 98, colectomy, or death. Rates of treatment failure were similar-54% for the infliximab group versus 60% for the cyclosporine arm.¹⁹ The authors concluded that cyclosporine was not superior to infliximab. Colectomy rates at day 98 were very similar-18% in the cyclosporine group versus 21% in the infliximab-treated arm. Over the longer term, colectomy rates up to seven years out from initiation in the trials were similar.²⁰ Thus, it is reasonable to consider either option as salvage therapy in steroid-refractory severe ulcerative colitis patients. The sequential use of cyclosporine followed by infliximab or vice versa is generally not recommended, because such a strategy does not improve colectomy-free survival, and it appears to be associated with a high rate of serious adverse events including serious and sometimes fatal infections.²¹

Tacrolimus, which has better oral bioavailability than cyclosporine, may be a reasonable alternative to the aforementioned options. In a Japanese randomized trial comparing low-trough level tacrolimus (5-10 ng/mL) to high-trough level tacrolimus (10-15 ng/mL) and to placebo, the rates of clinical improvement, clinical remission, endoscopic improvement, and endoscopic remission were significantly higher for the treatment arm randomized to the high-trough level arm.²²

Surgical options for ulcerative colitis include total proctocolectomy with Brooke ileostomy and total proctocolectomy with ileal pouch-anal anastomosis. In the acute severe colitis setting, the latter is typically offered as a 3-stage rather than 2-stage procedure. Such an approach is associated with reduced postoperative complications. Disappointingly, colectomy rates in the acute severe colitis setting have not changed over the past 40 years (since the advent of the Oxford regimen). A 2007 meta-regression of numerous studies of severe UC found that the mean weighted colectomy rate was 27% and there had been no change over time.⁴ The mortality rate for acute severe colitis was 1%. A landmark study of the Nationwide Inpatient Sample by Kaplan and coworkers found that only about 30% of the colectomies performed in U.S. hospitals for ulcerative colitis were proctocolectomies with ileal pouch-anal anastomosis (IPAA), and this was most frequently performed at centers with the highest volume of colectomies.²³ In that same study, it was noted that there was an inverse relationship between postoperative mortality and colectomy volumes. Centers with the lowest volume of colectomies had a postoperative mortality of 4%, whereas the highest volume centers had a postoperative colectomy mortality of only 0.7%. Emergency or urgent colectomy had a postoperative mortality of 5.4%, while mortality associated with elective colectomy was 0.7%.²³ We presented our experience at Mayo Rochester with severe ulcerative colitis in preliminary form.²⁴ Between 1997 and 2006, a total of 281 patients were hospitalized with acute severe colitis. The in-hospital colectomy rate was 44%. In multivariate analysis, predictors of colectomy included prior hospitalization for UC, previous need for steroids, a hemoglobin on admission of <12 g/dL, endoscopic severity with a Baron score of 3 or 4, and body mass index of <25 kg/m2.²⁴ Only 30% of those treated with cyclosporine were able to avoid colectomy, whereas 63% of those treated with infliximab could avoid in-hospital colectomy.

Putting this all together, one should exclude superinfections early on, get the colorectal surgeon involved early, treat with intravenous corticosteroids, assessing response at day three with a view to initiating salvage therapy or proceeding with colectomy if no clinical response by day five.^25,26

A Special Article

Chromoendoscopy in Community Practice

Samir A. Shah

Early detection of dysplastic tissue during colonoscopy allows early intervention and may decrease colon cancer and improve survival. Studies from several academic centers have demonstrated chromoendoscopy increases diagnostic yield for intraepithelial neoplasia in inflammatory bowel disease (IBD) compared with white-light colonoscopy (WLE). The feasibility of this technique, however, has not been adequately studied in the community setting. Our study evaluates a single physician’s experience with chromoendoscopy in patients with IBD.

Mohd Amer Alsamman, MD¹ Niren Jasutkar MD, PharmD² Steven E. Reinert³ Murray Resnick MD, PhD⁴ Jude Fleming MD⁵ Samir A. Shah MD⁶¹ ¹Internal Medicine, Alpert Medical School, Brown University, The Miriam Hospital, Providence, RI ²Riverside Medical Group, Secaucus NJ ³Lifespan Information Services, Lifespan Hospital System, Providence, RI ⁴Department of Pathology, Alpert Medical School, Brown University, The Rhode Island Hospital, Providence, RI ⁵Internal Medicine, Columbia University, New York, NY ⁶Division of Gastroenterology, Alpert Medical School, Brown University, The Miriam Hospital, Gastroenterology Associates Inc., Providence, RI

Background: Patients with inflammatory bowel disease (IBD) have increased risk of developing colorectal neoplasia associated with chronic inflammation. Surveillance colonoscopy for longstanding disease is the standard of care. Typically, conventional white light endoscopy (WLE) is used with random biopsies; however, studies from several academic centers have demonstrated chromoendoscopy increases diagnostic yield for intraepithelial neoplasia in (IBD) compared with (WLE).

Aims:
Compare the feasibility and yield of chromoendoscopy vs WLE surveillance colonoscopy in a community based practice.

Methods:
A retrospective review of surveillance colonoscopies performed by one physician in a community based private practice with and without chromoendoscopy in patients with IBD between January 2005 & August 2012. Demographic data, time for procedure, number of biopsies, number of jars, and yield of dysplastic lesions were obtained.

Results:
25 dysplastic lesions were found in 64 procedures with chromoendoscopy (39.1%) versus only 8 in 120 procedures (6.9%) with WLE (p<0.001).

Conclusions:
Chromoendoscopy is feasible in community private practice. Compared to WLE, chromoendoscopy yields a higher rate of dysplastic lesions, similar to the increased yield reported from academic centers.

INTRODUCTION

Early detection of dysplastic tissue during colonoscopy allows early intervention and may decrease colon cancer and improve survival.¹ Studies from several academic centers have demonstrated chromoendoscopy increases diagnostic yield for intraepithelial neoplasia in inflammatory bowel disease (IBD) compared with white-light colonoscopy (WLE).^2,3,4 The feasibility of this technique, however, has not been adequately studied in the community setting. Our study evaluates a single physician’s experience with chromoendoscopy in patients with IBD.

Background

Patients with Crohn’s and ulcerative colitis have increased risk of developing colorectal neoplasia associated with chronic colonic inflammation. This risk rises with duration and extent of disease and other factors including primary sclerosing cholangitis (PSC), family history of colon cancer, and histologic disease activity. Current ASGE guidelines recommend surveillance colonoscopy every 1 to 3 years starting approximately 8 years after onset of left sided colitis and Crohn’s disease involving at least 1/3 of the colon, and annually in cases of PSC with IBD (starting at time of PSC diagnosis).^5,6 Most endoscopists will take random four quadrant biopsies from every 10 cm of the colon with the aim of collecting at least 32 biopsies to maximize sensitivity in detecting dysplastic lesions. This approach relies on sampling luck and may overlook early neoplasia. In addition, previous studies have shown poor adherence in obtaining 32 biopsies. Furthermore, the yield of random biopsies is exceedingly low.^7,8 Dysplastic lesions often have flat or subtle borders and early lesions may not be detected by conventional standard definition or even high definition white light endoscopy (WLE).

Over the past decade, numerous studies from tertiary academic centers have established the advantage of chromoendoscopy over WLE.^9,10,11 The use of chromatographic dyes to better visualize colonic mucosa allows for easier detection of subtle dysplastic tissue. Contrast dyes, such as indigo carmine, coat the surface of gastrointestinal mucosa highlighting pit pattern of normal mucosa.12 Absorptive dyes, such as methylene blue, are taken up by normal mucosa, leaving dysplastic tissue unstained.^13,2 Irrespective of the dye utilized, chromoendoscopy facilitates targeted biopsy or lesion removal by highlighting the borders of flat or subtle neoplastic tissue. Previous studies have reported a 3 to 6 fold increase in number of lesions detected using chromoendoscopy with increase in sensitivity and specificity of detecting dysplastic tissue.^14,15

The feasibility and practicality of this technique in the community setting has not been adequately studied. There is a significant increase in length of procedure which some argue may make chromoendoscopy prohibitive in a private practice setting. However, if targeted biopsies have higher efficiency in detecting dysplasia, random biopsies may be avoided which would result in greater savings from pathology costs as well as keep procedure time comparable to conventional colonoscopy. Other barriers may include lack of exposure to chromoendoscopy during GI fellowship or afterwards, unfamiliarity with the Kudo pit classification, cost and availability of dyes for chromoendoscopy, lack of additional compensation for performing chromoendoscopy lack of specific billing code for chromoendoscopy, and finally lack of data showing reduction of incidence and death from colorectal cancer as a result of utilizing chromoendoscopy.

Methods

We performed a retrospective review of surveillance colonoscopies with and without chromoendoscopy in patients with IBD between January 2005 & August 2012. The choice of using chromoendoscopy (indigo carmine 0.1 to 0.4%) for a surveillance exam was at the discretion of the endoscopist (SAS) and was not randomized. Procedure reports and pathology were reviewed. On the procedure reports, a detailed description of the polyp detection before or after chromoendoscopy was specifically noted by the physician (SAS) performing all the surveillance colonoscopies. This was done with the anticipation of analyzing whether the extra time spent in doing chromoendoscopy would be justified by an increased yield. The scopes used transitioned from standard definition to high definition during the study period (2010 in the outpatient ambulatory center and 2006 at the hospital). Demographic data (age, gender), diagnosis (Crohn’s, ulcerative colitis, inflammatory bowel disease unspecified), smoking and family history, history of polyps, length of time for colonoscopy (defined as scope insertion to scope removal), complications from procedure, location & number of biopsies, and final tissue diagnosis from pathology were collected. The Lifespan/Rhode Island Hospital Institutional Review Board reviewed and approved the study protocol.

Results

A total of 184 colonoscopies were evaluated. Of these, 64 were performed using chromoendoscopy with indigo carmine dye. Cases comprised 118 individual patients, 64 males and 54 females, with a mean age of 51.6 years. There were no adverse events associated with colonoscopy with or without chromoendoscopy in the study population. These demographics are outlined in Table 1.

The average length of procedure was 38.8 [34.1, 43.4] minutes for chromoendoscopy, and 20.5 [18.1, 22.9] minutes without (p<0.001). Chromoendoscopy yielded an average of 42.0 [38.0, 46.0] biopsies in 13.1 [12.4, 13.86] jars per case, while white-light averaged 34.9 [32.4, 37.3] biopsies in 10.0 [9.68, 10.44] jars (p<0.001) per case.

White light colonoscopy found 87 polyps and chromoendoscopy found 157 polyps. An average of 2.4 [1.9, 3.0] polyps were resected per case during chromoendoscopy while white-light yielded 0.7 [0.5, 1.0] polyps per case on average (p<0.001). Chromoendoscopy led to discovery of 25 dysplastic lesions in 64 colonoscopies at a rate of 0.39 [0.23, 0.55] per case compared to 8 dysplastic lesions in 120 colonoscopies at a rate of 0.07 [0.02, 0.11] per case with WLE (p<0.001), (Figure 1). Of all polyps discovered via chromoendoscopy, 31% were dysplastic lesions. With white light, 7% (p=0.002) of all polyps resected were dysplastic. In our study, there was only one case, which found low grade dysplasia on a random biopsy; otherwise all remaining dysplastic lesions were resected polyps.

We divided our study population based on extent of disease, into left sided colitis, ileocolitis, and pancolitis. On analyzing different groups, percentages of dysplastic lesions found were 16.2%, 6.5%, and 77.3% respectively. We looked at the following variables, extent of disease, age, gender, family history, and, smoking in relation to total number of dysplastic lesions, using t test; P values, were 0.71, 0.74, 0.41, 0.75, 0.26, respectively. A previous personal history of polyps was significantly associated with subsequent dysplastic polyp detection (p = 0.001). These results are presented in Table 2.

Discussion

Chromoendoscopy allows for increased recognition of dysplastic polyps especially in higher risk populations such as patients with IBD.^16,17 Our analysis is consistent with published data from tertiary academic centers and demonstrates that chromoendoscopy can be done safely in a community private practice setting and with increased yield for dysplastic lesions.

In our study colonoscopy time was prolonged by an average of 18 minutes per procedure with chromoendoscopy, which is higher than the 11 minute average reported by Subramanian.¹⁷ This is at least in part due to the endoscopist still doing random biopsies with chromoendoscopy. Since early 2014, the endoscopist has given up random biopsies with chromoendoscopy and switched to chromoendoscopy for all surveillance in IBD with only targeted biopsies. For the few patients with co-existing PSC, a previous history of dysplasia on random biopsies, or multiple pseudopolyps, random biopsies in addition to chromoendoscopy is still employed. A review of the last 20 cases with chromoendoscopy from October 2017 to February 2018 showed an average time of 29.6 minutes per case and 5.7 jars per case and included several patients with multiple pseudopolyps in whom multiple random biopsies were taken. Thus with this approach most cases are done under 30 minutes making it practical from a scheduling and community practice perspective. In addition, all colleagues within the same community practice have adopted chromoendoscopy into their practice for selective cases without difficulty.

The technique allowed for a five-fold higher rate of detection of dysplastic lesions compared to white light colonoscopy. This correlates with published data citing a 3 to 5 fold difference.^10,18 Our experience is consistent from the “real world” experience from a multicenter study in Spain with 350 IBD patients from 2012-2014 who underwent WLE followed by chromoendoscopy with indigo carmine. In this study, 41.5% of the procedures were with standard definition scopes and 58.5% were with high definition. A total of 94 dysplastic (1 Cancer, 5 HGD, 88 LGD) lesions were found with a dysplasia miss rate 40/94 (57.4% incremental yield with chromoendoscopy). No significant learning curve was observed, no difference was noted between experts and non-experts in chromoendoscopy and increased yield with chromoendoscopy was seen regardless of whether standard or high definition scopes used. The authors concluded that any endoscopist can do chromoendoscopy and it works better than WLE high definition or standard definition. In contrast, a recent single center, prospective study in Calgary Canada randomized 270 patients with longstanding IBD 1:1:1 to surveillance dye spray chromoendoscopy, high definition WLE and “virtual chromoendoscopy” using the Pentax iScan technology. All of the procedures were performed by a single highly experienced endoscopist with only targeted biopsies for all cases. Initially for dye spray chromoendoscopy 0.4% indigo carmine was used and later .03% methylene blue due to shortage of indigo carmine. No difference in dysplastic lesion detection between the three techniques arguing against chromoendoscopy.

In our population, random biopsy yielded low grade dysplasia in only one patient. This patient has chosen to not have colectomy and remains under surveillance with annual chromoendoscopy without further dysplasia detected with the exception of a few visible dysplastic polyps seen with chromoendoscopy. Thus, the yield of random biopsies finding dysplasia was approximately 1 in 6,600. This is consistent with other studies^19,7 that the utility and cost effectiveness of random biopsies is exceedingly low. Furthermore, the 32 random biopsies are estimated to sample only 0.03% of the mucosal surface. Two studies concluded that even with standard white light endoscopy, most dysplastic lesions found were endoscopically visible.^8,20 These studies reported that 73-77% of dysplastic lesions and 89-100% of invasive cancers in UC patients were detectable endoscopically with white light colonoscopy.

The expense from random biopsy must also be taken into account. The most recent Medicare fee-schedule lists an average pathology cost of $73 per specimen jar submitted for gross and microscopic examination (laboratory processing and pathologist reading). As for private insurance, one commercial insurer in our region pays $150 per specimen jar (personal communication, James Carlsted, MD). As chromoendoscopy yielded 13.1 jars per case the average pathology cost was $956.3 for patients who had Medicare and $1,965 for private insurers. On the other hand, WLE yielded 10 jars per case resulting in $750 for Medicare and $1,500 for private insurance. However, chromoendoscopy cases in our analysis averaged a higher number of biopsy jars compared to WLE, but these included both targeted as well as random biopsies. While it was outside the scope of our study, abandoning the practice of random biopsy and performing targeted biopsies alone would significantly reduce the pathology cost associated with surveillance over the lifetime of a patient with IBD. We estimate that the number of jars with targeted biopsies with chromoendoscopy would average 4 (sampling for disease activity and removal of visualized lesions). The estimated cost saving in terms of pathology costs would be $438 for Medicare patients and $900 for commercially insured patients per case. This is particularly important in showing value in the current MACRA/MIPS view of physician services. Furthermore, since a negative chromoendoscopy colonoscopy is associated with a lower risk of colectomy for dysplasia/cancer the interval between surveillance may be increased based on other risk factors leading to further cost savings.¹⁸ In line with this, the British Society guidelines²¹ suggest 5 year intervals for low risk IBD patients.

There are several limitations to the generalizability of our study. All procedures were performed by a single endoscopist. Patient selection toward chromoendoscopy was not random and patients with longer duration of disease, history of dysplastic findings or other risk factors may have generated a higher index of suspicion to select use of chromoendoscopy and hence yield of dysplastic polyps. Over the time period of our analysis, newer generation high-definition endoscopes were introduced which was not factored into our study design. The absence of statistically significant relation between variables known to be associated with risk such as FH, smoking, gender, and number of dysplastic polyps detected is not surprising given the sample size, and retrospective non-randomized design.

Our data adds to growing body of literature supporting the practice of chromoendoscopy as an effective tool in detecting dysplastic lesions and thereby preventing colorectal cancer. It should be utilized more frequently in patients with IBD undergoing surveillance colonoscopy. Our experience shows it can be performed successfully and safely in the community practice setting.

All authors contributed substantially to the manuscript and approved the final manuscript. The study was conceived by SAS. NJ and SAS wrote the protocol for IRB approval with input from MR. NJ did the initial chart reviews and collection of data. JF and MAA performed a critical review of the previous data and focusing on risk factors for colon cancer and filling in gaps in missing data. SR performed all the statistical analysis with input from SAS, NJ and MAA. The bulk of the manuscript was written by NJ, MAA and SAS with critical input from all the authors. Each author read and approved the final, submitted manuscript.

There was no grant support or other assistance.

There were no conflicts of interest on behalf of all authors.

A Case Report

Autoimmune Enteropathy: An Uncommon Presentation

Alan Naim,Kaivan Salehpour,Camron Kiafar

Alan Naim MD,^1,3 Kaivan Salehpour MD,² Camron Kiafar DO, AGAF, FACG^1,3 ¹Department of Gastroenterology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ ²Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ ³Department of Gastroenterology, Phoenix VA Health Care System, Phoenix, AZ

INTRODUCTION

Diarrhea is a common gastrointestinal complaint, with infection, irritable bowel syndrome, inflammatory bowel disease (IBD) and malabsorption syndromes (such as lactose intolerance and celiac disease) being the most common etiologies. We report a case of a 70-year old male with a two-month history of profuse, watery diarrhea. An abdominal computerized tomography (CT) scan on initial presentation revealed pneumatosis intestinalis. Extensive workup that included enteroscopy and colonoscopy revealed histology suggestive of autoimmune enteropathy. Anti-enterocyte antibodies confirmed the diagnosis. Although rare, autoimmune enteropathy (AIE) represents an important consideration in the differential diagnosis of intractable diarrhea in adults.

Presentation

A 70-year old male with a history of resected Meckel’s diverticulum and acid reflux was admitted for profuse, frequent, watery diarrhea and hypotension. Two months prior, he had presented to an outside hospital with similar symptoms including mild abdominal pain; he was found to be severely dehydrated with associated acute kidney injury. At that time, a computed tomography (CT) of the abdomen and pelvis revealed pneumatosis intestinalis of the small intestine and colon. Due to his presentation and CT findings, the patient underwent an exploratory laparotomy. There was no evidence of ischemia, perforation or necrotic bowel noted during laparotomy. Subsequent colonoscopy at the outside hospital was normal. However, random biopsies were suggestive of lymphocytic colitis for which the patient was discharged on budesonide therapy along with total parenteral nutrition (TPN). He presented to our hospital with ongoing intractable diarrhea despite compliance to his medication therapy.

At the time of presentation, he endorsed greater than 15 watery stools per day with nocturnal symptoms. A gluten-free and lactose-free diet failed to improve his symptoms. He had lost nearly 20 pounds in the last two months. He denied recent travel or sick contacts. He had no history of autoimmune disease as well as no family history of gastrointestinal or autoimmune disease. He had a longstanding smoking history but denied alcohol or drug use.

Vital signs were all within normal limits. On physical exam, his findings were only significant for a deconditioned gentleman as well as rectal exam showing peri-anal excoriations. Laboratory studies demonstrated a normocytic anemia, elevated creatinine, and low albumin level of 2.5 gm/dL (nl 3.4-5.0 gm/dL). Human immunodeficiency virus (HIV) status as well as stool studies, which included stool culture with Shiga toxin, Clostridium difficile toxin B PCR, giardia antigen, ova and parasites, fecal lactoferrin and fecal leukocyte testing were all negative. Serum tissue transglutaminase Ab IgA was undetectable with a normal IgA level. CT abdomen/pelvis imaging findings at our institution again demonstrated pneumonitis intestinalis of the small intestine and colon (Figure 1).

Given his non-response to budesonide therapy, and in consideration for an alternative diagnosis, the decision was made to undergo upper enteroscopy and repeat colonoscopy. Esophagogastroduodenoscopy (EGD) and upper enteroscopy findings were normal and random biopsies of the duodenum and jejunum were taken. The colonoscopy showed boggy, edematous appearing mucosa. Random biopsies of the colon were taken as well. Small bowel biopsies all indicated moderate to severe villous blunting, with marked lamina propria infiltrate (plasma cells and lymphocytes) (Figure 2). No goblet or paneth cells were identified. There was marked crypt apoptosis. Colon biopsies exhibited active colitis with preserved crypt architecture. Markedly increased crypt apoptosis was again demonstrated (Figure 3). No goblet or paneth cells were visualized.

Serum Anti-Enterocyte IgG antibodies were present in elevated titers and demonstrated positive linear periapical staining of the enterocytes and staining in the goblet cells. Anti-enterocyte IgA antibody also demonstrated positive linear periapical staining of enterocytes in elevated titers.

When the diagnosis of autoimmune enteropathy was established, he was placed on intravenous methylprednisolone. Shortly after, he was started on TPN for nutritional support. The patient began responding positively to intravenous steroids on the third day of treatment, resulting in a decrease in frequency and volume of bowel movements. As he clinically improved, he was transitioned to oral prednisone and discharged with a steroid taper for outpatient gastroenterology follow-up.

Discussion

Autoimmune enteropathy is a rare cause of intractable diarrhea in children and an even rarer cause in adults. It is best defined as a presentation of chronic diarrhea, malabsorption, with specific small intestinal histologic features and is typically confirmed by the presence of circulating auto-enteric antibodies. Extraintestinal manifestations may include hypothyroidism, nephrotic syndrome, autoimmune hemolytic anemia, and rheumatoid arthritis.^1-3 A lack of response to a gluten-free diet or other dietary exclusions is also described, as is a predisposition to other autoimmune diseases.^1-3 The disease was first described in 1982 in London in a 15 month-old child with protracted diarrhea and weight loss. Since that time, only a handful of adult cases of AIE have been reported with the largest case series from Mayo Clinic Rochester comprising of 15 patients.¹

AIE is histologically characterized by findings including: villous blunting, increased mononuclear inflammation in the lamina propria, lymphocytic infiltration into deep crypt epithelium with a relative decrease of surface lymphocytosis (< 40 lymphocytes per 100 epithelial cells), as well as the presence of increased crypt apoptotic bodies.¹ Mononuclear infiltrates are comprised of both plasma cells and lymphocytes. Colon histopathology shows similar histologic abnormalities to those seen in the small bowel. Gastric biopsies not uncommonly demonstrate an autoimmune atrophic gastritis as well.¹ CT findings are typically non-diagnostic.¹ This is the first known case to report the findings of pneumatosis intestinalis in autoimmune enteropathy.

The presence of anti-enterocyte or anti-goblet cell antibodies is supportive of the diagnosis of AIE, although the detection of these antibodies has been described as “observer dependent.” The significance of circulating auto-enteric antibodies in regards to pathology has not been fully delineated. Akram et al. did not show association between the clinical course, intestinal histology, and the type of circulating auto-enteric antibodies.¹ While anti-enterocyte antibodies have not been reported in celiac disease and inflammatory bowel disease, anti-goblet antibodies have been reported in patients with chronic inflammatory bowel disease, as well as in their asymptomatic first-degree relatives.^4,7,8 Despite concerns regarding their sensitivity and specificity, anti-enterocyte antibodies aid in establishing a diagnosis of AIE in cases with protracted diarrhea and malabsorption.

Much of the pathophysiology behind autoimmune enteropathy is unknown, but some studies have pointed to a deficiency or dysfunction in CD4+ and CD25+ regulatory T cells which are involved in the down-regulation of a variety of bodily immune responses.5 Mutation in the FOXP3 gene (forkhead box p3) in T cells, for instance, has been found in inherited forms of autoimmune enteropathy such as the rare X-linked recessive disorder of early childhood known as IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome.^2,5,6

Scarce data exists regarding epidemiology, disease course, and treatment options for AIE. Anecdotal experience guides a number of treatment decisions including use of corticosteroids as well as immunosuppressive drugs such as azathioprine, cyclophosphamide, tacrolimus, cyclosporine and infliximab. In a retrospective study, over half of the patients responded to steroid therapy. However, two-thirds of these patients either became steroid-dependent or refractory requiring additional immunomodulating or biologic therapy for maintenance of remission.¹

CONCLUSION

Autoimmune enteropathy represents a rare and important consideration in the differential diagnosis of intractable diarrhea in adults. It should be especially sought out in cases of malabsorption and small bowel villous atrophy not responding to a gluten-free diet. This disorder may also be considered in patients presenting with pneumatosis intestinalis when other common causes have been excluded. Treatment can be challenging and often requires both nutritional support with immunosuppressive medications.

A Special Article

Food Additives, the Gut Microbiota, and Inflammatory Bowel Disease:Interpreting the Interplay

David Valadez,

Mazyar Malakouti,

Tisha Lunsford

David Valadez MD, Resident, Department of Medicine, UT Health San Antonio Mazyar Malakouti, MD, Fellow, Division of Gastroenterology, Department of Medicine, UT Health San Antonio Tisha Lunsford, MD Associate Professor, Division of Gastroenterology, Department of Medicine, UT Health San Antonio, Long School of Medicine San Antonio, TX

The interaction between diet, gut microbiota, and inflammatory bowel disease is an immense process with many complex mechanisms. Food additives are one component of the human diet that face intense scrutiny by society, governing bodies, and science. Simply defined, food additives are compounds added to food. This definition has changed throughout history, which provides context for how additives are regulated. Food additives can include, but are not limited to, taste enhancers, emulsifiers, microparticles, preservatives, antioxidants, and polyphenols. Research has shown that food additives modulate the activity of inflammatory bowel disease, particularly through microbial mechanisms, as food additives impact bacterial dysbiosis, colonization, and metabolism. While the available literature is rich with useful information for the primary care physician and gastroenterologist, it highlights the need for continued research on long-term and clinical outcomes.

BACKGROUND HISTORY

The human diet and its impact on inflammatory bowel disease (IBD) have been extensively studied, and we know that both food itself and its relationship with the gut microbiota modulate the natural course of IBD.^1-3 Given society’s boosted attention to health and nutrition, the content of what we eat is facing increasing scrutiny. Food additives are of particular interest because their presence in one’s food is frequently unknown to the consumer. Scientific literature generally defines a food additive as a compound added to foods during any part of their production, processing, treatment, packing, or storage.⁴ The regulation of food additives is a comprehensive process to ensure the safety of such substances for widespread consumption.⁵ However, there are regulatory differences based on definitions and legal stratifications.

The Food and Drug Administration (FDA) is the federal agency that oversees food safety for the United States. In 1958, the Food Additives Amendment to the Federal Food, Drug, And Cosmetic Act defined a food additive as “any substance intentionally added to food,” unless that substance is designated as Generally Recognized as Safe (GRAS). Substances with GRAS exemption have the general consensus, but not necessarily unanimity, of “qualified experts” that their intended uses in food are safe.⁶ These substances are not subject to specific food additive regulations or premarket approval by the FDA. There are over 1,000 substances currently with GRAS exemption.⁷ Since 1997, the FDA no longer affirms GRAS exemption status for substances when petitioned, but instead permits individuals to notify the FDA that they believe a substance meets GRAS exemption. The FDA will review this notification within 30 days, but does not provide affirmation of the individual’s claim.⁸ The FDA can report the notification did not provide a “basis for a GRAS determination,” which has occurred in only 17 out of the 780 GRAS exemption notifications since 1998.⁹

While food additives represent technologic advancements in how we process and consume food, there are still concerns regarding their safety, especially with the possibility of conflicts of interest in regulatory oversight. Common food additives have previously been shown to induce metabolic disease through interactions with the gut microbiota.¹⁰ Table 1 includes examples of food additives within categories by function. Here, we review how certain food additives may influence the pathogenesis of IBD, with an emphasis on how food additives affect mechanisms of the gut microbiota. We begin with a brief review of the relationship between IBD and the microbiota itself.

MICROBIOTA AND IBD

The gut microbiota is the community of micro-organisms, predominately bacteria, which influences gut health through metabolic functions and host responses.¹¹ The core microbiota represents the majority of bacterial species shared among most individuals, and commonly includes Bacteroides, Firmicutes, Fusobacterium.¹² Dysbiosis, an imbalance to the microbiota and a lack of bacterial diversity, has been associated with both Crohn’s disease (CD) and ulcerative colitis (UC).^13-15

Dysbiosis is supported by increased colonization and adherence of bacteria, generally more associated with IBD: Bacteroides, enterobacteria, E. coli (particularly pathogenic AIEC strains), and sulfite-reducing bacteria such as Fusobacterium and B. wadsworthia.^16-22 In particular, increased transportation of E. coli species across the follicular associated epithelium and biofilms of gram-negative species, including Bacteroides fragilis, have been found in microscopic samples in IBD patients.^23-25 Once bacteria have permeated the gut, they can exert direct and indirect influence on the degree of inflammation. Lipopolysaccharide (LPS), bacterial toxins, and hydrogen sulfide, a byproduct of sulfite-reducing bacteria, have been associated with increased inflammation and IBD.^26-29 Short-chain fatty acids (SCFA) are other bacterial byproducts. Butyrate, in particular, is commonly generated by Firmicutes and Faecalibacterium, and may protect against inflammation by enhancing the integrity of the gut barrier, altering gene expression, and promoting Treg cell differentiation.^14,29-35

REVIEW OF FOOD ADDITIVES

Food additives can be natural or synthetic and serve a variety of purposes in food preparation, including, but not limited to, flavoring, preservation, coloring, or stabilizing.^4,36 For our review, we have focused on food additives that have been shown to influence the microbiota and IBD, and stratified them into categories based on their similar characteristics: taste enhancers, emulsifiers, microparticles, preservatives, antioxidants, and polyphenols.

Taste Enhancers

Taste is a sensation with multiple aspects (sweet, salty, bitter, etc.) and taste enhancers serve to augment these various components. Taste enhancers can include sweeteners (natural or artificial) and monosodium glutamate (MSG)^4,36 Sweeteners have been frequently studied given their impact on metabolism and obesity, and it is suggested that alterations in gut microbiota may play a role.³⁷³⁹ Non-caloric artificial sweeteners have been associated with significant dysbiosis and modification of over 40 microbial operational taxonomic units, primarily with an increase in the Bacteroides genus.³⁷ Increased Bacteroides content was also seen in rat models that consumed sugar monosaccharides.⁴⁰ A direct link between sweetener-induced microbiota changes and IBD has not been closely studied. However, a broad review of dietary risk factors did find that increased consumption of sucrose or refined carbohydrates was more common in CD patients.⁴¹ The polysaccharide maltodextrin was also shown to promote E. coli biofilm growth, which may improve colonization of invasive E. coli species.⁴² Gut microbiota in CD has also been found to have an increased amount of maltodextrin-related byproducts.

Contrarily, two artificial sweeteners have been associated with gut environments less favorable for IBD development. Aspartame and xylitol, two ubiquitous dietary sweeteners, have been shown to increase the Firmicutes:Bacteroides ratio and promote increased levels of SCFA, including propionate and butyrate.^27,43 MSG was also seen to promote F. prausnitzii colonization, with this microbe previously shown to have anti-inflammatory effects.⁴⁴

Emulsifiers

Emulsifiers, or food stabilizers, are substances that help avoid the breakdown of food items, specifically by preventing separation, melting, or precipitation.³⁶ Emulsifiers can include polysorbates, gums, lecithin, or gelatins.^4,36 Emulsifiers have been linked to IBD, with studies noting an increase in CD incidence and the development of gut inflammation in animal models when exposed to emuslifiers.^45-47 Bacterial colonization is thought to be aided by the presence of these compounds, with polysorbate 80 and carboxymethylcellulose (cellulose gum) cited as two particular substances.^48,49 Consumption of emulsifiers promote a breakdown of the protective gut mucus layer, which increases the gut permeability and improves the ability of bacteria to both adhere and migrate along the GI tract.^47,50 In particular, increased translocation of E. coli across M cells and human Peyer’s patches is associated with polysorbate 80.⁵¹ Studies have also noted an increase in bacteria-associated pro-inflammatory molecules, such as LPS and flagellin.^47,49 On a larger scale, emulsifiers have also been associated with a decrease in microbial diversity, in particular increasing levels of Bacteroides or decreasing levels of Firmicutes and clostridales.⁴⁹ As previously discussed, these compositional changes have been linked with IBD.

Not all emulsifying food additives have been positively correlated with inflammatory changes, however. Chronic consumption of guar gum was linked to the prevention of colitis in mice. Specifically, guar gum was associated with an anti-inflammatory environment with increased growth of clostridial species and higher levels of fecal SCFA.⁵² Guar gum has been also been shown to downregulate the level of lipopolysaccharide-binding protein in rat models.⁵³

Microparticles

Microparticle is a general term describing non-biologic particles, with sizes in the micron to submicron range, which are similar to bacterial sizes. The two most common dietary microparticles are titanium dioxide and aluminum-based silicates.⁵⁴ Titanium dioxide is a commonly used food additive that can increase whiteness or brighten foods.⁵⁴ Its consumption alone has not been shown to significantly alter the existing microbiota composition.⁵⁵ However, bacterial LPS has been shown to conjugate with titanium dioxide, and this combination can potentiate downstream inflammatory effects in IBD patients.^56,57 Specifically, this molecular conjugate promotes the assembly of the intestinal inflammasome and increases the secretion of IL-1.^58,59 Aluminosilicates help to prevent caking of powder-based foods in association with pressure, moisture, or temperature.⁵⁴ Aluminum-based microparticles have also been shown to bind with LPS to produce pro-inflammatory effects similar to titanium dioxide.^54,56 Aluminum itself was also shown to worsen the intensity and duration of colitis in mice models, with possible mechanisms including damaging the gut barrier and inducing granuloma formation (with in vitro studies).⁶⁰

Preservatives

Preservatives promote food safety and maintain reasonable shelf lives by preventing microorganism growth. Common preservatives include benzoates and sulfites.4,36 Benzoate, or benzoic acid, was found to increase the proportion of lactic acid producing bacteria, including Lactobacillus.⁶¹ Lactobacilli have been postulated to compete for colonization against more pathogenic species. However, catechols (such as 1,2-dihydroxybenzene), which are intermediates in the metabolism of benzoates, have been associated with increased growth and virulence of Enterobacteriaceae species.⁶² Sulfites have been shown to decrease four species of beneficial bacteria, including Lactobacilli.⁶³ This study was notable for using sulfite dilutions at “safe for food” levels.

Antioxidants

Antioxidants are compounds that slow food spoilage and prevent oxidation of food’s fatty content. Common antioxidants include vitamin C and vitamin E.4,36 Oxidative stress or an inadequate antioxidant response has previously been associated with IBD.^64,65 In vivo, LPS has been shown to inhibit the intestinal absorption of ascorbic acid (vitamin C), which underscores importance of adequate dietary intake in individuals with gut inflammation.⁶⁶ Antioxidants can also impact microbial compositions, as administering an antioxidant blend to piglets was shown to increase counts of Lactobacillus and decrease counts of E. coli.⁶⁷

Polyphenols

Polyphenols, or phenolic compounds, are naturally occurring compounds found in fruits, vegetables, and grains.⁶⁸ Their role in nutrition has been expanded to utilize them as food additives in a multipurpose fashion as antioxidants, antimicrobials, texture modifiers, and preservatives.^69,70 In general, polyphenols are considered to be anti-inflammatory and promote growth of “good” microbiota. Studies have associated polyphenols with increases in Lactobacilli and bifidobacterium species.⁷¹ Other studies have noted an ability of polyphenols to reduce luminal pH and potentially inhibit proteolytic bacteria often found in IBD.⁶⁸ More pathogenic gut bacteria, such as Enterobacteriaceae, certain clostridiales (C. perfringens and C. histolyticum), and gram-negative Bacteroides have decreased in number when exposed to polyphenols.^68,71-73 Polyphenols have also been seen to inhibit certain pro-inflammatory markers, such as TNF and IL-6, and reduce oxidative stress.^68,74 These properties may help explain how polyphenol extract was associated with prevention of colitis development in rat models.⁷⁵ Curcumin is a particular polyphenol trending as a therapeutic option in IBD. It has been shown to increase the amounts of Lactobacillus species, butyrate-producing bacteria and promote Treg cell expression in the gut mucosa.^76,77 Still, polyphenols have also been associated with a decreased Firmicutes:Bacteroides ratio and can decrease circulating SCFA, two characteristics found in IBD patients.^68,74

CONCLUSION

This review, while not comprehensive, summarizes the effects of food additives on the gut microbiota and IBD, and highlights the potentially clinical relevant substances. While many food additives are generally thought of as safe for consumption, further research is needed to better assess if chronic exposure to these substances is associated with IBD and how the long-term clinical course of patients is impacted.

A Special Article

Combining Women’s Cancer Screening Examinations Shows A Positive Impact On Colorectal Cancer Screening Rates

Marianne T. Ritchie,

Apeksha Shah,

Bilal A. Asif

Colorectal cancer (CRC) is the 3rd most common cancer among women. In the article we present PINK PLUSTM, an innovative program combining three women’s screenings in one visit; mammogram, gynecology exam (GYN) and pre-colonoscopy visit (GI). PINK PLUSTM is a flexible and convenient program demonstrating a high rate of compliance with colonoscopy, which could serve as a national template aimed at increasing adherence to all women’s cancer screenings, especially in underserved communities, by combining these life-saving screenings into one visit.

Marianne T. Ritchie, MD, Clinical Associate Professor, Jefferson Gastroenterology and Hepatology Director, Sidney Kimmel Cancer Center Colon Cancer Screening/Outreach Apeksha Shah, MD, Fellow, Gastroenterology and Hepatology Bilal A. Asif, MD, Resident, Internal Medicine Thomas Jefferson University Hospital

INTRODUCTION

Timely colorectal cancer (CRC) screening can detect and remove precancerous polyps before they become cancer1,2 and find CRC at an early stage, when a cure is more likely.3 Yet according to the American Cancer Society,³ only 60% of women over age 50, the recommended age to begin CRC screening, undergo screening with endoscopy (colonoscopy or sigmoidoscopy). Lower still is the adherence rate among women ages 50 to 64 (55%). As a result, CRC is the third leading cause of cancer death in US women and a major public health risk.

Women are less likely to undergo CRC screening than men even though CRC mortality rates are similar (4.6% for men vs. 4.2% for women).³ Barriers to screening in women differ from those in men but are not clearly understood.^4,5 Lack of physician recommendation has been cited as a barrier to CRC screening,^6,7 along with embarrassment, expense, discomfort, fear of results, and inconvenience.⁸ Past sexual abuse may also deter women from colonoscopy, as it may stir unwanted memories.⁹

Patient education appears to play an important role. In one study, women were invited to have a conversation about CRC screening while visiting a health care center for a mammogram. Capturing the attention of patients during the visit for mammography led to increasing their CRC screening rates, especially when the program included navigation.¹⁰

Previous studies have also shown that women who engage in other cancer prevention behaviors are more likely to undergo CRC screening.^8,11 For women who had a mammogram within 2 years or Papanicolau smear within 3 years, the likelihood of CRC screening increased from 24% to 60.6% and from 33.3% to 56%, respectively.¹¹

Yet women who practice other forms of preventive care may still avoid CRC screening. CRC screening rates for women lag behind screening rates for breast cancer by about 10% and cervical cancer by about 20%.¹² This lag may result from a lack of public awareness that CRC is both common and preventable,¹¹ and that CRC occurs about equally in men and women. It may also reflect increased general awareness of the benefits of breast cancer screening and cervical cancer screening compared to CRC. Finally, the higher rates of screening for breast and cervical cancer may simply reflect differences in the ease of completing these tests compared to CRC screening.

Gender-related distinctions also exist in location of colonic neoplasia. Women are more likely to have purely right-sided polyps and tumors.¹³ Surveillance, Epidemiology, and End Results Program (SEER) data show CRC in the right colon more often in women (45%) than in men (36%).¹⁴ Another factor that increases the risk for proximal cancers is cholecystectomy, which is more commonly performed in women than in men.¹¹ These data should be considered when making screening recommendations.

Another consideration is ethnicity. Hispanic women have the lowest risk while black women manifest the highest rates of CRC, similar to the white male population.³ There also appears to be a more proximal distribution of CRC and adenomas in African Americans (AA).¹³

Based on what is known about CRC screening barriers and behaviors among women, we created PINK PLUS™, a program that aims to enhance screening rates and compliance by combining screening for breast, cervical, and CRC in one setting. The objective of this report is to describe the implementation of PINK PLUS™ and to detail its impact on screening rates among patients who enrolled in the program.

METHODS

PINK PLUS™ is a program that offers women bundled cancer screenings in one visit at one location by all women health care providers. A pilot at the Thomas Jefferson University Breast Imaging Center was promoted with campus flyers and university intranet announcements. Twelve women participated, each undergoing a mammogram, gynecology examination (GYN) and pre-colonoscopy visit (GI), all within 2.5 hours. A gastroenterologist conducted the GI visit; a history and physical followed by an explanation of the preparation and risks of colonoscopy. Based on positive feedback from the initial cohort, the program was expanded to include several screening combination options during evening hours (mammogram-GI, mammogram-GYN-GI) and daytime hours (mammogram-GI, GYN-GI). At the end of each brief GI visit, patients were scheduled for colonoscopy. Patients were considered ineligible because they were not due for screening, not medically stable, or had insurance issues. A retrospective chart review of all PINK PLUS™ participants collected data including patient age, family and personal history of CRC/polyps, date of subsequent colonoscopy, and any findings of advanced lesions.

RESULTS

In all, 118 women (average age 57.1 years) participated in the program. Eighteen were excluded because they were ineligible for CRC screening (Table 1). Of the 100 remaining women, 77 returned for colonoscopy screening (77%) (Figure 1). Of those individuals who returned for colonoscopy screening, 28 (36.4%) had undergone a prior colonoscopy. Of these patients, 15 (19%) had a personal history of colon polyps (Table 2). A majority of patients had no family history of CRC or polyps; 16 (21%) had a family history of only CRC and an additional 5 (6%) had a family history of both CRC and polyps (Figure 2). On colonoscopy, 35 patients (45%) had a normal examination, 26 patients (34%) had adenomatous polyps, and 15 patients (19%) had hyperplastic polyps. Of those who underwent mammography, 10% had abnormal findings, defined as new mass or lesion detected on mammogram. Of these 77 patients who underwent colonoscopy, most (61%) had the colonoscopy within 3 months, and an additional 14% had colonoscopy within 3 to 6 months (Table 3). DISCUSSION Past attempts to enhance screening rates by media campaigns, fecal occult-blood tests, and other methods have met with limited success, especially in medically underserved communities.¹⁰ By bundling women’s cancer screenings, PINK PLUS™ provides an innovative approach to improving women’s health.

A major strength of the program is convenience. With one phone call, a patient can have up to three cancer screenings in one place on one day, during daytime or evening hours. We showed that the practice of combining two or three cancer screening examinations in one visit improved CRC screening rates in the women who participated in PINK PLUS™. CRC screening was included in each of the three PINK PLUS™ options offered because of the three screenings, CRC has the lowest adherence rates. To our knowledge, no other program adds CRC screening with other women’s cancer screenings in one clinical setting.

Our program’s bundled approach to women’s cancer screenings was built on findings that women who adhere to screening for breast and/or cervical cancer are more likely to undergo CRC screening.^8,11 In particular, one study found that women who had breast and cervical cancer screenings were four times more likely to undergo endoscopic CRC screening.⁶

Several studies have identified a primary care physician (PCP) recommendation as a strong predictor for cancer screening adherence.8 Studies also show that some women consider their Obstetrician-Gynecologist (OB-GYN) doctor as their PCP.¹⁵ PINK PLUS™ enables OB-GYN doctors to refer patients for double or triple screenings, which will help boost CRC screening rates. In addition, there is an association between the risks for CRC and gynecologic cancers. Approximately 10% of patients with both endometrial cancer and CRC are due to the Lynch Syndrome (inherited CRC syndrome) but in the majority of cases, no genetic disorder is found.¹⁶ If endometrial cancer is diagnosed before age 50 or ovarian cancer before age 65 (especially before age 50) there is a marked increase in CRC risk.⁹ PINK PLUS™ considers these related risks by combining these screening options in one visit. Screening recommendations should also reflect these effects on CRC risk.

PINK PLUS™ was also based on capturing opportunities for physicians to provide patients with education about preventive cancer screening. One program that bundled education about breast, cervical and CRC led to positive changes in knowledge and attitude about screenings.¹⁷ Another study added CRC screening education at the time of a mammogram and resulted in improved CRC screening rates.10 The PINK PLUS™ education advantage also includes a full explanation of risks and benefits of various screening tools, and particularly, of colonoscopy over fecal immunochemical testing (FIT) screening¹⁸ or flexible sigmoidoscopy. Colonoscopy enables visualization of the entire colon, and unlike screening tests for other women’s cancers (breast, cervical), is both diagnostic and therapeutic. Precancerous polyps can be removed and prevent the progression to malignancy.¹

PINK PLUS™ enables physicians to focus on the specific needs of women that relate to CRC screening, addressing the potential for different risk factors and presentations in women than in men. Adenomas and CRC in the proximal colon are more common in women, especially African American women under age 40,¹⁹ or those who are post-cholecystectomy.¹¹ Women are also more likely to have flat (sessile serrated) polyps with advanced pathology and cancer,¹³ which also have a predilection for the proximal colon. Smoking is a significant risk for colorectal adenomas and CRC for both men and women, but recent studies show that female smokers are more susceptible than male smokers in developing sessile serrated polyps and proximal CRC, as well as an earlier age of onset and death from CRC.¹³ Upon learning about the several factors that increase the likelihood of proximal colon neoplasia, women understand why colonoscopy is the most optimal screening tool because it enables visualization of the entire colon.

PINK PLUS™ can also eliminate obstacles that may reduce screening rates for some patients. A recent decline in incidence and mortality from CRC that has been noted in white patients has not been paralleled in minority communities. CRC incidence rates are about 20% higher in blacks than in non-Hispanic whites and death rates are 40% higher, according to data from 2009-2013.³Age appropriate Hispanics are less likely to undergo CRC screening (45%) than non-Hispanic whites (61%), as reported in a study from 2013.²⁰ Racial and ethnic disparities in CRC result from several factors including differences in socioeconomic status and levels of education, differences in behavior that increase risk (smoking, obesity) and underuse of screening.^7,19,21 Obstacles to screening include lack of health insurance and health care, language barriers and lack of physician recommendation.^6,7,21

Since the ACS recommends mammography at age 45 with the option to begin at age 40, PINK PLUS™ is an ideal program to identify at-risk patients and facilitate earlier CRC screening when needed. This would include patients with a family history of CRC or colon polyps, inherited CRC syndromes, or those with a personal history of inflammatory bowel disease. In addition, CRC incidence has increased steadily in patients under age 50, from 6% in 1990 to 11% in 2013.³ Most of these cases (72%) are found in patients in their 40s. The risk for developing CRC at a younger age is particularly high for African Americans.¹⁹ In 2017, the Multi-Society Task Force of Colorectal Cancer recommended initiating CRC screening for African American patients at age 45.²² More recently, the American Cancer Society updated their guidelines by adding a qualified recommendation that all average-risk patients should begin CRC screening at age 45.²³ Should the United States Preventive Services Task Force²⁴ also change their national guidelines to begin CRC screening at age 45, PINK PLUS™ will facilitate the screening of these younger patients who are also undergoing mammography.

PINK PLUS™ offers several other advantages aimed at improving cancer screening rates. The convenience of “one-stop shopping” with daytime and evening hours appeals to women of all socioeconomic strata and education levels. One visit with multiple screenings saves costs for transportation and childcare. A face-to-face visit with the gastroenterologist and a navigator is more likely to win the trust of a patient whose cultural fears or a language barrier might otherwise obviate access to screening.

Direct-access-colonoscopy is a growing trend which eliminates an office visit prior to the procedure. With PINK PLUS™, a brief GI visit may also increase the appeal of CRC screening for those patients who are more comfortable meeting the endoscopist before examination day. PINK PLUS™ is staffed by all women health care providers which may eliminate embarrassment as a barrier. In general, data show that women are more compliant than men in utilizing health care services.²⁵ If PINK PLUS™ draws women for screenings, perhaps it will bring additional family members for preventive health services.

Our report on PINK PLUS™ has some limitations. This summary does not describe a formalized study and the cohort includes a small number of patients. Also, patients were not surveyed to learn whether the convenience of PINK PLUS™ enhanced their adherence to screenings. In addition, for those with a personal history of colon polyps, their procedures were considered surveillance and not screening examinations; however the program still facilitated a convenient follow-up plan. Lastly, for patients who did not return for colonoscopy, it would have been helpful to give each one a FIT kit so some form of screening could have been documented.

Looking to the future, we see PINK PLUS™ playing an important role in addressing shifting U.S. demographics. By the year 2050, more women will be heads of households, living under the poverty level, and facing food insecurity and lack of adequate health care.¹³ Rates of CRC are predicted to increase among women, and CRC screening efforts should reflect and address their specific needs. Gender differences in location of CRC in women, along with racial and socioeconomic disparities, should be considered in future strategies for screening, prevention and treatment protocols.

To learn more about the effectiveness of PINK PLUS™ for improving screening rates for women’s cancers, particularly CRC, we plan to conduct a prospective, randomized study with a large primary care group with a diverse population. Based on our findings to date, we believe that the program can have a positive impact on screening rates by increasing convenience, accessibility and education. With the success at our institution, PINK PLUS™ could serve as a national template for other health care institutions with the same goals.

Dispatches From The Guild Conference, Series #16

Advances in Barrett’s Esophagus

Alina Wong,

Seth A. Gross

Barrett’s esophagus is the strongest risk factor for esophageal adenocarcinoma making evaluation for Barrett’s esophagus of utmost importance. Currently screening and surveillance are accomplished with regular white light endoscopy; however, new advances in both population screening and surveillance are being developed. This review will cover selecting the appropriate patient population for Barrett’s esophagus screening, available and upcoming technologies for screening and surveillance, and lastly treatment of Barrett’s esophagus.

Alina Wong, MD¹ Seth A. Gross, MD² ¹Division of Gastroenterology, University of Washington, Seattle, WA ²Department of Gastroenterology, New York University Langone Medical Center, New York, NY

BACKGROUND

Esophageal cancer is increasing in frequency and is the sixth leading cause of cancer death in the world.^1,2 While squamous cell carcinoma is more common in the developing world, adenocarcinoma is more common in the United States. Esophageal adenocarcinoma carries a poor prognosis, making it imperative to diagnose it early. The strongest risk factor for esophageal adenocarcinoma is Barrett’s esophagus, which increases the risk of esophageal adenocarcinoma 30-50 fold.^3,4

Barrett’s esophagus is defined as the replacement of squamous epithelium by intestinal epithelium. Diagnosis requires endoscopic evidence of columnar mucosa in the esophagus with histologic confirmation of intestinal metaplasia with goblet cells. The Prague classification system is used to systematically describe a segment of Barrett’s esophagus. The classification system assesses the circumferential and maximal extent of an endoscopically visualized Barrett’s esophagus segment to help facilitate diagnosis and treatment.⁵ Barrett’s esophagus has been divided into long segment (≥3 cm in length), short segment (< 3 cm in length), and very short segment (< 1 cm in length).^5,6 Increasing length of Barrett’s segment is associated with increased risk of dysplasia.⁷

Very short segment Barrett’s esophagus remains controversial as the most recent guidelines from the American College of Gastroenterology (ACG) and British Society of Gastroenterology require at least 1 cm of columnar mucosa for the diagnosis of Barrett’s esophagus, while the American Gastroenterological Association does not have a similar restriction.^6,8 This controversy stems from previous studies showing that very short segment Barrett’s esophagus, otherwise known as an irregular Z line, does not have the same association with high-grade dysplasia or adenocarcinoma.⁹ A recently published paper performed a prospective, multicenter cohort study of patients who underwent endoscopic examination for Barrett’s esophagus in the United States and Europe and found that none of the patients with irregular Z line developed high-grade dysplasia or esophageal adenocarcinoma within a median follow-up period of 4.8 years.¹⁰

Risk factors for Barrett’s esophagus include age over 50, male sex, chronic reflux disease, white ethnicity, smoking, and obesity.^11,12 Roughly 5-15% of patient with chronic gastroesophageal reflux disease have Barrett’s esophagus.¹³

Screening

Despite retrospective studies showing that adenocarcinomas diagnosed in screening programs tend to be earlier stage, screening for Barrett’s esophagus remains controversial. The main questions revolve around whom to screen, as symptomatic gastroesophageal reflux disease remains a poor predictor of Barrett’s esophagus on endoscopy. The most recent guidelines by the ACG published in 2016 recommend screening for Barrett’s esophagus be considered in men with chronic (>5 years) and/or frequent (weekly or more) symptoms of gastroesophageal reflux and two or more risk factors for Barrett’s esophagus including age >50, Caucasian race, presence of central obesity, history of smoking, or a family history of Barrett’s or esophageal adenocarcinoma.⁶

Conventional endoscopy remains the gold standard for screening for Barrett’s esophagus. This involves using standard white light endoscopy with collection of biopsy specimens from any suspicious lesions as well as random four quadrant biopsies of endoscopically visible columnar tissue. The examination should be conducted carefully with a high-definition endoscope. Longer Barrett’s inspection time significantly increases high-grade dysplasia and adenocarcinoma detection rates.¹⁴ Special attention needs to be paid to the right hemisphere of the Barrett’s segment as early adenocarcinomas have a predilection to develop in this area.¹⁵ If initial endoscopy does not show Barrett’s esophagus, society guidelines do not recommend repeating future endoscopies.⁶

Given the costs and specialist expertise associated with upper endoscopy, investigators have studied other techniques for Barrett’s detection. Transnasal endoscopy involves using a smaller caliber endoscope that is inserted nasally without the need for sedation. It has been shown to have similar efficacy compared to standard endoscopy.16 Non-endoscopic techniques have also been developed. The cytosponge is a gelatin-coated sponge attached to a string that is swallowed and collects cytology specimens when withdrawn. Cells are retrieved from the cytosponge and analyzed for expression of markers specific to Barrett’s esophagus. Trefoil factor 3 is a marker that distinguishes the columnar cells in Barrett’s esophagus cells from columnar cells in the rest of the gastrointestinal and upper airway tracts. Studies with cytosponge have shown 73% to 90% sensitivity for detecting Barrett’s esophagus, however, the diagnostic accuracy is still being determined.^17,18

Biomarkers have been investigated extensively and the most promising of these include P53, copy number alterations and methylation panels. However, as of now no single biomarker is adequate for risk stratification. Though, when coupled with the cytosponge, biomarkers could potentially provide a cost-effective method for community based screening for Barrett’s esophagus by risk stratifying patient’s risk of progression to dysplasia and adenocarcinoma. The recently done BEST2 multicenter cohort study showed that the Cytosponge could be coupled with biomarkers (P53, c-Myc, Aurora kinase A, and methylation markers) to identify a cohort of patients at low risk of progression of Barrett’s esophagus who may be suitable for non-endoscopic follow-up.¹⁹ However, more studies are needed, especially randomized control trials to address accuracy and long-term follow-up. A new screening technique under development for the identification of Barrett’s esophagus is breath testing. Breath testing uses an electronic nose device to measure subtle volatile organic compounds (VOC). A group from Mayo Clinic performed a cross-sectional study and evaluated the breath VOCs of a cohort of patients with a history of dysplastic

Barrett’s esophagus for the presence or absence of Barrett’s esophagus.²⁰ They were able to detect Barrett’s esophagus with 82% sensitivity and 80% sensitivity. More data will be needed on testing healthy subjects, but if successful may potentially become an important non-invasive community screening technique for Barrett’s esophagus.

Surveillance

Early detection of esophageal adenocarcinoma improves survival. Several studies have demonstrated that adenocarcinomas detected in surveillance programs are detected in earlier stages thus suggesting a potential improvement in survival.^21,22 While there is no prospective data proving this concept, a large population based cohort study found that patients with adenocarcinoma who had undergone endoscopic surveillance had increased survival compared to patients who had not undergone surveillance.²³

Surveillance is aimed at detecting dysplasia, which can be categorized as indeterminate, low-grade, high-grade, or adenocarcinoma. The degree of dysplasia dictates recommended surveillance intervals. Similar to screening, surveillance endoscopy is accomplished with high definition white light endoscopy. According to the Seattle protocol, random four quadrant biopsies are taken every 2 cm.²⁴ However, adherence to the Seattle protocol in the community is low and non-adherence is associated with decreased dysplasia detection.²⁵ The Seattle protocol is also time-intensive, labor-intensive, expensive and fraught with sampling error. Subsequently, new imaging techniques for Barrett’s surveillance have been developed.

Advanced imaging modalities include narrow band imaging (NBI), chromoendoscopy with acetic acid, and confocal laser endoscopy (CLE). NBI allows for enhanced visualization of subtle mucosal and vascular changes thus allowing for targeted biopsies. Using the Barrett’s international NBI group (BING) criteria, a newly validated NBI classification system, NBI can identify dysplasia in patients with Barrett’s esophagus with 80% sensitivity and 88% specificity.²⁶ Chromoendoscopy uses dye to highlight irregular areas for biopsy. CLE provides up to 1000-fold magnification of the esophageal mucosa as well as real-time histologic evaluation of esophageal mucosa.

The American Society of Gastroenterology (ASGE) created the Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) initiative to establish diagnostic and therapeutic thresholds for endoscopic technologies. The committee established that imaging technology for targeted biopsy should have a per-patient sensitivity of ≥90%, a negative predictive value of ≥98% for the detection of high-grade dysplasia and/or esophageal adenocarcinoma, and a specificity of 80% compared to the gold standard. Only NBI, acetic acid chromoendoscopy and CLE currently meet these criteria.²⁷ However, most of the studies examined in the meta-analysis were performed by experts at referral centers. Since community centers have not been adequately studied, the PIVI guidelines only recommend the use of advanced imaging techniques by endoscopists proficient in these modalities.

Wide-area transepithelial sampling (WATS) is a new brush sampling technique that can provide extensive as well as full thickness sampling results. Analysis is complemented by a computer scan that identifies potentially abnormal cells. A recent multicenter, prospective randomized trial showed that the use of WATS in addition to standard four quadrant biopsies increased the detection of high-grade dysplasia and esophageal adenocarcinoma compared to biopsy sampling alone.²⁸ However, this modality adds extra time to an already time intensive procedure. It has also not been studied with other advanced imaging techniques or in the community setting.

Treatment

Proton pump inhibitors (PPI) remain the mainstay of medical treatment even in patients without reflux symptoms. A meta-analysis in patients with Barrett’s esophagus showed a 71% decrease in the risk of progression to esophageal adenocarcinoma and/or high-grade dysplasia. This effect was seen independent of the presence of erosive esophagitis.²⁹

Endoscopic treatment for Barrett’s esophagus depends on confirmation of dysplasia on biopsy samples. This is in itself controversial as there is significant inter-observer variability between pathologists in the interpretation of dysplasia. Current guidelines subsequently recommend the confirmation of dysplasia by a second experienced pathologist.⁶

Per recent society guidelines, flat mucosal non-dysplastic Barrett’s lesions should have repeat endoscopic surveillance in 3-5 years. Indefinite lesions should be optimized with PPI therapy and have repeat endoscopy in one year. Low-grade or high-grade dysplasia in both flat and nodular lesions merits endoscopic ablative therapy.⁶ Treatment of low-grade dysplasia with ablative endoscopic therapy was once disputed. However, recent data shows that presence of low-grade dysplasia along with Barrett segment length, and nodularity were independent predictors for progression to high-grade dysplasia and adenocarcinoma.⁷ Furthermore, other studies demonstrate that ablative therapy for low-grade dysplasia significantly reduces progression to high-grade dysplasia and adenocarcinoma.³⁰ Endoscopic treatment for low-grade dysplasia has now become commonplace.

CONCLUSION

Barrett’s esophagus is highly prevalent among the United States population. It is an established risk factor for esophageal adenocarcinoma and follows a direct sequence from metaplasia, to low-grade dysplasia, to high grade-dysplasia, and eventually adenocarcinoma. Given esophageal cancer’s poor survival rate and association with Barrett’s esophagus, screening and surveillance are important. This is currently an exciting field with advances in population screening and surveillance technology. However, risk of progression to adenocarcinoma will have to be balanced with cost-effectiveness and patient tolerability as we continue to explore new technology.

Frontiers In Endoscopy, Series #45

Endoscopic Management of Zenker’s Diverticulum

Bilal Aslam,

Moamen Gabr

Zenker’s diverticulum (ZD) is a pharyngeoesophageal pulsion diverticulum which presents in the elderly and contributes to morbidity due to dysphagia and pulmonary aspiration. Open surgery and rigid endoscopy have previously been the primary modalities for therapy, however with a favorable safety profile and similar success rates, flexible endoscopy has become an emerging therapeutic modality in the treatment of ZD. This review seeks to highlight endoscopic techniques and tools in the management of ZD.

INTRODUCTION

Zenker’s diverticulum (ZD), first reported by Ludlow in 1769,¹ is a pharyngeoesophageal pouch characterized by posterior herniation through Killian’s triangle or Killian dehiscence, anatomically located superior to the cricopharyngeus muscle and inferior to the inferior pharyngeal constrictor muscle (Figure 1). After a detailed case series of pulsion diverticula was published in 1867 by Friedrich Zenker, the entity was eponymized.² An uncommon entity with a reported prevalence of 0.01%-0.11%,³ ZD often presents in the seventh to eighth decade, with a male predominance.⁴

Although the mechanism of development is not entirely clear, diminished upper esophageal sphincter (UES) opening leading to increased intraluminal pressures and subsequent tissue migration through an anatomic defect has been suggested;⁵ structural abnormalities of the cricopharyngeus muscle have been implicated as an explanation for the diminished UES relaxation and increased bolus flow pressure.⁶ Reported to have an association with GERD,⁷ also of unclear mechanism, acid-induced muscle shortening has been proposed as a unifying hypothesis linking the two conditions.⁸

Presentation includes, but is not limited to, dysphagia, post-prandial emesis, regurgitation of food, retention of food and other contents within diverticular space, halitosis, cough, weight loss, malnutrition and pulmonary aspiration. Dysphagia in patients suffering from ZD can manifest as malnutrition⁹ reported in 54% of patients in one series. ZD has been associated with the retention of video capsule and subsequent endoscopic retrieval.^10-12 There are also case reports of ZD complicated by the presence of carcinoma within the diverticulum,^13-17 however this is exceedingly rare.

The most common modality for diagnosis is a barium-contrasted study (i.e. barium esophagram/barium swallow, videoflouroscopy/modified barium swallow) (Figure 2), with outpouching most prominently characterized on lateral projections;18 there is also a role for cross-sectional imaging and endoscopy. There are limited reports of characterizing ZD on ultrasound,^19-22 however this has no role in initial diagnostic workup. Validated scoring tools for the assessment of dysphagia (SWAL-QOL, Dakkak-Bennet) have been reported and used for evaluating pre and post intervention status.^23,24

The mainstay of treatment was previously open surgical correction and endoscopic management with rigid endoscope, but advances in flexible endoscopic tools and techniques have brought flexible endoscopic management to the forefront over the past two decades. This review seeks to highlight endoscopic techniques and tools in the management of ZD.

Management

Although there are no specific guidelines for treatment, intervention should be reserved for symptomatic patients only. The current treatment modalities are open surgery (including diverticulectomy, diverticulopexy, diverticular inversion, myotomy), rigid endoscopy (electrocautery, CO2 laser, stapler, Harmonic scalpel) and flexible endoscopy. As previously reported, the rate of successful management of ZD is comparable between the three established modalities, however adverse effects including mortality are significantly lower in the flexible endoscopic approach.²⁵ Rigid endoscopy and flexible endoscopy share similar outcome profiles, but flexible endoscopy does not require general anesthesia or neck hyperextension.

The first flexible endoscopic therapy for ZD was reported in 1995.²⁶ The mainstay of therapy has focused on the division of the cricopharyngeal muscle through an endoscopic myotomy resulting in obliteration of the diverticular cavity and improvement of dysphagia; with many accessories (APC, bipolar forceps, clutch cutter, hood, hook knife, needle knife, stag beetle knife, transparent cap) and new techniques (Z-POEM) at endoscopists’ disposal, flexible endoscopic approaches are numerous and effective for treatment of ZD.

Flexible Endoscopic Septum Division:

Flexible endoscopic septum division (FESD) (Figure 3) is the incision of the mucosal layer and myotomy, partial or complete, of the cricopharyngeal muscle resulting in septum division. In a recent meta-analysis²⁷ FESD reported overall good outcomes with pooled success of 91%, pooled adverse event (AE) rate of 11.3% and pooled recurrence rate of 11%. As there is no standardization to FESD, there is wide heterogeneity among studies and numerous approaches to septum division. Most endoscopic approaches to FESD are multi-modal with combination of accessories or techniques employed. The blind pouch of the diverticulum increases perforation risk, as it can be confused for the esophageal lumen, most often highlighted during endoscopic retrograde cholangiopancreatography (ERCP).²⁸

The introduction of transparent caps or soft rubber duck-billed diverticuloscope (Cook Medical, Winston-Salem, NC) has improved visualization and endoscopic outcomes.²⁹ The diverticuloscope and cap devices allow for improved visualization, through exposure and fixation of the septum, and aiding in the separation of fibers with gentle spreading pressure. When compared to caps, diverticuloscope use is associated with fewer AE, decreased procedure time, and superior symptom remission,²⁹ however the overtube system unfortunately is not currently approved by the United States Food and Drug Administration, and its use is reported only in case series from Canada and Europe.

Widely reported,30-34 the use of a Savary guide wire with nasogastric (NG) tube placement delineates the esophagus from ZD orifice and protects the anterior wall of the septum during myotomy. There is also reported variation across the literature regarding the use of closure clips at the end of the procedure and antibiotics given prior to and after endoscopic treatment.

Post-intervention care lacks a standardized approach but primarily consists of hospital observation, soft diet, and barium contrasted studies to evaluate for perforation.30,32,34,35 Rates of AE (perforation/cervical emphysema, hemorrhage) vary with FESD, however overall remain relatively low,27 and are predominantly managed with a conservative approach. There are varying rates of symptom recurrence, with most being amenable to repeat FESD having reasonable outcomes.

Septum Division Techniques
Needle Knife

Ishioka et al. reported the first FESD in 1995; intervention was carried out with Needle-Knife (NK) and noted improvement in all patients within the series (N=23).³⁰ Subsequent studies^{29,31,32,34-37} detailed effectiveness of NK in the endoscopic management of ZD. Costamagna et al. evaluated prognostic variables for FESD success and reported on short and long-term success (6 and 48 months respectively) having a correlation with septotomy length and size of ZD.³⁸ The criticism of NK approach is the concern for perforation risk. Hesitancy to extend septotomy length due to lack of direct visualization may contribute to recurrence rates.

Hook Knife

The Hook Knife (Olympus Corporation, Center Valley, PA,USA) first reported by Recipe at al.,³⁹ showed clinical efficacy in septal myotomy; this finding has been reproduced in subsequent studies33,34,40-43 and clinical trends appear to favor Hook Knife as the preferred endoscopic tool for FESD. The inherent advantage of the Hook Knife is that the upward pulling of muscle fibers prior to obliteration minimizes perforation risk at time of intervention.

Thermal Therapy

Mulder et al. first reported on a pilot study in which Argon Plasma Coagulation (APC) was used to perform FESD with symptom improvement and no AE;26 similar results are reported with varying reports of perforation which is the concern with the modality.^{26, 44-46}

Submucosal Tunneling
Endoscopic Septum Division

Submucosal tunneling endoscopic septic division (STESD/Z-POEM) (Figure 4) is a novel endoscopic technique in the management of ZD first reported by Li et al.47 Z-POEM was created utilizing techniques from peroral endoscopic myotomy (POEM) to decrease the risk of perforation encountered during FESD, which is reported in as high as 6.5% of patients.²⁷ The approach to Z-POEM consists of the following four steps: mucosal incision (consisting of submucosal injection 3cm proximal to diverticular septum and 1-2cm longitudinal mucosal incision to create tunnel entry), submucosal tunneling (either to the end of the diverticulum or 1-2cm distal), septum division (septal myotomy) and mucosal closure (through the scope clips). Reports from small case series reveal that Z-POEM shows good success with return to normal anatomy, lack of perforation and symptom resolution on follow-up.^47-49 The limited data and the expertise required to perform POEM limit Z-POEM as a widespread therapeutic modality.

Novel Modalities

FESD with the Clutch Cutter (Fujifilm, Tokyo, Japan) has shown promise when used with or without a clear cap; to our knowledge there are only two case reports,^50,51 both reporting success. The device, originally intended for endoscopic submucosal dissection (ESD), and is not approved by the FDA.

The Stag beetle knife (SB-knife; Sumitomo Bakelite, Tokyo, Japan) was first reported in the use of diverticuloplasty in 2013.52 Initially intended for ESD, SB-knife has shown good outcomes in a small series and case reports.53-56 with the concomitant use of an overtube. Myotomy was performed in midline fashion except for Battaglia and Golder who provided a novel approach by creating two lateral dissections and using a monopolar snare to complete myotomy. Despite current reported success, further prospective trials are needed to determine long-term efficacy and recurrence rates.

DISCUSSION

The advancement of endoscopic tools, with similar efficacy and decreased risk of AE as compared to prior accepted modalities of surgery and rigid endoscopy, are increasingly making endoscopic therapy the “first line” approach to ZD management. The introduction of the diverticuloscope has allowed for better outcomes in European case series,38 owing to greater stabilization of the endoscopic field and improved visualization during septum division. In the United States, a transparent cap serves a similar purpose. Emerging tools such as the SB-knife and Clutch Cutter are likely to yield improved outcomes as they allow for grasping and thermal therapy, limiting perforation risk. New endoscopic approaches such Z-POEM appear promising but are limited by endoscopic skill required and lack of data. It is clear that there needs to be highly scrutinized prospective data comparing flexible endoscopy and its wide armament of tools against rigid endoscopic approaches.