NUTRITION ISSUES IN GASTROENTEROLOGY, SERIS #184

Part II Enteral Feeding: Eradicate Barriers with Root Cause Analysis and Focused Intervention

February 2019 • Volume XLIII, Issue 2
Carol Rees Parrish,Stacey McCray

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Identifying issues that interfere with adequate provision of enteral nutrition (EN) and getting to the root cause of EN intolerance or complications increases the likelihood that patients will receive the nutrition intended. Part I of this series discussed the practice of listening to bowel sounds and checking gastric residual volumes as determinants of GI tract function. In Part II, several other barriers to effective EN are discussed, including diarrhea, nausea, vomiting, pain, constipation and initiation and progression of EN.

CASE

A 40 year old male was admitted with severe odynophagia, dysphagia & “tube feeding intolerance.” His recent medical history includes squamous cell carcinoma of the tongue. He is now undergoing chemo and radiation therapy, with a percutaneous endoscopic gastrostomy (PEG) placed prior to starting this therapy. His medical history also includes hypertension, alcohol misuse, and significant smoking. His home EN regimen prior to admission was 6 cans per day of a 1.5cal/ mL product, but the patient has only been able to take in 3-4 cans per day. He recently saw an LIP for his inability to tolerate EN and was changed to 2.0cal/ mL product; however, he was admitted right after it was delivered to his home and he had yet to try it. Upon interviewing the patient, it was evident he was in agony and that it clearly hurt him to answer basic questions-swallowing even his own saliva felt like “swallowing ground glass.” Due to the patient’s obvious pain, the interview was kept short and consisted of only yes and no questions. The barriers keeping him from consistently taking his EN were: poor pain control and feeling full/nauseated soon after taking his EN. He stated he took his tube feeding over the course of 30 minutes at home — (i.e., was not bolusing the formula in over 5 minutes), and was also not constipated, despite the use of opiates. The primary team was planning on escalating his pain medications. The nutrition support clinician reviewed the patient’s medication orders and noted an antiemetic ordered “pro re nada (PRN),” but only one dose had been given to the patient in 3 days. It was recommended to the primary team to schedule patient’s antiemetic to every 8 hours vs. prn. Twenty-four hours later, after he had received 3 doses of his antiemetic, the patient was tolerating all of his feedings without complaint. 

INTRODUCTION

In this era of high tech medicine, clinical skills may be eclipsed by new technologies, diagnostics, and therapeutic advances. However, basic clinical assessment skills are critical for accurate assessment of the enterally-fed patient. Many issues interfere with patients receiving the full amount of enteral nutrition (EN) ordered (see also Part 1 of this series). Not the least of these issues are patient specific barriers, which are often widely referred to as, “EN intolerance or complications” (Table 1). However, “EN intolerance or complications” is extremely vague and requires further exploration by the clinician in order to effectively intervene. The real problem may be related to the underlying disease state, inadequate or inappropriate medication treatment (such as PRN orders that are never given), or perhaps the wrong medication for the “job.” In some cases, the patient may not be able to articulate what is wrong, and it is easy to attribute the patient’s symptoms to EN. Simply blaming symptoms on EN may prevent the clinician from identifying the root cause of the barrier, resulting in decreased EN delivery to patients. Part I of this 4 part series reviewed the evidence (or lack thereof) behind the use of bowel sounds as a determinant of GI function and the waning (but persistent) use of gastric residual volumes as a surrogate measurement of EN tolerance. Part II will cover other common GI issues that get in the way of effective EN delivery, including diarrhea, nausea, vomiting, pain, constipation, and initiation and progression of EN. With a better understanding of the GI tract and normal GI function, it is possible to overcome many GI barriers and develop successful EN regimens that actually meet the nutritional needs of our patients.

PATIENT’S SYMPTOMS AS A BARRIER

Diarrhea

Diarrhea is an alteration of the normal balance of absorption to secretion within the bowel. Under normal circumstances, nine to ten liters of endogenous and exogenous fluid are introduced to the GI tract each day (see Part I of this series). Yet, the normal stool volume in adults is only 100-200mL. Diarrhea results from increased water content of stool due to an imbalance in intestinal processes involved in the absorption of ions, organic substrates, and thus water. In osmotic diarrhea, stool output is proportional to the intake of the non-absorbable substrate; stool volume decreases quickly with discontinuation of the offending nutrient/agent. In secretory diarrhea, the epithelial cells’ ion transport processes reverse into an active secretory state. The volume of stool output and fluid loss can be very high; however, nutrient absorption often remains intact. 

The reported incidence of diarrhea in the hospitalized patient varies greatly from 20% – 70%. This is due to the multiple definitions of diarrhea in the literature, no defined volume or frequency that quantifies diarrhea, subjective diagnoses of diarrhea by both clinicians and patients, and other factors. Lebak identified 33 definitions in the literature, and the definition appeared to be based on the preference of the investigator.1 It is also of utmost importance to ask patients what their normal stool habits are at home/or pre-illness, so clinicians are not trying to fix something that has been going on long before EN was initiated (although in some cases the problem may still need to be fixed, it is just clearly not the result of EN).

Diarrhea can be both a sign and/or a symptom of an underlying issue, but it is not a disease unto itself. Diarrhea occurs for a variety of reasons in hospitalized patients,2-8 regardless of whether they are on an oral diet, EN, PN or even NPO.2,9- 11 (Table 2). In the enterally-fed population, diarrhea has long been associated with (and blamed on) the enteral formula and/or delivery method. However, randomized, prospective trials demonstrating EN as a cause of diarrhea, have yet to be done and diarrhea has yet to be causally linked to EN (liquid in ≠ liquid out).12-15 As far back as 1981, Bloom remarked, “gastrointestinal upset in nasogastrically-fed patients is not always the result of the tube feeding and should not be an accepted consequence”.16 The authors went on to carefully explore diarrhea in EN-fed patients and were able to identify medications as the primary causative agents. In fact, in one study of EN-associated “GI intolerance”, diarrhea was observed in 26% (36/137) of patients, while 29% (40/137) exhibited constipation.17 What is perplexing is that if a patient has diarrhea while on a clear, full, or regular diet, the diet is not typically blamed; hence, why is EN blamed for diarrhea? This assertion is counterintuitive to GI physiology. 

Malabsorption

Some clinicians have the misconception that diarrhea equals malabsorption. In fact, the GI tract is so effective in its digestive and absorptive role, >90% of nutrients are completely absorbed within the first 5 feet (150cm) of jejunum in normal subjects.18,19 A large portion of the GI tract or digestive organ function must be lost to result in malabsorption. Patients with moderately impaired GI tracts are still able to absorb many intact nutrients,20,21 and even those with a total pancreatectomy are able to utilize greater than 60% of intact protein.22 Patients fed into the duodenum or jejunum do not routinely require a pre-digested formula, as the digestive capacity of the small bowel is enormous. While malabsorption is certainly on the list of things to consider in those patients who have risk factors, only a small percentage of the EN-fed population malabsorb. In any patient suspected of malabsorbing their EN, a 48-72 hour fecal fat collection (done while the patient actually receives the prescribed formula that they are thought to be malabsorbing) will provide the answer. 

Contributions of Medications

Medications are a common, but often unrecognized, cause of diarrhea in the EN-fed patient. Liquid medications frequently contain sorbitol or other sugar alcohols, which can be very diarrheagenic.4,5,10,23,24 Sorbitol is a poorly absorbed polyalcohol; 20-50g/day has been shown to cause osmotic diarrhea, although even 5-10g is enough in some patients.25 For example, one dose of acetaminophen liquid contains 5.47.g of sorbitol/500mg dose; amantadine, 6.4g/100mg; and finally, metoclopramide liquid, 3.5g/10mg (therefore, the diarrheagenic effects of liquid Reglan are NOT from its prokinetic effects as it only is effective on the upper gut, not the colon).26 Liquid medications are also additive in their effect; the more liquid meds, the higher likelihood diarrhea will follow. Diarrhea is often associated with EN in these cases as once enteral access is obtained, medications are frequently changed to liquid form for ease of administration via the feeding tube. Hence diarrhea seems to start at the same time as the EN (Table 2).

Antibiotic-Associated Diarrhea

Antibiotic-associated diarrhea and Clostridium difficile (C. difficile) are frequent causes of diarrhea in the hospitalized patient.4,6,12,15,27,28 Patients receiving EN are at a higher risk for acquiring C. difficile.8 One study reported EN-fed patients were nine times more likely to develop C. difficile-associated diarrhea than matched non-EN-fed patients (possibly from the hands of health care providers); the risk was even greater when patients were fed postpylorically (delivery below the gastric acid barrier may facilitate the introduction and survival of C. difficile organisms).8

Hypoalbuminemia

Although hypoalbuminemia has been cited as a risk factor for EN related diarrhea, no evidence exists to support this notion.6 Hypoalbuminemia is also associated with sicker patients (ICU, abdominal abscess, etc.), and sicker patients get more infections (hence, more antibiotics), and are in the hospital longer (with even more medications and more infections). These factors are known to precipitate diarrhea. There is no data that patients with hypoalbuminemia absorb less than healthy controls or absorb inadequate amounts.29

Osmolality or Hypertonicity 

Despite the perception that osmolality (or hypertonicity) is responsible for triggering diarrhea in patients receiving EN, there is no evidence to support this. The GI tract is adept at diluting and digesting food and liquids of various tonicities. When volume is delivered into the stomach, the volume receptors in the stomach respond by adding a secretory volume.30 After mixing with gastric secretions and saliva in the stomach, chyme leaves the stomach and is further diluted by bile salts, pancreatic enzymes, bicarbonate, and water secreted into the small bowel. Borgstrom demonstrated that a 500mL test meal (625kcal w/ 40% fat, 15% protein, 45% carbohydrate) is diluted to a volume of 1500-2000mL during passage through the duodenum.18 This process increases the pH and dilutes the solution — “auto-isotonicity” if you will. This is a normal function of the stomach and small bowel. It is incorrect to think that when EN is infused it is the only thing present in the stomach and bowel. One study showed that hypertonic formulas (544mOsm) infused gastrically are nearly isotonic by the time they reach the ligament of treitz (10 inches [25cm] distal from the pylorus),31 while another found that hypertonic formulas infused at the ligament of treitz are nearly isotonic 14 inches (35cm) distal in the jejunum.19 Pesola demonstrated a difference in stooling frequency prior to initiation of EN in 39 subjects (5 volunteers, 10 head and neck cancer patients, and 24 ICU patients).32However, after initiation of full strength, hypertonic EN (Ensure Plus ® – 690mOsm) at 30cal/kg/day by gravity drip or bolus (head and neck patients), no significant difference in diarrhea between groups was found during feeding.32 Jones et al found no evidence to implicate hypertonicity of EN as an etiology of diarrhea in their study.15 Finally, Kandil et al continuously infused an average of 275mL/hour (range: 198 to 340mL/hour or 5000 to 8650 kcal/day) of standard, polymeric EN into the duodenum of five healthy volunteers before precipitating diarrhea in their subjects.33 The authors suspected it was the sheer amount of magnesium that was infused with that volume of EN that precipitated the diarrhea (given how poorly absorbed magnesium is). 

Diluting Enteral Formulas to “Treat” Diarrhea

As discussed above, diluting enteral formulas to decrease osmolality in patients with normal anatomy flies in the face of GI physiology, and is without evidence. Researchers have shown that hypertonic formulas are tolerated in both healthy subjects34 and in those with impaired GI function.35 Furthermore, the practice of diluting EN can be detrimental to patients as fewer nutrients are provided, and more handling introduces potential contamination with infectious agents. Regardless, with the recent adoption of the ready to hang system, dilution of EN is not possible in the hospitalized setting. Finally, many items commonly provided to our hospitalized patients, including medications, popsicles, fruit juice, soda, and sherbet all have an osmolality much higher than that of EN (Table 3). If high osmolality causes diarrhea, “isotonic” medications, beverages, and oral diets would be needed to prevent diarrhea in all our patients.

There are two circumstances when the dilution of formula may be helpful (primarily in the home setting). With some particularly viscous EN formulas, dilution may be needed. If a highly viscous EN formula is slow to infuse, adding water can thin the formula and enhance flow through small bore feeding tubes. Also, in some patients with higher fluid requirements, water can be added to the EN formula and the mixture run at a higher infusion rate to provide additional hydration. This will decrease the burden of large, frequent water flushes and decrease caregiver time. 

Diarrhea is seen in EN-fed patients for a variety of reasons, but EN is very rarely, if ever, the cause. Risk factors other than the enteral formula should be explored including: medications, infectious etiologies, underlying disease state, GI anatomy, and even constipation (stooling around an impaction) in susceptible individuals.11 These issues should be addressed and appropriate steps taken before reducing or suspending enteral feeding. Management of diarrhea in EN-fed patients requires a systematic approach to identify and remove risk factors where possible.6 (Table 4). Ferrie decreased the incidence of diarrhea in critically ill patients from 37% to 24% by careful attention and monitoring of factors known to cause or aggravate diarrhea.36 Once infectious or other etiologies have been ruled out, anti-diarrheal agents can be initiated to improve patient comfort and protect from skin breakdown. Diarrhea as a symptom does not indicate the need for cessation of EN. 

Nausea, Vomiting, Abdominal (or any) Pain

It is not uncommon for patients in the hospital setting (or any patient with ongoing medical issues) to have nausea, vomiting, or pain. These symptoms often result in inadequate oral intake in patients who are eating. In patients being enterally-fed, these symptoms often cause EN to be held due to a belief that EN is causing the symptoms. In some cases, parenteral nutrition (PN) is initiated. Effective use of medications, such as antiemetics, prokinetics, or analgesia agents, can improve nausea and vomiting, and these modalities should be optimized before surrendering to PN. Of course, the route of medication delivery is an important consideration. For example, oral medications may not be effective if the patient is frequently vomiting. A medication delivered into the stomach will not be utilized if the patient is on gastric suction or is frequently ‘venting’ a gastric tube to relieve nausea. The timing of medications may also be important in these settings (e.g. 1/2 hour before meals to maximize efficacy) and, if so, these instructions should be included in the recommendations and orders.

The Curse of “PRN” Medications

PRN drug use, or medications given when the need arises, traditionally meant “as little as possible.”37 PRN orders are routine in hospital, rehabilitation, and nursing home settings and are the default ordering method in many institutions. It has been reported that 35-60% of medication orders are PRN.38,39 Many patients have suffered at the mercy of these “PRN” orders, as no medication is beneficial if not received by the patient. There is a paucity of data regarding PRN medications and how often they are actually given.39-41There are numerous reasons that PRN orders may not be given: patient does not (or cannot) complain of symptoms routinely, patient does not know meds are available to them (let alone know how to pronounce them), nurses do not get to fully assess the patient’s symptoms, or nurses just run out of time to give PRN meds. A Cochrane review was unable to find any trials comparing scheduled dosing with giving the same medication only “when needed”.40 One study investigated the non-use of PRN medications in a hospital-affiliated with a large mid-western university and found that 62% were unused (4793 of 7735 PRN orders).38 Non-use by service category was also assessed, revealing that cardiovascular surgery had the highest laxative prescribing rate (almost 100% of patients), yet 89% went unused. The percent of all PRN orders unused ranged from a low of 50% for renal transplant to a high of 81% for ophthalmology. In another study of PRN orders for acute pain management following laryngectomy, 68% of patients met the recommended minimum post-op dosing guidelines for pain, yet none of the patients received the intended dose during a 24 hour period while hospitalized.41 Of the 13 patients (35%) whose physicians were contacted because of inadequate pain relief, only 8 patients (22%) had their narcotic dose increased appropriately. Finally, in a study of children undergoing various elective surgeries, the authors verified that nurses administered 20% of the non-narcotics available under PRN orders, but only 10% of the available narcotics.37

In patients with ongoing symptoms that prevent consistent delivery of EN, it is important to ensure that medications to relieve such symptoms are actually being received by the patient. Always look to doses received, not just ordered. If the patient is not receiving the medication, it is important to find out why — is it being refused? Or, is the medication ordered only as a “PRN”? It may be important to explain to the patient the benefit of the medication, discuss with nursing to determine why it is not being given, or recommend to the primary team that the medication be changed from PRN to scheduled dosing. With some medications, it may be important to go one step further and ensure it is scheduled at specific times. It takes a village to get our patients safely and comfortably EN-fed through a hospitalization.

Constipation

Constipation is a frequent problem in hospitalized patients and is associated with abdominal discomfort, distension, small bowel bacterial overgrowth, poor tolerance of EN, confusion, intestinal obstruction, vomiting, and increased intra-abdominal pressure (which can impact respiratory function).42,43 Constipation has many possible causes (Table 5). In patients with significant constipation (especially rectal distension), abdominal distension, as well as delayed gastric emptying, can occur due to the recto-esophagogastric reflex.44 In more than one study, constipation was reported more frequently than diarrhea in patients fed exclusively by EN.17,45 Another study in cancer patients indicated that symptoms of constipation cause more distress than symptoms of pain.46 Modern definitions define constipation as a poly-symptomatic disorder including various aspects of disturbed defecation. Despite being such a common problem, constipation is often overlooked.42,47,48 While constipation in the EN-fed patient has often been referred to as a “complication” of EN, it is not possible for EN to cause constipation. Constipation in any patient is, pure and simple, due to an underlying condition and is often worsened by a lack of attention from the healthcare team to this issue.

One common intervention to “treat” constipation is to use a fiber-containing EN. However, fiber is no panacea.49 In one study of critically ill patients, constipation was observed as follows: fiber-free EN – the most widely used – (60% constipated), fiber-containing EN (51% constipated), both types used (85% constipated).43 See Table 6 for suggested guidelines to prevent and treat constipation.

Can Dehydration Cause Constipation?

Another myth that persists today is that dehydration causes constipation.50 Dr. Lawrence Schiller, a gastroenterologist affiliated with Baylor University Medical Center in Dallas, Texas, with years of clinical experience and numerous publications on the topic of both constipation and diarrhea, explained this common assumption this way:

“There is no support for this notion. The observation may be valid (dehydration and constipation coexist more than you would expect by chance), but it is not that dehydration causes constipation. More likely some factor leads to both dehydration and constipation. For instance, someone who is very ill may not drink much water, but they also are not eating so the main stimulus for colon motility (gastrocolic reflex-the stimulation of colonic contractions after food ingestion resulting in a bowel movement a short time after eating) is absent. Because the gut mucosa beyond the stomach is so permeable to water, there will always be “enough” intraluminal water for normal function, even if there is a total body water deficit. Electrolyte disorders that may accompany dehydration (e.g., hypercalcemia) may exaggerate constipation, but the water deficit is not the primary driver of the bowel symptoms.”

OTHER FACTORS GETTING IN THE WAY

Initiation & Progression

Initiation and advancement of EN varies among facilities (see Table 7 for one institution’s EN initiation protocol). There are no prospective randomized studies to determine the optimal rate to initiate feeding or how quickly to advance. Recommendations for initiation of continuous EN generally start at 20-50mL/hour, and advance by 10-25mL every 4-24 hours. Intermittent or bolus feedings protocols generally start at 120mL every 4 hours, and advance by 30-60mL every 8-12 hours.51 The results of a recent survey of dietitians in the United Kingdom (n = 606), demonstrated that 65% of respondents reported most commonly using a start rate of 24-49mL/hour, with 50-74mL/hour being the next most common initiation range.52 A significant association between the number of years in clinical practice and start rate was found–with those having more clinical experience using a higher start rate.

Extremely slow protocols for EN advancement can lead to decreased nutrition provided to patients. When one considers the actual amount of EN that is provided at a typical flow rate (for example, 60mL/hour equals 1/4 cup delivered over an hour), these advancement protocols seem very conservative. Over the years, various researchers have demonstrated that rates anywhere from 87mL/hour34 to 100-150mL/hour.53 are generally well tolerated. In fact, in two small studies (6-9 subjects), Heitkemper et al demonstrated that subjects tolerated gastrically infused full strength, hypertonic EN at rates of 30-60mL/minute (yes, mL/minute) up to a total of 500mL and 750mL.54,55 This translates into 500-750mL being infused over 8-25 minutes. Only at a rate of 85mL/minute did subjects experience GI discomfort.54

Although data are sparse on initiating patients at goal flow rates, in addition to the studies above, Taylor et al. compared two different EN starting regimens in 82 head-injured patients.56 The two groups were either started at a goal rate (90mL/hour) or with a starter regimen of 15mL/hour advancing every 8 hours as tolerated to 30, 60, and then 90mL/hour based on energy requirements. The 90mL/hour group (treatment) included both small bowel and gastrically-fed patients; the starter group enlisted only gastrically-fed patients. There were no significant differences in infectious complications or pneumonias (including aspiration pneumonia). At discharge, patients going home on pump feedings from University of Virginia Health System (UVAHS) are advised that they can advance their EN rate by 5-10mL/hour every three days or so, until they are running the set number of cans over the number of hours that suits them (or until further advancement is not tolerated). In general, 120-150mL/hour is an acceptable target as long as the patient is “comfortable.” Demonstrating just how much 120mL (1/2 cup) is to patients (using a cup available at bedside) may be a helpful visual. The exception to these instructions are those patients on insulin — coordination with their endocrine team is necessary to adjust insulin as the feeding regimen is changed.

Calculating Run Time for Patients on Continuous Feeding

Because of the many barriers to EN and the lost feeding time that results, patients often do not receive the prescribed goal nutrition. One approach to improve the amount of nutrition delivered is to base flow rate calculations on a less than 24-hour time period.57-59 For example, at UVAHS, the calculations of goal flow rate for continuously fed patients are calculated based on 22 hours/day for ICU and 20-21 hours for floor patients. The EN orders are then entered as continuous, but at the padded rate to account for the expected EN downtime. EN rates are then modified as needed, depending on the actual “dose received” in the days that follow.

SUMMARY

EN is a safe and effective way to nourish patients unable to eat enough on their own. Many barriers exist in the hospital setting that impede successful EN delivery to patients; however, many of these obstacles are based on the unsupported perception that EN causes GI symptoms. Part two of this series specifically addresses diarrhea, osmolality, infusion rates, nausea, vomiting, and pain as barriers to successful EN, and provides alternative approaches to maximize nutrient delivery in the enterally-fed patient.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #188

FODMAPS Everywhere and Not a Thing to Eat!

July 2019 • Volume XLIII, Issue 7
Amanda Motl,Nimish Vakil

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Amanda Motl, RD Aurora Medical Center, Summit, WI Nimish Vakil, MD, AGAF, FACG, FASGE University of Wisconsin School of Medicine and Public Health, Madison WI, Aurora Medical Center, Summit WI.

FODMAP is an acronym for fermentable oligosaccharides, disaccharides, monosaccharides and polyols. Dietary restriction of FODMAPs helps patients with the irritable bowel syndrome. Registered dietitians are essential for the education of patients in initial FODMAP restriction, structured re- introduction and final implementation of a personalized diet. Further areas of research include the adverse effects of FODMAP restriction on the microbiome, the effects of long-term FODMAP restriction on nutrition and intestinal health and the possible use of low FODMAP diets in other disease states.

Introduction
FODMAP is an acronym that stands for fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. These are all fermentable short-chain carbohydrates of 3-10 sugars and are commonly found in many everyday foods (Table 1). These are carbohydrates that are poorly absorbed and osmotically active in the small intestine, drawing water into the lumen and fermented by bacteria in the colon producing gas. Dietary restriction of FODMAPs improves symptoms of diarrhea, abdominal pain, distention and bloating in patients with irritable bowel syndrome. A comprehensive review of this subject has recently been published.1

Carbohydrates and Their Absorption Simple sugars are monosaccharides (glucose, fructose and galactose) and disaccharides (sucrose, lactose, maltose) that are present in milk, fruits, and vegetables that add varying degrees of sweetness to food. Disaccharides consist of two monosaccharides chemically joined together. The important disaccharides are sucrose (table sugar), lactose (milk sugar) and maltose (a product of starch digestion). Sugar alcohols are derivatives of monosaccharides. As with other sugars they taste sweet and are a source of energy, but they provide the same degree of sweetness as sugar with fewer calories and are therefore used as low-calorie sweeteners. They are absorbed more slowly than monosaccharides. Polysaccharides are long chains of monosaccharides. The way the monosaccharides are linked makes them absorbable (starch) or non-absorbable (fiber). Plants store energy as starch, which is a complex carbohydrate made of long chains of monosaccharides. Glycogen is also called animal starch and is used to store energy in humans and other animals. Most glycogen in slaughtered animals deteriorates within 24 hours. Pancreatic amylase breaks starch into smaller units of maltose.

FODMAP Absorption
Most carbohydrate digestion and absorption takes place in the small intestine. All carbohydrates must be broken down into monosaccharides for absorption. A sodium-dependent transporter moves the monosaccharides glucose and galactose into the enterocyte.

Monosaccharides
Fructose is a monosaccharide, which is absorbed in the presence of glucose. Fructose is transported primarily by either GLUT-2 or GLUT-5 carrier proteins across the intestinal epithelium. The GLUT-5 transporter is specific to only fructose, but the GLUT-2 transporter relies on glucose to facilitate passage of fructose.2 Clinical studies have shown that a fructose:glucose ratio of 1:1 is ideal for absorption for fructose; higher proportions of fructose are malabsorbed.3 Approximately half the U.S. population cannot absorb and tolerate > 25 grams of fructose, yet the fructose content of many diets regularly exceeds 50 grams (an amount that 100% of humans cannot absorb), primarily due to the ingestion of sweetened beverages (most often with high fructose corn syrup)4,5 (Table 2).

Oligosaccharides
Oligosaccharides are carbohydrates, which are made up of 3-10 simple sugars, composed mainly of fructans and galacto-oligosaccharides (GOS). A fructan is a polymer of fructose molecules. Fructans with a short chain length are known as fructo-oligosaccharides. They are poorly absorbed because the human body does not possess the enzyme to break them apart.

Disaccharides
Disaccharides such as lactose are variably absorbed because lactase, the enzyme needed to digest this sugar is genetically determined and absent in some populations (68% of the world’s population is lactase nonpersistent).6

Polyols
The last group consists of polyols, which are sugar alcohols that add the taste and texture of sugar with approximately half the number of calories. They are slowly absorbed by passive diffusion. Polyols are sugar alcohols found naturally in some fruits and vegetables (Table 3). They are also widely manufactured and used as artificial sweeteners. Absorption of sugar alcohols is dose dependent and influenced by the molecular size of the individual polyol. Sorbitol intolerance is a common problem in healthy individuals and can cause bloating and abdominal distress.7 These symptoms tend to occur with intakes of just 10-20 grams/day; greater amounts of up to 50 grams can have a laxative type effect.8 Sorbitol, mannitol and xylitol are examples of sugar alcohols used as sweeteners. For example, sorbitol is often used in chewing gum, breath mints, candy and many liquid medications such as cough syrups, analgesics, etc. and is an important source of symptoms in some patients. Many commonly used medications contain sorbitol 9 (Table 4).

Physiological Effects of FODMAPs
Small Intestine Water Volume
FODMAPs are osmotically active and draw water into the lumen of the small bowel. Using subjects with an ileostomy, a two-fold increase in ileostomy fluid output was demonstrated with the oral administration of fructose and sorbitol.10,11 The increase in intestinal volume results in distention of the small intestine and can cause pain in patients with visceral hypersensitivity.12 A scintigraphic study has demonstrated that ingestion of an oral fructose-sorbitol solution reduces transit time from the mouth to the cecum in healthy individuals, without altering gastric emptying; thereby demonstrating increased motility of the small intestine.13 An increase in motility in the small intestine contributes to symptoms of diarrhea.

Colonic Gas Production
Colonic bacteria ferment poorly absorbed carbohydrates that reach the colon resulting in the production of methane and hydrogen. Breath testing shows an increase in hydrogen and methane gas production with high FODMAP diets.14 An increase in colonic gas leads to bloating and distention, and in patients with intestinal hypersensitivity, causes pain. Oligosaccharides have shown a greater fermentative effect than other FODMAPs and MRI studies show greater colonic distension with inulin (a plant polysaccharide) compared to fructose (a monosaccharide).15

Visceral Hypersensitivity
 Fermentation results in the production of short chain fatty acids (SCFAs) in the colon. SCFAs consist of acetate, propionate, and butyrate and serve as a fuel source for colonocytes. They also play a role in lipid, glucose, and cholesterol metabolism and are important for intestinal health.16 High FODMAP diets increase serum levels of lipopolysaccharides leading to gut permeability, intestinal inflammation, and visceral hypersensitivity.17 This increases the likelihood of developing pain with intestinal distention.

Gut Microbiome
 Oligosaccharides are known for their prebiotic effect on the body. A restriction of these carbohydrates with a low FODMAP diet has been shown to reduce levels of luminal bifidobacter, which has been well established in contributing positive health benefits including improved immune function.14,18 A 3-4 week duration of FODMAP restriction resulted in 6-fold reduction in bifidobacteria (a desirable bacterial species in the microbiome) compared to controls.19 Another recent study also showed a change in the bacterial content of the intestinal microbiome after short-term administration of a low FODMAP diet.20 Co-administration of a probiotic while on a low FODMAP diet restored concentrations of bifidobacter along with providing symptom relief.21

Effect of Low FODMAP Diets on the Metabolome
Foods result in the generation of small-molecule chemicals in the body that have physiological effects. These chemicals are called the food-induced metabolome. Low FODMAP diets have an effect on the metabolome. Three active food-induced chemicals (histamine, p-hydroxybenzoic acid, and azelaic acid) were studied in an experimental intervention using a high FODMAP and a low FODMAP diet. Histamine, a measure of immune activation, was decreased 8-fold on the low FODMAP diet.22 Histamine may have a role in IBS as histamine levels have been shown to be elevated in these patients.23

Use in Gastrointestinal Disorders
Irritable Bowel Syndrome (IBS)
A meta-analysis of short-term studies on low FODMAP diets in IBS found 6 randomized controlled trials and 16 non-randomized trials demonstrating substantial improvements in IBS symptoms with a low FODMAP diet.24 A more recent meta-analysis found seven randomized controlled trials comparing a low FODMAP diet with control interventions. A low FODMAP diet was associated with reduced global symptoms compared with control interventions, but the quality of the data was low.25

Inflammatory Bowel Disease (IBD)
Functional gastrointestinal symptoms are present in a proportion of patients with inflammatory bowel disease. Functional symptoms are more likely in patients with Crohn’s disease compared to patients with ulcerative colitis perhaps due to disease location.26 There is some evidence to support use of a low FODMAP diet in patients with IBD in whom the inflammatory bowel disease is controlled, but symptoms persist. Improvements were seen in stool consistency and frequency along with decreased severity of abdominal pain, bloating, and flatulence.27

Celiac Disease on a Gluten Free Diet (GFD)
Life-long adherence to a gluten-free diet is the only current treatment for patients with celiac disease. Despite strict adherence to a gluten-free diet, symptoms are reported by 47% of patients with celiac disease.28 A randomized, controlled trial of patients with celiac disease on a gluten free, low FODMAP diet showed significant improvement in functional gastrointestinal symptoms and psychological health scores.29

Non-Celiac Gluten Sensitivity
 Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in the absence of celiac disease. Wheat is a very important source of fructans in the U.S. diet. A recent study aimed to evaluate the effects of gluten and fructans on the genesis of symptoms in patients with non-celiac gluten sensitivity. In a double-blind trial, patients with non-celiac gluten sensitivity and IBS were given a low FODMAP diet for 2 weeks followed by a high-gluten, low-gluten and a control period of whey protein.30 Symptoms improved on the low FODMAP diet, but worsened equally when gluten or whey protein was added to the diet suggesting that the cause of food sensitivity may be multi-factorial. Skodje et al. studied subjects who did not have celiac disease, but were on a self-imposed gluten-free diet.30 These individuals were administered diets containing gluten, fructans or placebo concealed in muesli bars for 7 days. After a wash-out period, the subjects were re-randomized until all three diets were administered to all subjects. Symptoms of bloating and overall symptoms of IBS worsened during fructan administration, but the effect of gluten containing diets was similar to placebo. This trial suggests that fructans may have a role in the development of symptoms and therefore a low FODMAP diet could help these patients. Another recent study evaluated the effect of a low FODMAP compared to a gluten-free diet on clinical symptoms, psychological well being, intestinal inflammation and integrity, and stool microbiota in subjects with non-celiac gluten sensitivity. Both the low FODMAP diet and the gluten free diet resulted in a significant improvement in symptoms in patients with non-celiac gluten sensitivity. There was a decrease in duodenal intraepithelial lymphocytes and mucin-producing Goblet cells after administration of a gluten free diet. Significant changes were seen in the stool microbiota composition in patients with non-celiac gluten sensitivity and controls. This study suggests that symptom generation may be multi-factorial in patients with non-celiac gluten sensitivity.31

Low FODMAP Diet Implementation
 A practical guide to implement the FODMAP diet in clinical practice has recently been published and this subject is only briefly covered here.32

Elimination
The elimination phase is the first of three phases of the low FODMAP diet (Table 5). It is during this time that patients restrict all high FODMAP foods from the diet for 2-6 weeks. The goal during this phase is to determine if there is sensitivity to FODMAPs because not all patients will elicit a response. A biomarker may be helpful to identify patients who would benefit from a low FODMAP diet. In one study, measurement of volatile organic compounds in stool predicted with 97% accuracy whether an IBS patient responded to a low FODMAP diet.33 Further validation of this biomarker is needed. A number of resources are listed in Table 6 and can help patients through this phase.

Re-introduction
The low FODMAP diet is too restrictive for long-term use. Therefore, the next step is to systematically challenge the patient with each FODMAP component. The general principle is to introduce small amounts of one group and gradually increase the dose on day two and three if the food is tolerated. If symptoms develop, the challenge is stopped and a 3-4 day wash out period is started until symptoms resolve. If no symptoms are observed, the next FODMAP challenge begins. This process typically lasts 6-8 weeks. No evidence-based guidance is available at this time, but Table 7 shows our approach to the re-introduction of foods.

Maintenance
 The final phase of the diet modification is long-term adherence to a personalized FODMAP plan. The individualized plan is created based on the results of the previous phase. FODMAPs that trigger symptoms are limited, but the others are added back to the diet.

FODMAPS and Enteral Feeding
 FODMAPs may have an important role in adverse effects caused by enteral feeding. In a retrospective study of patients with diarrhea caused by enteral feeding in Australia, the FODMAP content of the enteral feeding ranged from 10.6 to 36.5 g ⁄ day. A low FODMAP enteral formula was associated with a five-fold reduction in diarrhea rates.34 A randomized, controlled trial of a low, moderate, and high FODMAP enteral feeding was conducted in Korea. There was a significant reduction in diarrhea and improvement in nutritional parameters and clinical outcome in patients randomized to the low FODMAP enteral feeding formula.35 Quantifying FODMAPs in enteral formulas has proved to be difficult because of the interference with in vitro assays of fructans and raffinose caused by the maltodextrin content of the formula.36 Therefore, there is a no ready source for the FODMAP content of enteral feeding formulations in the United States. However, in symptomatic patients, a trial of FOS, fiber, and inulin free formulas may be beneficial.

The Role of a Dietitian
 A low FODMAP diet is restrictive and can be confusing to implement without guidance. Patients benefit from instruction provided by a dietitian who specializes in GI nutrition and is familiar with the low FODMAP diet.37 A recent survey of over 1,500 gastroenterologists suggested that most felt that dietary intervention was as good, or better, than other available treatments for IBS.38 The survey also demonstrated that only a small portion of gastroenterologists refer patients to a dietitian with specialized GI training despite the fact that the majority believed that GI trained dietitians would be of benefit to their patients. This may be related to the lack of access to dietitians with specialized training. Resources for low FODMAP diets are becoming more available to the general public and there is a tendency to give the patient a handout and refer them to on-line resources (Table 6). We gave up this approach in our department when patient dissatisfaction and a poor response to dietary intervention lead us to re-evaluate it. All our patients are now instructed by a registered dietitian and are followed until a personalized diet plan is developed. The dietitian may also have a role in monitoring the nutritional status of patients who are on low FODMAP restricted diets for long periods of time.
Long-Term Risks and Unanswered Questions Dietary intervention carries the risk of being considered “all-natural” and risk-free. Limited data are available on the nutritional consequences of prolonged restriction of FODMAP s in the diet. Changes in the microbiome and in the composition of gut content may have adverse effects on health. For example, short chain fatty acids are decreased in the colon on low FODMAP diets. Short chain fatty acids are trophic to the colon mucosa and essential for intestinal health.

CONCLUSION
 A low FODMAP diet can be an effective treatment for IBS, but increasing evidence suggests a possible use in symptomatic patients with quiescent inflammatory bowel disease, non-celiac gluten sensitivity, and celiac disease with persistent symptoms on a gluten-free diet and normal celiac serology. In some patients, FODMAPs in enteral feeding formulas can cause bloating and diarrhea in tube-fed patients. Registered dietitians are essential for the education of patients in initial FODMAP restriction, structured re-introduction and final implementation of a personalized diet. Further areas of research include the adverse effects of FODMAP restriction on the microbiome, the effects of long-term FODMAP restriction on nutrition and intestinal health and the possible use of low FODMAP diets in other disease states.

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Naturlax: Your All-Natural, Sugar-Free Fiber Supplement

July 2019 • Volume XLIII, Issue 7

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Naturlax is an all-natural fiber supplement that contains no artificial ingredients and comes in over 80 delicious flavors.
ORANGE, CA–Naturlax, a fiber supplement company, offers an all-natural, sugar-free psyllium fiber supplement available in over 80 unique flavors.
Although other fiber supplement brands may have sufficient fiber per serving, Naturlax psyllium husk supplement is 100% free of any artificial ingredients. Naturlax focuses on being the premiere all-natural, sugar-free fiber supplement for young and old patients alike. Unlike traditional flavors such as orange and berry, Naturlax offers over 80 unique, gourmet flavors completely derived from all-natural fruits, vegetables, and plant extracts.

  • Active ingredient is psyllium husk
  • Over 80 delicious, all-natural flavors
  • Sugar-free, sweetened with our proprietary blend of stevia and erythritol

Naturlax is a family-owned and run company located in Orange, California that specializes in providing an array of psyllium fiber flavor options because everyone deserves a fiber supplement suited to their own unique taste. Naturlax ensures that all of their products and ingredients are of the highest quality so that we can provide superior natural supplements that support a healthy lifestyle.

Medical Bulletin Board

Louisiana Launches Hepatitis C Innovative Payment Model with Asegua Therapeutics, Aiming to Eliminate the Disease

July 2019 • Volume XLIII, Issue 7

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Modified Subscription Arrangement Reflects Shared Commitment to Significantly Increase Access to Hepatitis C Cures in Louisiana; State’s Goal is to Serve 31,000 Patients by End of 2024.
Baton Rouge, LA and Foster City, CA – Governor John Bel Edwards joined Secretary Rebekah Gee of the Louisiana Department of Health, Secretary James LeBlanc of the Louisiana Department of Corrections, and Asegua Therapeutics LLC, a wholly-owned subsidiary of Gilead Sciences, Inc. (Nasdaq: GILD), to announce a deal that will allow the implementation of an innovative payment model for hepatitis C treatment, part of Louisiana’s plan to eliminate the disease.

“This new model has the potential to save many lives and improve the health of our citizens. It is an important day for our state, for our partner Asegua Therapeutics, for providers, but most importantly for the patients and their families who will benefit from treatment,” said Governor Edwards. “Asegua was willing to come to the table to work with us to help Louisiana residents and we are pleased to initiate this five year partnership. Ultimately, our goal is to eliminate this disease in Louisiana, and we have taken a big step forward in that effort.”

In the United States, hepatitis C kills more people than all other infectious diseases combined. At least 39,000 people in Louisiana’s Medicaid program and prison system suffer from hepatitis C infection.

“An elimination plan and innovative payment model will ensure that we can cure this deadly disease and prevent long-term illness and disability in those who have it,” said Dr. Rebekah Gee, secretary of the Louisiana Department of Health. “The Department of Health’s goal is to treat at least 31,000 people by the end of 2024 and eventually eliminate this disease.”
After extensive research and work with policy experts across the nation, the Department of Health released a solicitation of offers in January of 2019 in search of a pharmaceutical company willing to partner with Louisiana on a subscription model. Asegua Therapeutics was announced as the selected partner in April, and through subsequent discussions the parties have agreed to a modified model.

“We are pleased that Asegua has the courage to be a pioneer and chart a new path forward that will allow us to save many lives and improve the health of our citizens,” added Gee.

The innovative payment model for Louisiana addresses the needs of patients and joins the goals of both Louisiana and Asegua to extend a cure to those in need.

“This partnership will have a direct and immediate impact on the most vulnerable populations with hepatitis C – people who are on Medicaid or who receive care through the state corrections system. These populations are disproportionately affected by hepatitis C and often face the greatest difficulty in accessing care,” said Gregg Alton, Chief Patient Officer at Gilead Sciences. “We are committed to supporting efforts to eliminate hepatitis C in communities around the world and are excited to partner with the visionary leaders in Louisiana to make this public health opportunity a reality in this state.”

The innovative payment model allows the state to purchase an unlimited amount of Asegua’s direct-acting antiviral medication, the authorized generic of Epclusa® (sofosbuvir/velpatasvir) to treat patients within Louisiana’s Medicaid and Department of Corrections populations and caps the State’s medication costs.

“With this model to purchase hepatitis C medications, we can cure those within the state facilities who have this life-threatening illness and prevent the spread of the illness within our facilities,” said James LeBlanc, secretary of the Louisiana Department of Corrections. “We will also work closely with the Department of Health to implement a plan to screen and treat the local level population either while incarcerated or upon release into supervision. Most importantly, we can make sure these men and women have an opportunity to be even more successful and healthy when they return to their communities.”

The Department of Health and Asegua completed and signed a formal contract for the purchase of Asegua’s hepatitis C medication, the authorized generic of Epclusa, over five years, and for people enrolled in the Medicaid program and incarcerated people in Louisiana. The Department of Health continues to implement an elimination plan that engages partners across the state to educate the public on the availability of a cure and reach out to high-risk populations for screenings; connect people living with hepatitis C to care; expand provider capacity; and establish partnership across the state to eliminate hepatitis C in Louisiana.

About Louisiana Department of Health
The Louisiana Department of Health strives to protect and promote health statewide and to ensure access to medical, preventive and rehabilitative services for all state residents. The Louisiana Department of Health includes the Office of Public Health, Office of Aging & Adult Services, Office of Behavioral Health, Office for Citizens with Developmental Disabilities, and Healthy Louisiana (Medicaid).

Visit LDH Website

About Asegua Therapeutics
 Asegua Therapeutics is a wholly-owned subsidiary of Gilead Sciences, Inc. Gilead Sciences is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements
 This press release includes forward-looking statements related to Asegua Therapeutics, a subsidiary of Gilead Sciences, Inc., within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that the parties not may not realize the potential benefits of this partnership. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2019, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
For more information, please visit: gilead. com or call Gilead Public Affairs at: 1-800-GILEAD-5 or 1-650-574-3000

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #23

IgG4-related Sclerosing Cholangitis

July 2019 • Volume XLIII, Issue 7
Raj A. Shah,Kris V. Kowdley

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Raj A. Shah, MD Liver Care Network and Organ Care Research Swedish Medical Center, Seattle WA Kris V. Kowdley, MD, FACP, FACG, AGAF, FAASLD Director of the Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA.

IgG4-related disease, characterized by IgG4-rich inflammatory infiltrates and variable degrees of fibrosis, encompasses a variety of disorders involving multiple organs. IgG4-related sclerosing cholangitis (IgG4-SC) is frequently associated with autoimmune pancreatitis. The disease is associated with a clinical presentation of obstruction, jaundice, weight loss and abdominal pain. IgG4-SC is typically diagnosed in middle-aged and older men and therefore may lead to a suspicion of cholangiocarcinoma or primary sclerosing cholangitis. The association with autoimmune pancreatitis and an elevated IgG4 level (>135 mg/dl) should increase the clinical suspicion of IgG4-SC. There are typical histological features of an IgG4-rich plasma cell infiltrate on liver histology as well as storiform fibrosis and obstructive phlebitis. Cholangiographic changes in IgG4-SC are distinct from PSC and four types of IgG4-SC have been described. All diagnostic modalities should be used to evaluate patients with suspected IgG4-SC including imaging, endoscopic methods and biopsy as well as a thorough history, physical examination and laboratory assessment to evaluate for extrahepatic disease. Corticosteroids are the mainstay of therapy, with a starting dose of prednisone of 0.6 mg/kg/day. Other immunosuppressive therapies can be used for steroid-intolerant or refractory patients. This review describes the epidemiology, diagnosis and management of IgG4-SC.

Epidemiology
IgG4-related disease (IgG4-RD) is a fibroinflammatory process with multiorgan manifestations, of which IgG4-related sclerosing cholangitis (IgG4-SC) is a known biliary complication.1 IgG4-SC is frequently accompanied by autoimmune pancreatitis (type I AIP) as found by a cohort in UK, which showed that 87% of cases diagnosed with IgG4-SC also had intrapancreatic involvement.2 The incidence and prevalence of AIP in Japan was estimated to be 1.4 and 4.6 per 100,000 of the population, respectively.3 Of this population with AIP, 23.5% had IgG4-SC within the intrahepatic ducts and 10.3% had disease at the porta hepatis.
IgG4-SC has a three to five-fold higher prevalence in men than women, and the mean age of presentation is in the sixth decade.3,4 In one study, 92% of cases had a medical history of AIP, 77% had obstructive jaundice on presentation, and 74% had increased serum IgG4 levels on presentation.4 Occupational exposure may play a role as 61% of patients in a cohort had worked ‘blue collar’ jobs for at least one year prior to diagnosis and 52% reported prolonged exposure to solvents, industrial dusts, pesticides, industrial oils, or polymers.5 This is in contrast to a 14% reported history of blue collar occupation in those diagnosed with primary sclerosing cholangitis (PSC).5 History of allergy and atopy has been noted in 63% and 40% of patients with IgG4-RD, respectively.6 In fact, the study also observed IgE-positive mast cells and eosinophilia in biliary tissue in these cases. IgG4-SC is often accompanied by other autoimmune disorders, the most common being inflammatory bowel disease afflicting 10% and thyroid disease in 7%.2

The presence of IgG4-SC is an important prognostic indicator in IgG4-RD, predicting relapse after discontinuation of corticosteroid therapy.2,4 IgG4-SC may impart an increased risk of all-cause mortality,2 though this may be at least partially attributable to the advanced age of those diagnosed.7 Increased risk of malignancy has been associated with diagnosis of IgG4-SC in some studies,2,8 though another cohort did not find a significant difference in incidence of malignancy from the general population.9 One proposed hypothesis for an increased risk is the chronic inflammation caused by the disease.7 The K-ras mutation is frequently found in the pancreas, bile duct, and gallbladder of patients with AIP.10 The relative risk of cancer at the time of diagnosis of IgG4-RD has been found to be 4.9, which decreases to 1.5 in subsequent years.8 This finding indicates malignancy may be a cause, rather than the result, of IgG4-RD. Increased B-cell secretion of IgG-4 has been observed in malignancy, specifically melanoma.11

Diagnosis
 IgG4-SC is diagnosed in patients with AIP in 87-92%2,4 of cases. As the disease process is similar, the diagnostic criteria of AIP have therefore been adapted for the diagnosis of IgG4-SC.12 Diagnostic criteria for AIP, proposed in 2006,13,14 involve five criteria: histology, imaging, serology, other organ involvement, and response to steroid therapy (HISORt criteria). Histology involves the findings of periductal lymphoplasmacytic infiltrate with > 10 IgG4+ cells per high power field on immunofluorescence staining, obliterative phlebitis, and storiform fibrosis. Imaging, while for AIP would reveal pancreatic abnormalities, for IgG4-SC should reveal biliary structures either in intrahepatic ducts, proximal extrahepatic ducts, or intrapancreatic ducts.12 Serologic criteria include IgG4 levels ≥ 135 mg/dL.15 Other organ involvement may include pancreatic, renal, salivary or lacrimal, or retroperitoneal fibrosis. Response to steroid therapy would be demonstrated by either radiologic improvement of stricturing or by biochemical response.

Japanese clinical guidelines15 support cholangiographic classification of IgG4-SC into four types, characterized by location and pattern of biliary strictures, and used to inform the clinician regarding potential alternative diagnoses that must be considered. Type 1 involves stenosis in the distal bile duct. Pancreatic cancer (PC) and cholangiocarcinoma may mimic this presentation and would therefore warrant consideration prior to diagnosis of IgG4-SC.16 Type 2 is characterized by diffusely distributed stenosis both in the intra- and extrahepatic ducts, due to which PSC must be ruled out. Type 3 includes hilar biliary strictures along with distal stenosis. Type 4 involves only the hilar strictures. Cholangiocarcinoma may present similarly to either type 3 or 4.

The differentiation of IgG4-SC from PC, cholangiocarcinoma, and PSC remains a diagnostic challenge and requires a multimodal approach. Serologic examination of the secretory mucin MUC5AC along with CA19-9 has shown a sensitivity of 83% and specificity of 80% in diagnosis of PC.17 Imaging modalities such as CT, MRI, and EUS have different contexts for use and limitations in diagnosis of PC, and are discussed elsewhere.18 EUS-guided fine needle aspiration may be required if clinical suspicion remains high.18

Cholangiocarcinoma can also be assessed with serologic testing of CA 19-9 and duke pancreatic monoclonal antigen type 2, both of which are significantly more elevated with this disease compared to IgG4-SC.19 As IgG4-SC is nearly always associated with AIP,2,4,19 pancreatic involvement on imaging can be a sign of the disease. Serum IgG4 levels can be elevated in cholangiocarcinoma, and increased specificity of 87% can be obtained with a higher cutoff at 157.5 mg/dL20. Serologic tumor markers that may be elevated in cholangiocarcinoma include CA 19-9, CA 242, and carcinoembryonic antigen (CEA).20 EUS may be a useful tool to differentiate imaging characteristics. In one study, a thickened wall was detected on EUS in 94% of patients with IgG4-SC as opposed to 30% with cholangiocarcinoma, while a space occupying lesion was seen in only 6% of those with IgG4-SC versus 80% with cholangiocarcinoma.20 Obtaining biopsy samples for histopathologic assessment may be useful as storiform fibrosis and obliterative phlebitis are present in IgG4-SC but not in cholangiocarcinoma.21 Immunofluorescence may be of limited utility in this context as 16% of cholangiocarcinoma cases and 17% of cases with PC can have ≥ 20 IgG4+ plasma cells on histologic assessment.22

Serologic evaluation in PSC may show elevation of serum titers of IgM, anti-smooth muscle antibody, anti-nuclear antibody, and anti-neutrophil cytoplasmic antibody but none of these are specific for the disease.23 IgG4 elevation is also present in 9-15% of those with PSC, and the extent of any relationship between this subset of PSC and IgG4-SC remains undetermined.24 While type 2 IgG4-SC may mimic characteristics of PSC on imaging, cholangiography can detect certain features that favor IgG4-SC such as multifocal strictures, bile duct wall thickness > 2.5 mm, and the lack of hepatic parenchymal changes.25 Characteristics of PSC on cholangiography include a beaded appearance or the presence of diverticulum-like outpouchings.15 Patient history may be helpful in differentiating PSC from IgG4-SC. Average age at diagnosis of PSC is 41 years old26 compared to 62 years old at diagnosis of IgG4-SC.4 IBD is present in 70-80% of patients with PSC26 as opposed to 10% of those with IgG4-SC.2 Furthermore, PSC is not associated with pancreatic disease whereas IgG4-SC coexists with AIP in up to 92% of cases.4 Histologically, the fibroinflammatory process of IgG4-SC exhibits a transmural distribution whereas PSC demonstrates mucosal damage.25

While a criterion of > 10 IgG4+ plasma cells per high powered field is included in diagnostic criteria, other disease processes such as PSC, PC, and cholangiocarcinoma can mimic this finding.22 Another criterion that has been shown to be more specific for IgG4-SC, with a specificity of 90.2%,27 is a ratio of IgG4+ plasma cells to IgG+ plasma cells that is > 40%. Research has also shown that determination of dominant IgG4+ B-cell receptor clones via next-generation sequencing may be accurate in differentiating IgG4-SC from PSC or cancer.28 Moreover, the same study identified a cutoff of 5% for the ratio of IgG4 to IgG RNA using quantitative PCR that yielded a sensitivity of 94% and specificity of 99% in identification of IgG4-SC. Other assays, such as IgG4:IgG1 ratio, continue to be studied to develop robust biochemical parameters that can be used to diagnose and prognosticate this illness.1

Treatment
 Corticosteroid therapy is the cornerstone of therapy for IgG4-SC12,15,25 and leads to rapid and durable remission in 90% of patients.29 The dose is dependent on the center but commonly used is either a dose of 0.6 mg/kg/day of prednisolone or 30-40 mg daily.30 This was usually continued for four weeks followed by a taper whereby the dose would be decreased by 5 mg every 1-2 weeks predicated on the patient’s clinical response.29,30 Standard practice in Europe and North America has been to subsequently discontinue steroid therapy in three months without maintenance dosing.30 By contrast, in Asia, prednisolone is tapered to a maintenance dose of 5 mg daily, which is continued for three years prior to consideration for discontinuation15. As the disease responds swiftly to steroid therapy, obstructive jaundice without acute cholangitis may be safely managed without biliary drainage under close clinical monitoring, thereby avoiding the risks associated with endoscopic retrograde cholangiopancreatography (ERCP).30

Relapse of IgG4-RD after a course of steroid therapy is common, occurring in 45% of cases with AIP in a cohort at Mayo Clinic.31 In this cohort, those who relapsed received either a repeat course of steroids or a combination of steroids and steroid-sparing immunomodulators, such as azathioprine, 6-mercaptopurine, mycophenolate mofetil, or methotrexate. The two groups had a similar rate of relapse-free survival, with a total of 77% achieving remission. The remainder, who were either intolerant or resistant to treatment, received rituximab, which achieved remission in 83% of the remaining patients. Rituximab, an anti-CD20 antibody causing B-cell depletion, has been tested in an open-label pilot trial for treatment of IgG4-RD with disease response observed in 97% of participants and complete remission achieved in 47% at 6 months.31

Elucidation of the pathophysiology of IgG4-SC and the overarching diagnosis of IgG4-RD has opened avenues to explore for targeted treatments. The IgG4 molecule has a uniquely unstable hinge region that allows dissociation to two ‘hemi-IgG4’ molecules that can then reassociate with other hemi-IgG4 molecules to form antibodies that are specific to two different antigens, but that have poor affinity for both Fc receptors and complement.32 Hence, the molecule is considered anti-inflammatory due to its competitive binding of antigenic sites without subsequent activation of inflammatory response. This is indeed observed in its role in blunting immune response to malignancy33 and moderating allergic reactions.34 The discovery of the role of circulating CD19+ plasmablasts, progenitors of plasma cells, in disease activity35 has led to clinical investigation of targeted drug therapy. XmAb5871, a monoclonal antibody for CD19 with an Fc domain that binds to the inhibitory receptor of B-cells, is currently in phase II of development for treatment of IgG4-RD.36

In summary, IgG4-SC is a protean disease that remains a diagnostic challenge requiring a holistic approach. While more specific markers are on the horizon, the HISORt criteria remain the most studied diagnostic tools to assist the clinician. Corticosteroid treatment is first-line for the disease and induces remission in the vast majority of patients,12,15 and rituximab may be of benefit in refractory cases.37 As the immunologic milieu of this disease process is further illuminated, targets for future therapy may become more apparent.

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FRONTIERS IN ENDOSCOPY, SERIES #53

Endoscopic Ultrasound Elastography: An Emerging Clinical Tool

July 2019 • Volume XLIII, Issue 7
Kapil Gupta,Ingrid Schwartz,James H. Tabibian,Mohit Girotra

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Kapil Gupta, MD PGY2 Resident in Internal Medicine, University of Miami/JFK Medical Center Palm Beach Regional GME Consortium, West Palm Beach, FL Ingrid Schwartz, MD PGY2 Resident in Internal Medicine, University of Miami Miller School of Medicine, Miami, FL James H. Tabibian, MD, PhD Health Sciences Clinical Associate Professor, Geffen School of Medicine at UCLA, Director of Endoscopy, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA Mohit Girotra, MD FACP Assistant Professor of Clinical Medicine, University of Miami Miller School of Medicine, Director of Endoscopy at University of Miami Hospitals and Clinics, Miami, FL.

Endoscopic ultrasound (EUS), a technology developed in the 1980s, has become well established in clinical practice throughout the world. EUS has proven to be beneficial in diagnosis and staging of a wide variety of pathologies throughout the gastrointestinal (GI) tract and has progressed throughout the years, with inclusion of tissue sampling and therapeutic procedures such as gallbladder (GB) or common bile duct (CBD) drainage, pseudocyst drainage and necrosis management. In terms of technology, the introduction of Doppler provided an ability to view vasculature. Moreover, in recent years, there has been an expansion in EUS technology, principally with ability to perform EUS Elastography (EUS-EG) and Contrast Enhanced EUS (CE-EUS).1 Elastography (EG) is a noninvasive imaging modality of tissue evaluation that characterizes mechanical properties of tissues. Changes in tissue stiffness and/or elasticity have been theorized as a possible marker of either inflammation, fibrosis, or neoplastic infiltration.2,13 EG has been studied for potential noninvasive diagnosis for several pathologies, even cancers, given the altered elasticity with increased tissue stiffness in different diseases.10

EUS-EG refers to the application of elastography within the imaging capability and platform of EUS. EUS-EG has been primarily deliberated as a novel approach to assess tissue in the pancreas, but more recently investigators are examining this approach to other areas in the GI tract and hepatobiliary system. Real time elastography (RTE) is the use of ultrasound along with the measuring of stress applied to the tissue being studied; comparing it to the strain/deformation it produces. RTE measures strain (compression causing tissue deformation) within the region being studied while being visualized with a color overlay on B-mode ultrasonography.2
EUS-RTE allows estimation of the stiffness of tissues, which are approachable through the GI tract, and may allow early stage differentiation of benign and malignant tissues.2-5 Tissue diagnosis, including EUS-guided fine needle aspiration/biopsy (EUS-FNA/FNB) is the gold standard for the diagnosis of malignancies (in the GI tract, including pancreatic cancer). While some groups have attempted to describe EUS-EG as having the potential to provide a “virtual biopsy”,59 in reality, most agree that such technologies may at best act as an adjunct to biopsy and tissue diagnosis.2-5

The present article is intended to provide endoscopists a comprehensive review of this novel technology, while appraising the literature on it, and contemplating its potential uses in clinical practice.

[I]. How is EUS-EG Performed?
There are two different modalities of EUS-EG: qualitative and quantitative.

Qualitative Elastography
Qualitative elastography is an objective measurement of the compression of tissues using a B-mode ultrasound image as an indicator of stiffness.1,10 This modality detects the deformations from compression on a B-mode ultrasound image on regions of interest (ROI).1,10,12 Prior to evaluating the ROI, a sufficient basis of either reference tissue (normal tissue) surround the ROI is imperative. Dietrich et al. suggest the most accurate images were achieved when the target lesion was about 25-50% of the ROI.2 In this mode of imaging, it is also imperative to avoid large blood vessels, so as to minimize flow related motion artifact.1,10,12 In qualitative measurement, elasticity (stiffness) can be measured in a number scale that corresponds with a color scheme. Stiff tissue on elastography is seen as a darker blue; intermediate tissue as green; medium tissue (less hard than intermediate) as yellow; and soft tissue as red.1,10,12 The elastographic pattern is performed and reviewed as a color pattern that overlays a classic B-mode ultrasound picture.1,10,12

Quantitative Elastography
Strain Ratio (SR)
In addition to qualitative data, SR can be calculated by measuring mean strain of the reference area/lesion divided by the mean strain in total ROI. This ratio depends on the important assumption that strain is evenly distributed throughout the entire ROI.2 Two different regions (Region-1 and Region-2) are chosen for qualitative analysis. Region-1 includes the largest amount of target lesion possible with the smallest amount of surrounding normal parenchyma. Region-2 includes the softer (higher density of red) areas of ROI that do not include the target lesion.1,10 The strain of the ROI is then compared to a region of normal surrounding tissue (reference) that receives similar stress.2 SR quantifies the difference of strain in the areas within the same ROI.2

Histogram Analysis
 In a strain histogram (SH), a diverse distribution of different strain patterns obtained qualitatively can be statistically analyzed and measured for quantitative evaluation,2 allowing depiction of range and overall pattern of strain through much of the ROI. The SH represents elasticity measured qualitatively from 0 (hardest) until 255 (softest) along the X-axis,1 and the important parameters being mean strain, standard deviation of the mean, percentage of blue area, and complexity of blue area. The shape of the SH is described by a distribution of numbers that reflects the homogeneity of the color pattern studied in an elastography image.2,6-9

[II]. EUS-EG of the Pancreas
EUS allows high-resolution imaging of the pancreas aiding in accurate diagnosis (and staging) of chronic, cystic, inflammatory and neoplastic pancreatic disorders. However, EUS cannot reliably differentiate between cancer and focal pancreatitis, with only B-mode imaging,12 and this is a potential area where EUS-EG may add worth. This was first evaluated by Hiroka et al.13 The normal parenchyma of the pancreas appears homogenously green on EUS-EG (soft tissue), a well-defined reproducible characteristic.12

a. Solid Masses
The imaging of pancreatic lesions has been historically performed using abdominal ultrasound, CT, MRI, and PET scan.14 The aggressiveness and morbidity of pancreatic cancer (PC) have made it imperative to discover alternative methods to assist with the diagnosis. EUS-FNA/FNB is most commonly used diagnostic modality, with a high specificity but a lower sensitivity, and EUS-EG had been proposed as an alternative or adjunct method to detect masses and even predict malignant potential. This was conceived because of the belief of increased stiffness (decreased elasticity) with malignant pancreatic lesions.15

Qualitative Analysis
 In 2006, Giovannini et al. studied the use of EUS-EG in the qualitative analysis of 24 solid pancreatic lesions, and using color patterns of the image, they were scored with blue lesions being malignant.16 The authors described a 5-point scoring system for description of a solid pancreatic mass: 1 = normal pancreatic tissue with mainly predominantly (mostly homogenously) green color pattern; 2 = little degree of fibrosis with increased heterogeneity, but still in the soft tissue range, which meant green with some shade of yellow and red; 3 = concerning for an early PDAC, with presence of blue with minimal heterogeneity; 4 = presence of neuroendocrine tumor or possible metastases, with area of green surrounded by a larger area of blue (less elastic tissue); 5 = advanced PDAC, with predominantly blue elastographic image, and some heterogeneity suggesting tissue necrosis.16 In this study, although limited by size, the sensitivity and specificity for predicting malignancy was 100% and 67% respectively16.

Giovannini et al. published in 2009 a follow up multicenter study where 121 pancreatic lesions were analyzed with qualitative EUS-EG,18 using the same scoring system as above, and attributed 1-2 as benign, 3 as indeterminate and 4-5 as malignant. This EUS-EG was then compared to final pathology obtained using EUS-FNA or surgical pathology. The sensitivity and specificity of EUS-EG to differentiate between malignant and benign masses were 92.3% and 80.6% respectively, and positive (PPV) and negative predictive values (NPV) were 93.3% and 78.1% respectively, with a global accuracy of 89.2%. The study had 7 false negatives, which authors attributed to lesions with necrotic tissue and/or high vascularity, which would be read as softer tissue on EG images. The authors, however, acknowledged inter-observer variability of images leading to difficulties with interpretation.18 Similarly, Iglesias-Garcia et al. used qualitative EUS-EG to analyze 20 controls (with a homogenous green pattern) and 130 pancreatic lesions, which included 78 malignant lesions (77 PDAC, 1 metastatic), 42 inflammatory mass (CP) and 10 neuroendocrine tumor (3 insulinoma, 1 glucagonoma, 5 non-functioning).17 For the diagnosis of malignancy, EUS-EG was found to have a sensitivity of 100 % and specificity of 85.5%, with PPV of 90.7% and NPV of 100%, and overall accuracy of 94%. In this study, the elastographic images were evaluated by a single endosonographer, who was blinded to the pathology, and a second operator re-evaluated the same images, blind to both clinical information and histopathological diagnosis.17 The authors noted that with patients of CP, inflammation could be particularly difficult to image and may be confused with malignancy, and hence emphasized on need for histopathological diagnosis for an accurate and proper diagnosis.17

Jannsen et al. studied qualitative EUS-EG to evaluate normal pancreas (n=20), CP (n=20), focal pancreatic lesions (n=33), and elastographic patterns were classified in terms of homogeneity and color.19 Elastographic homogeneity was classified into three types: 1 = homogenous; 2 = inclusive of 2 or 3 colors; 3 = “honeycomb” pattern, while elastographic color patterns were represented with letters A = blue; B = green/yellow; C = red.19 To discern between benign pancreatic lesion and malignancy, the authors achieved a sensitivity of 93.8%, however, compared to other studies, a lower specificity and accuracy of 65.4% and 73.5% respectively. The authors also noted an overlap in their elastographic images between CP and pancreatic neoplasm,19 as well as low PPV for pancreatic neoplasms. This led authors to conclude that advanced CP is difficult to differentiate from hard pancreatic masses on EUS-EG,19 and hence emphasized EUS-EG cannot be a standalone diagnostic indicator, and it must be used as complement or supplement tissue diagnosis.19 Hirche et al. reported challenges in evaluating a ROI lesion greater than 35 mm in diameter with EUS-EG, lesions with increased distance from the transducer, and due to presence of fluid,20 and hence low sensitivity and specificity of 41% and 53% along with an accuracy of 45%.20

Quantitative Analysis
Iglesias-Garcia et al. in 2010 evaluated 86 patients with pancreatic masses using EUS-EG to analyze their SR,21 which was found to higher with patients with malignant lesions when compared to inflammatory masses, and both had higher SR than normal pancreas.21 The authors inferred that quantitative EUS-EG with SR was more accurate than qualitative EUS-EG, with a sensitivity and specificity of 100% and 92.9%. Through the years, multiple other studies have evaluated the SR for differentiation of malignant lesions, and cut-off values have varied from 3.7 to 24, resulting in sensitivity ranging between 67-98% and specificities between 45-71%.22-27
In 2008, Saftoiu et al., in a prospective study, evaluated the hue-histogram quantitative EUS-EG28 (22 controls with normal pancreas, 11 CP, 32 PDAC, 3 NET). Each EUS-EG image collection was reported as a numerical value in the form of a vector value (a number from 1 to 256). A frame of 10 images was given a value, and the mean of 10 frames was defined as the mean value.28 With a defined cutoff value of 175, the authors achieved a sensitivity of 91.4%, specificity of 87.9% with an accuracy of 89.7% to differentiate between benign and malignant masses, with PPV 88.9%, and NPV 88.9%. A major limitation of this study was inclusion of normal pancreas, which could have been used as a reference point for normal EUS-EG characteristics.28 When the authors analyzed the data for diagnosis of focal masses excluding normal pancreas, the sensitivity remained similar at 93.8%; however, the specificity dropped down to 63.6% with an accuracy of 86.1%, which raises doubt on the ability of EUS-EG to differentiate between benign and malignant masses.28 In a subsequent multi-centric study, the same authors evaluated hue histogram quantitative EUS-EG on 258 patients (211 PDAC and 47 CP).7 Using the same methodology and cut-off, the analysis yielded a sensitivity, specificity, and accuracy of 93.4%, 68.9%, and 85.4% respectively, with NPV 68.9% and PPV 92.5%.7

EUS-EG using SR was compared to contrast-enhanced EUS (CE-EUS) for diagnosis of 62 consecutive solid pancreas lesions.29 The authors concluded that the overall accuracy for determination of malignancy using combination of EUS-EG and CE-EUS was comparable to EUS-guided tissue acquisition (91.9% vs. 91.5%), which was not higher than EUS-EG (98.4%) or CE-EUS (85.5%) when used alone. Thus combining the two modalities does not offer additional diagnostic advantage. A meta-analysis from 2012 evaluating 13 studies with 1042 patients with solid pancreas masses found a pooled sensitivity and specificity of 95% and 69% respectively, for EUS-EG for differentiating benign from malignant lesions.36 A subsequent meta-analysis from 2017 on 19 studies with 1687 patients echoed the previous overall results, but did not find any statistical difference between qualitative and quantitative EUS-EG for accurate diagnosis of malignant pancreatic lesions.14 The authors proposed both qualitative and quantitative EUS-EG as valuable complementary techniques to EUS-FNA for accurate differentiation of solid pancreas lesions.14

Similar results were reported from a recent multi-centric study on small solid pancreatic masses, where EUS-EG determined the lesions to be less/equally stiff as surrounding parenchyma (soft lesions) or stiffer (hard lesions).62 The authors noted that EUS-EG can rule out malignancy with high level of certainty if the lesion appears soft, while stiff lesions can be benign or malignant.62

b. Chronic Pancreatitis (CP)
The diagnosis of CP is challenging because of the histopathologic diversity and variable clinical presentation. EUS is utilized as a diagnostic modality for early CP in clinical practice, by evaluation of parenchymal and ductal features, as defined by Rosemont criteria (RC);58 however, it has limitations, which include a lack of heterogeneity for a number and/or a threshold for diagnosis. Furthermore, Rosemont criteria have poor reproducibility and insufficient histopathological correlation.

A study on consecutive 191 patients with epigastric pain or known CP using EUS-EG with SR and comparison with standard EUS-RC, suggested a strong direct linear correlation between the number of EUS-RC and the SR (r = 0.813; P < 0.0001, ROC area 0.949).57 The authors estimated EUS-EG accuracy of 91.1% for diagnosing CP (with cut-off SR of 2.25).57 In a subsequent study, 96 patients with known CP, pre-classified as 4 stages of RC (normal, indeterminate for CP, suggestive of CP, and consistent with CP) were subjected to EUS-EG.55 The ‘mean-value’ of each group, which negatively correlated with pancreatic fibrosis was calculated using histogram analysis, and found to be 90.1 ± 19.3, 73.2 ± 10.6, 63.7 ± 14.2, and 56.1 ± 13.6, respectively. The ‘mean-values’ were significantly different between different stages, and there was a significant negative correlation between ‘mean-value’ and number of EUS-RC features (r s = -0.59, p < 0.001). Regression analysis demonstrated that hyperechoic foci with shadowing and lobularity with honeycombing were most important diagnostic variables. While the authors hence provided an objective diagnostic apparatus for potential use as an adjunct to qualitative RC,55 the limitations of the study were evident, including lack of reproducibility of EUS-EG images and image influence by ROI size/position, and amount of strain applied.

CP also results in pancreatic exocrine insufficiency (PEI), resultant from tissue fibrosis and loss of acinar cells, the measurement of which includes inefficient/inadequate testing including 72-hour quantification of fecal fat, C-mixed triglyceride breath test (infrequently available), fecal elastase/chymotrypsin (measure secretion and not digestion). Dominguez-Munoz et al. have attempted to utilize EUS-EG as a tool to quantify fibrosis, as a surrogate for PEI in patients with CP.56 In this single center prospective study, 115 patients (22 undetermined, 49 suggestive, 44 consistent with CP) were included, 35 of which had pre-determined PEI using C-MTG (13C-mixed triglyceride) breath test. EUS-EG was performed by EUS experts blinded to PEI results, and SR was calculated. The authors observed higher SR in patients with PEI, compared to those with normal breath test (4.89 vs. 2.99), and the probability of PEI increased linearly with SR (4.2% with SR < 2.5, and 92.8% with SR > 5.5). The authors proposed adding EUS-EG with SR as an adjunct in EUS evaluation of CP, to act as surrogate for pancreatic fibrosis and likelihood of PEI. However, reproducibility of EUS-EG results remains a major limitation in this study also, in addition to use of C-MTG breath test for estimation of PEI, as opposed to a more reliable test (coefficient of fat absorption, CFA quantification).

[III]. EUS-EG of Lymph Nodes
 EUS can accurately image several groups of lymph nodes (LNs); however, EUS imaging alone cannot differentiate benign from the malignant ones. Attempts have been made to predict malignant potential, using EUS features like round shape, hypoechoic intensity, >10 mm size, and sharp margins, but have been suboptimal, with low specificity. Endoscopists have to ultimately resort to FNA of the LN for accurate diagnosis, which may have difficulties and complications. EUS-EG has been tried for the detection of malignant LNs in a wide variety of malignancies (GI tract and hepatobiliary system).

Giovannini et al.16 from France evaluated 31 LNs from 25 patients (3 cervical, 17 mediastinal, 5 celiac, 6 aortocaval) using qualitative EUS-EG (blue=malignant, green=benign) to predict malignant potential, and reported sensitivity of 100%, specificity of 50% when compared to EUS-FNA or surgical pathology, thus opening an avenue for further research in this area.16 Subsequently, they pooled their data with other European centers (101 LNs),18 with reported sensitivity of 91.8%, specificity 82.5%, PPV 88.8%, NPV 86.8% and overall accuracy of 88.1% for qualitative EUS-EG prediction of malignant LNs.18 Subsequently, Saftiou et al. evaluated quantitative EUS-EG on 42 LNs and noted slightly improved sensitivity (95.8% vs. 91.7%) and accuracy (95.2% vs. 92.9%) and at-par specificity with qualitative EUS-EG; they proposed use of EUS-EG as an adjunct to tissue diagnosis of LNs.40 A similar study on 66 LNs noted that 31/37 benign LNs had largely homogenous pattern, and 23/29 malignant LNs had predominantly hard pattern, yielding high overall accuracy with good inter-observer agreement for prediction of malignant LNs.39 A meta-analysis on 431 LNs in 368 patients suggested sensitivity of 88% and specificity of 85% for EUS-EG differentiation of benign and malignant LNs, further endorsing its potential for use as an adjunct screening method.

Knabe et al. utilized EUS-EG in LN staging in esophageal cancer patients.42 The authors evaluated 40 LNs, 21 of which were confirmed malignant by cytology/surgical histopathology, and observed that EUS-EG evaluation of LNs yielded a sensitivity of 100%, specificity of 64.1% and PPV of 75%. As a secondary step the investigators employed computer based analysis of elastographic images, which increased specificity to 86.7%, with a slight drop on sensitivity to 88.9%.42 The authors hence proposed a potential role for EUS-EG in clinical staging of malignancies. Likewise, SR (with cut-off at 7.5) has been reported to have better sensitivity (83%) and specificity (96%) than conventional EUS characteristics for determining malignant nodal disease in esophago-gastric cancer, with an overall accuracy of 90%.44 Similarly, analysis of 55 LNs in 75 patients with biliary malignancies (40 cholangiocarcinoma, 35 galbladder cancer) suggested sensitivity of 96% and specificity of 89% with EUS-EG for malignant nodal disease.45

However, in a contrasting report, Larsen et al. compared EUS, qualitative EUS-EG and quantitative EUS-EG to histology, to determine the most accurate method of loco-regional staging.43 In 56 patients with upper GI cancers planned for surgery, regional LNs were evaluated with EUS, and qualitative and quantitative EUS-EG before EUS-FNA/B was performed. The sensitivity of EUS for differentiating malignant from benign LNs was 86%, compared to 55-59% with EUS-EG.43 These divergent results do not support that qualitative or quantitative EUS-EG being better than conventional EUS for differentiation of malignant LNs.43

Based on the available literature, it may be prudent to screen LNs using EUS-EG and then perform EUS-FNA/B on those that are predominantly hard and blue on EUS-EG patterns or with high SR. Even with obvious merits including no/minimal change in time of procedure or cost, and avoidance of complications associated with attempted FNA/B of small LNs, wide adoption of this as a protocol is hindered by lack of standardization for diagnosis and the small number of supportive studies.

[IV]. EUS-EG of the Liver and Biliary Tract
Data on use of EUS-EG in liver are limited to a single study in 2009 reporting EUS-EG for solid hepatic masses.63 Additionally, this qualitative technique was utilized to evaluate the bile duct in 41 patients (20 with IBD/PSC and 21 controls),49 where the investigators noted a stiff/intermediate elastography score in 16 patients (compared to 4 controls), while 17 controls and 4 patients had a soft score, and proposed using this technology as non-invasive screen for PSC in IBD patients.49 However, no further developments happened in these areas.

While liver biopsy is the gold standard to determine degree of fibrosis in patients with chronic liver disease, similar assessment with Elastography (FibroscanTM) is an established non-invasive office-based approach, practiced widely.47 More recently, a study from Boston reports computation of liver fibrosis index (LFI) by utilizing EUS-EG images, and noted significantly increased mean LFI in patients with cirrhosis, when compared to those wit fatty liver (3.2 vs. 1.7, p=s) and normal liver (3.2 vs. 0.8, p=s). Similarly, significant increase was noted in fatty liver group compared to normal liver (1.7 vs. 0.8, p=s)46. While this single center, single endoscopist study demonstrates that LFI can be reliably computed from EUS-EG images, and correlates with abdominal imaging, but small number of cirrhosis patients (n=8) is a major hindrance to its widespread adoption. Nevertheless, this approach may have potential advantages over trans-abdominal elastography approach; including better signal penetration through thin gastric wall, compared to skin and subcutaneous fatty layer in obese patients, and deserves to be investigated further.

[V]. EUS-EG of the GI Tract
 EUS is widely utilized to view the layers of GI tract, to identify and characterize any thickenings or lesions, to evaluate depth of lesions as well as differentiate between T1a and T1b lesions to determine their best management strategy. Limited literature is available for EUS-EG in various subepithelial lesions, rectal lesions and in IBD patients, as discussed here.

a. Subepithelial Lesions (SELs)
Very sparse data exists on use of EUS-EG for evaluation of SELs. A small study of 25 patients with gastric SELs evaluated with EUS-EG using Giovannini elastic score, and higher elastic score were found in patients with GIST (stiffer lesions) than pancreas rests, leiomyomas, schwannomas, all with low/medium elastic scores (soft/mixed lesions).52

The results may suggest that benign SELs have homogenous strain pattern, representing low/intermediate elasticity/stiffness, while lipomas are generally homogenous soft. For detection of malignant SELs, conventional EUS features include size >30-40 mm, presence of ulcer or irregular contour, heterogenous appearance, or presence of LN involvement, and on EUS-EG they appear to have a heterogenous pattern with predominantly stiff pattern.12,52

b. Trans-rectal EUS-EG
Transrectal EUS-EG (TRUS-EG) has been evaluated for diagnosis of benign and malignant rectal tumors and fecal incontinence. Waage et al. evaluated 69 patients with TRUS-EG and reported sensitivity 91%, specificity 87% and accuracy 90% for detection of malignant rectal tumors, with best SR cut-off value of 1.25 as evaluated with ROC analysis.54

c. IBD
As a pilot effort, Rustemovic et al. evaluated the use of TRUS-EG for the diagnosis and characterization of IBD (and phenotype).53 55 IBD patients (30 CD, 25 UC) and 28 non-IBD controls were subjected to TRUS-EG and significant difference in rectal wall thickness and SR was noted between CD patients (even in patients without rectal involvement) and controls. Similarly, difference in rectal wall thickness was also found in patients with active UC, compared to quiescent UC. Interestingly, significant difference in rectal wall thickness and SR was also found between CD and UC patients, especially patients with active CD having much higher SR than active UC.53 The authors felt a potential for EUS-EG as a modality to differentiate between UC and CD, and also to evaluate tissues for diseases with transmural inflammation.

[VI]. Future Directions in use of EUS-EG
a. Combination of EUS-EG and CE-EUS
Contrast enhanced endoscopic ultrasound (CE-EUS) is another emerging clinical modality, which may assist in diagnosis of solid masses. CE-EUS is reported to have a high specificity and sensitivity for the diagnosis of PDAC.29 Multiple retrospective studies evaluating CE-EUS and EUS-EG have postulated a potential benefit of combining the two modalities for diagnosis of solid lesions, but have agreed to need for further evidence.23,30,32,34 The study by Iglesias-Garcia et al., which defined the accepted SR and strain histogram numbers used by future studies, analyzed 62 solid pancreatic lesions with CE-EUS, SR EUS-EG and strain histogram EUS-EG, and reported better numbers with EUS-EG than CE-EUS.29

b. EUS-EG and EUS-FNA/B
EUS-FNA/B is well accepted as gold standard for tissue diagnosis of PDAC, but may have potential for false negatives, and hence many authors suggest benefits of EUS-EG as adjunct, especially in cases when malignancy is strongly suspected, but negative or indeterminate EUS-FNA/B results.59 In a study of 28 solid pancreatic lesions, EUS-FNA alone versus combination of results of FNA and SR provided sensitivity of 90% versus 95.2% and NPV 80% versus 83.3%, thus suggesting that negative results of both EUS-FNA and SR together were more reliable to exclude malignant solid pancreatic lesions.25 The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines now advocate for EUS-EG as a diagnostic aid, rather than first line for diagnosis.60

[VII]. Challenges with EUS-EG
While we have highlighted the literature on EUS-EG in various fields of study, EUS-EG is yet not mainstream in North America given several limitations in its technology, wide gaps in literature and lack of widespread commercial availability. The foremost amongst its technical limitations is lack of standardization in EUS-EG procedure, particularly in quantitative assessments of stiffness, which hinders its usage in clinical practice, even at centers that it is available. Equally importantly, this technique is also inundated by the fact that it is highly operator dependent, and the results are based on subjective analysis of relative stiffness compared to surrounding tissue.1,2,10,12,17,18 Evaluation is also highly dependent on choosing ROI, which can lead to selection bias at the very outset.1,18 In addition to strong operator dependence, what is even more bothersome is limited reproducibility of these findings. The subjectivity of tissue compression is also another well-known limitation of EUS-EG. Motion artifact due to cardiac and respiratory movements can cause increased difficulty in obtaining an accurate image.2,10 To add to technical struggle, excessive compression of parenchyma can potentially lead to inaccurate strain measurement, making the results inconsistent. Also, imposing structures, which include the heart and other major vessels, must be avoided in order to obtain accurate images as well. Furthermore, in EUS-EG, the applied stress value is an unknown factor; therefore, the operator can never get an absolute elasticity value (through the calculation with Young’s modulus). Finally, EUS-EG does require technical skill and extensive training in order to produce high quality image, and the length of training to be proficient in EUS-EG is not yet defined. With all these technical limitations, its not surprising that EUS-EG has had a restricted scope of growth.

[VIII]. Conclusions
 From the multiple studies evaluating EUS-EG, it can be safely concluded that EUS-EG cannot replace tissue diagnosis, but there are several conceivable merits that value its candidacy as an able adjunct to clinical diagnosis. While EUS-EG may not have sensitivity, specificity and accuracy of the highest order to definitively diagnose a malignancy, but in combination with EUS-FNA/B it may provide an improved negative predictive value to safely exclude one. Clinicians who practice EUS-EG see in this technology a great potential for an additive study to supplement the histopathologic diagnosis, and those who do not practice it may feel overwhelmed by its technological limitations and operator learning curve. As the saying goes, “New technology is not good or evil in and of itself. It’s all about how people choose to use it”. It remains to be seen how EUS-EG is adopted from this point on.

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Peer-Reviewed Medical Journal Publishes Landmark Study On Efficacy and Safety of FDgard® (Colm-Sst), Demonstrating Rapid Reduction of Functional Dyspepsia (FD or Recurring, Meal-Triggered Indigestion) Symptoms Within 24 Hours

June 2019 • Volume XLIII, Issue 6

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  • FDgard® (COLM-SST), a solid-state microsphere formulation of caraway oil and l- Menthol, taken daily and proactively 30-60 minutes before meals, showed statistically significant, rapid reduction of Functional Dyspepsia (FD) symptoms within 24 hours and, additionally, relief of severe FD symptoms.
  • FDREST™ clinical trial with FDgard represents an important medical advance, as no previous trials have shown rapid relief of FD symptoms. There are no approved products for this highly prevalent condition.
  • In FDREST, patients received greater and more durable benefits with the addition of FDgard taken daily and proactively to their typical medical regimen.
  • FDREST is the first clinical trial in FD to use patented, Site Specific Targeting (SST®) technology to deliver the FDgard formulation to the upper belly (duodenum), the primary site of disturbance in FD.
  • FDgard represents an effective, safe and well-tolerated option to address the unmet medical needs of millions of adults with FD.

Clinical and Translational Gastroenterology, published on behalf of the American College of Gastroenterology (ACG), is dedicated to innovative clinical work in the field of gastroenterology and hepatology.

The FDREST study demonstrated that patients who took COLM-SST (FDgard®) on a daily and proactive basis, 30 to 60 minutes before meals, along with commonly used off-label FD medications versus patients who took placebo along with commonly used off-label FD medications, experienced a statistically significant, rapid reduction of FD symptoms within 24 hours across the FD study population.

This study had a higher hurdle than previous studies on a similar combination of ingredients. Firstly, concomitant medications for FD symptoms were allowed in order to assess FDgard in a real-world setting. Second, only a subgroup of patients in FDREST was categorized into the high-symptom burden, while they constituted the entire groups in previous studies. Among this subgroup of patients with the high-symptom burden, FDgard showed efficacy at 24 hours. In spite of the polypharmacy and use of rescue medications for FD, after 48 hours of first dose, FDgard helped further improve symptoms at 4 weeks, especially in those high-symptom burden patients. In all cases, FDgard was safe and well-tolerated.
The study results of FDREST were first presented at Digestive Disease Week (DDW), the largest gathering of gastroenterologists, in May 2017.

Study Commentary
 Commenting on the study, lead author William Chey, M.D., FACG, Director in the Division of Gastroenterology, Michigan Medicine Gastroenterology Clinic, Ann Arbor, said, “This landmark study was designed to answer a very important scientific question about the effectiveness, safety, and tolerability of a novel and innovative formulation of caraway oil and l-Menthol designed as solid state, enteric coated microspheres for targeted duodenal release for FD. In patients taking their usual medications for FD, FDgard was found to be effective, safe and well tolerated in rapidly reducing symptoms and in relieving severe symptoms.” Chey continued, “The positive finding at 24 hours is clinically important as symptoms are often triggered by a meal and patients are looking for rapid relief of those symptoms.”

The study authors also cited the importance of utilizing the microsphere-based site-specific targeting of FDgard (caraway oil and l-Menthol, the active ingredient in peppermint oil) to the duodenum. They wrote, “This site (duodenum) was targeted primarily due to mounting evidence that gastroduodenal mucosal integrity and low-grade inflammation play a role in FD. Furthermore, studies have shown that caraway oil and peppermint oil act on the duodenum to induce smooth muscle relaxation, and that l-Menthol has anti-inflammatory effects.” This may help normalize motility effects.

About FDREST™
FDREST™ (Functional Dyspepsia Reduction and Evaluation Safety Trial) was a multi-centered, post-marketing, parallel group, U.S-based study conducted at seven university-based or gastroenterology research-based centers (study period July 1, 2015, to September 14, 2016). The study was designed to compare the efficacy, safety and tolerability of FDgard plus commonly used, off-label medications for FD vs. a control group of placebo plus commonly used, off-label medications prescribed for FD.

Ninety-five patients were enrolled (mean age = 43.4 years; 75.8 percent women). At 24 hours, the active arm reported a statistically significant reduction in Postprandial Distress Syndrome (PDS) symptoms (P = 0.039), and a nonsignificant trend toward benefit of Epigastric Pain Syndrome (EPS) symptoms (P = 0.074). In patients with more severe symptoms, approximately three-quarters showed substantial global improvement (i.e., clinical global impressions) after 4 weeks of treatment vs. half in the control arm. These differences were statistically significant for patients with EPS symptoms (epigastric pain or discomfort and burning) (P = 0.046), and trending toward significance for patients with PDS symptoms (early satiety, abdominal heaviness, pressure and fullness) (P = 0.091). There were no statistically significant differences between groups for Global Overall Symptom scores for the overall population at 2 and 4 weeks.

Dr. Chey said, “The results of this high-quality study highlight an advance in the management of FD, as current off-label medications such as PPIs, H2RAs and antidepressants offer only a modest level of therapeutic gain over placebo and may be associated with adverse events, especially with continued use. FDgard addresses a significant unmet medical need for a product to help manage symptoms in the 1 in 6 adults suffering from this common disorder.”

About Functional Dyspepsia (FD)
Functional dyspepsia is a very common disorder affecting 11 percent – 29.2 percent of the world’s population1, making it comparable in prevalence to IBS. However, unlike IBS, there is no FDA approved product to treat FD. Sufferers are often treated off-label with prescribed proton pump inhibitors (PPIs), histamine type-2 receptor antagonists (H2RAs), antidepressants, and prokinetics. While offering relief to a portion of FD patients, some of these have been associated with adverse events. Functional dyspepsia can have a negative effect on workplace attendance and productivity, with associated costs estimated in excess of $18 billion annually.

In FD, which is typically recurring, meal-triggered indigestion with no known organic cause, the normal digestive processes are disrupted along with digestion and absorption of food nutrients. FD is accompanied by symptoms such as epigastric pain or discomfort, epigastric burning, postprandial fullness, inability to finish a normal sized meal, heaviness, pressure, bloating in the upper abdomen, nausea, and belching. When doctors diagnose FD, they often identify patients as those who have these symptoms for at least three months, with symptom onset six months previously.

Visit FDgard’s Website

BOCA RATON, FL – IM HealthScience today announced that Clinical and Translational Gastroenterology (CTG), a peer-reviewed medical journal, has published the U.S. results of a landmark, double-blind, placebo-controlled study, FDREST™ (Functional Dyspepsia Reduction Evaluation and Safety Trial), which showed statistically significant, rapid reduction of Functional Dyspepsia (FD or recurring, meal-triggered indigestion) symptoms within 24 hours and, additionally, relief of severe FD symptoms.

The study, entitled “A Novel, Duodenal-Release Formulation of a Combination of Caraway Oil and L-Menthol for the Treatment of Functional Dyspepsia: A Randomized Controlled Trial,” is now available to the public via open access on the Clinical and Translational Gastroenterology website.

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #22

Diet and Inflammatory Bowel Disease: What is the Role?

June 2019 • Volume XLIII, Issue 6
Adam S. Cheifetz,Joseph D. Frasca

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Patients often question the role of diet in inflammatory bowel disease (IBD). Despite the interest in this topic, little consensus exists on how to address diet in patients with IBD. Animal studies and population-based human studies serve as the knowledge base for IBD risk associations. Such studies have demonstrated the potentially positive effects of omega-3 fatty acids, amino acids, plant polysaccharides, vitamin D, fiber, fruits, vegetables, and fish, in addition to the potentially deleterious effects of high total fat, red meat, omega-6 fatty acids, food additives, and a general Western diet. Exclusive enteral nutrition, the most studied dietary therapy in IBD, has demonstrated benefit in pediatric patients with Crohn’s disease. Less studied diets, including the specific carbohydrate diet, anti-inflammatory diet, and the low-FODMAP diet, may be of some potential benefit.

INTRODUCTION
In a a recently proposed hierarchy of needs of patients with inflammatory bowel disease, there is discordance between patient needs and the focus of the physician, especially when it comes to the role of diet.1 Clinicians tend to focus on defining and achieving therapeutic targets while patients often are concerned with what they can eat and if any diets are helpful or harmful with respect to IBD. Though the role of diet in IBD is becoming increasingly discussed, there is limited, if any, consensus on the topic. In this article, we aim to review several aspects of the function of diet in IBD including its role in the changing epidemiology, disease pathogenesis, and risk of IBD. We will also examine several defined diets that have been proposed and studied as potential therapies for IBD.

Epidemiology
The incidence and prevalence of both Crohn’s disease (CD) and ulcerative colitis (UC) have increased over time, and it is suggested that diet may play a role. Though the incidence and prevalence of IBD remains the highest in industrialized areas of North America and western Europe,2,3 there has been a rise in previously low-prevalence areas, including parts of Asia, South America, and the Middle East.2 The reasons for this changing global landscape are unclear, but several factors have been proposed,4 including infection, hygiene standards, medications, and pollutants. Notably, diet has also emerged as a possible key contributor to this increasing incidence of IBD in the developing world, largely due the rise of the Western diet throughout the world.5 Furthermore, emigration from a low-prevalence region to a high-prevalence region has been shown to increase the risk for developing IBD and has recently been associated with changes in microbiome composition.6,7 It is likely that diet and the other factors noted are similarly involved with this risk. Furthermore, obesity has been proposed as a diet-related lifestyle factor that may be associated with an increased risk of IBD.8 These parallel observations suggest that diet likely plays a role in the changing global epidemiology of IBD.

Diet in the Pathogenesis, Risk, and Outcomes of IBD
 The interplay between diet and IBD has largely been investigated through animal models of intestinal inflammation and epidemiologic studies on IBD risk associations. Animal models have been used to study the potential pathogenesis of specific dietary components in causing intestinal inflammation. In addition, several large, population-based cohorts have been utilized to investigate IBD risk associations with specific dietary components. With the limited amount of clinical trial data in the area of diet and IBD, these studies provide an important framework for better understanding the interplay between diet and IBD.

Studies Involving Animal Models of Intestinal Inflammation
 When it comes to the pathogenesis of diet and IBD, several contributing factors have been proposed, including dysbiosis, altered intestinal barrier function, and effects on innate immunity.9 It has been suggested that diet-related changes in the intestinal microbiome lead to decreased production of short-chain fatty acids (SCFAs).9 This may disrupt the intestinal barrier and lead to bacterial translocation and deleterious downstream effects on the innate immune system.9 This proposed mechanism is largely based on animal studies of diet-derived factors, such as macronutrients, vitamins and minerals, and food additives.10

Animal studies investigating a high-fat diet have generally demonstrated a pro-inflammatory effect. One study in a Crohn’s ileitis-like mouse model showed that a high-fat diet led to accelerated development of Crohn’s disease via increased intestinal permeability and altered luminal processes.11 Furthermore, in a dextran sulfate sodium (DSS)-induced colitis mouse model, a Westernized high-fat diet led to accelerated weight loss, an effect that was exaggerated by the addition of heme, an abundant component of red meat.12 While these studies suggest a pro-inflammatory effect from a high-fat diet, omega-3 fatty acids have typically demonstrated an anti-inflammatory effect.13-17

Several amino acids have also been investigated for their role in intestinal inflammation. Glutamine and arginine are thought to have immunomodulatory effects18 and have been shown to improve inflammatory measures in colitis-induced mouse models.19-22 In addition, histidine, a precursor to histamine, inhibited pro-inflammatory cytokine production in a murine colitis model.23 Threonine, likely through its beneficial effects on intestinal mucus production, and tryptophan have also been shown to reduce colitis in pig and mouse models.24,25 Similarly, plant polysaccharides, in addition to fibrous plant products, have largely been shown to have an anti-inflammatory effect.26 The proposed mechanism for this effect is increased production of SCFAs, which act to improve the barrier function and immune tolerance of colonocytes.27,28 Other plant-based compounds, including curcumin, green tea, fermented grains, and polyphenols have also demonstrated anti-inflammatory properties in various animal models.10,29,30

Furthermore, several vitamins and minerals have been studied in the pathogenesis of IBD using animal models of intestinal inflammation. Vitamin D has notably been recognized as a regulator of immune pathways as demonstrated in several animal models.10,31 In IL-10 knock-out mice, deficiency of vitamin D and vitamin D receptor were shown to accelerate IBD symptoms and death.32 Vitamin D was also shown to maintain mucosal integrity in a DSS-induced colitis mouse model by attenuating the effects of luminal antigens.33 Calcium has been shown to have an important role in augmenting these effects of vitamin D on immune regulation.10,34 In addition to vitamin D, dietary and supplemental iron has been shown to have a potential role in intestinal inflammation through oxygen free radical formation and also through alteration of the gut microbiome.10,35 One Crohn’s disease-like ileitis model showed that depletion of luminal iron had a preventative effect on inflammation.36

Lastly, food additives have generally demonstrated a pro-inflammatory effect in animal models.9 Carboxymethylcellulose and polysorbate-80 have been investigated in IL-10 knock-out mice and have shown to disrupt intestinal barrier function, ultimately leading to increased intestinal inflammation.37,38 Carrageenan and titanium dioxide (TiO2) have similarly shown to increase intestinal inflammation through disruption of the intestinal barrier.39 Malodextrin, a soluble dietary fiber, was shown to increase total intestinal IgA levels.40 This effect was also associated with increased SCFA production, making it unclear if this effect is pro- or anti-inflammatory.

Human Studies on Dietary Risk Associations with IBD
IBD risk associations with specific dietary factors have largely been studied using two large population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses’ Health Study.41-48 Risk associations with fatty acid intake were investigated by both cohorts. In the EPIC cohort (n=203,193; 126 incident cases of UC), high intake of linoleic acid (omega-6 fatty acid found in vegetable oils) was associated with an increased risk of developing UC (OR=2.49, 95% CI 1.23-5.07, p=0.01).41 Conversely, high intake of docosahexaenoic acid (omega-3 fatty acid found in fish oils) was associated with a lower risk of developing UC (OR=0.59, 95% CI 0.37-0.94, p=0.03).41 Similarly, the Nurses’ Health Study showed that an increased omega-3:omega-6 ratio was also associated with a lower risk for developing UC (multivariate HR 0.69, 95% CI 0.49-0.98, p=0.03).42 The Nurses’ Health Study showed no association seen between fatty acid intake and risk of CD.42

The EPIC and Nurses’ Health Study cohorts were also used to examine a variety of other dietary factors. A recent analysis from the EPIC study (n=401,326; 104 incident cases of CD, 221 incident cases of UC) examined dietary fiber intake and showed no significant association between fiber intake and risk of CD or UC.43 However, the Nurses’ Health Study (n=170,766; 269 incident cases of CD, 338 incident cases of UC), showed that the high fiber intake was associated with a 40% reduced risk of CD (multivariate HR 0.59, 95% CI 0.39-0.90) but not UC.44 This protective association with CD risk appeared to be greatest for fiber derived from fruits. Furthermore, the Nurses’ Health Study II cohort (n=39,511; 70 incident cases of CD, 103 incident cases of UC) examined high school diet using a validated food frequency questionnaire and showed that a high school diet consisting of high intake of fruits, vegetables, and fish was associated with a decreased risk of CD but not UC.45 It should be noted that these findings are subject to a high degree of recall bias. Lastly, the Nurses’ Health Study cohort (n=165,331; 261 incident cases of CD, 321 incident cases of UC) and EPIC cohort (n=262,451; 193 incident cases of UC, 84 incident cases of CD) demonstrated no risk associations with dietary iron and heme intake46 and alcohol intake,47 respectively.

Vitamin D has become an increasingly recognized for its potential role in IBD and has shown associations with both IBD risk and IBD outcomes.48,49 The Nurses’ Health Study cohort (n=72,719; 122 incident cases of CD, 123 incident cases of UC) showed an association between increased predicted plasma 25(OH)-vitamin D level and decreased risk of CD (multivariate HR 0.55, 95%CI 0.30-1.00, p=0.02).48 In addition, increased supplemental vitamin D intake was associated with a decreased risk of UC (multivariate HR 0.64, 95% CI 0.37-1.10, p=0.04).48 Furthermore, five-year follow-up data from a longitudinal IBD registry showed that low-vitamin D levels were associated with more steroid usage, biologics, narcotics, hospitalizations, emergency department visits, and surgery (p<0.05) among patients with CD and UC.49 In aggregate, these findings support a potentially protective role for vitamin D in regards to IBD risk and IBD outcomes.

Dietary IBD risk associations were also investigated in a commonly-referenced systematic review by Hou et al., which included 19 studies, 2,609 IBD patients, and 4,000 controls.50 Notably, high intake of total fats, PUFAs, omega-6 fatty acids, and meat were associated with increased risk of CD. In addition, high fiber and fruit intake were associated with decreased risk of CD, and high vegetable intake was associated with a decreased risk of UC.50 While it is interesting that these findings are somewhat similar to findings from the EPIC and Nurses’ Health Study cohorts, it should be noted that a majority of studies from this systematic review were not statistically significant and only reflected statistical trends.

Defined Diets in the Treatment of IBD
Exclusive Enteral Nutrition
Exclusive enteral nutrition (EEN) is the most widely studied dietary intervention in IBD and has been most studied in the pediatric IBD population. It is more often used for the treatment of pediatric CD, especially in Canada, Japan, and Europe.51 EEN consists of elemental, semi-elemental, or defined formula liquid diets. It is also one of the few dietary treatments in IBD that has been studied in prospective observational and randomized controlled trials,52-59 albeit mostly in the pediatric population and a relatively small number of patients. One of the initial randomized controlled trials consisted of 50 pediatric CD patients and compared EEN to partial enteral nutrition (PEN).52 This study showed remission rates [defined by pediatric Crohn’s disease activity index (PCDAI)<10] of 42% for EEN vs. 15% for PEN (p=0.035). Another trial of 37 pediatric CD patients that randomized patients to receive either a polymeric diet or corticosteroids in open-label fashion showed significantly higher mucosal healing rates with a polymeric diet compared to corticosteroids (75% vs. 33%, p<0.05).53
In addition, several non-randomized prospective studies have also demonstrated a potential benefit for EEN as a dietary therapy in IBD.54-56 The GROWTH CD study prospectively followed newly diagnosed pediatric CD patients for 2 years and found EEN was associated with higher rates of remission compared to corticosteroids (63% vs. 46%, p=0.036).54 In addition, an open-label study by Grover et al. prospectively followed 34 newly diagnosed pediatric CD patients who received EEN for a minimum of 6 weeks along with initiation of an immunomodulator.55 This study showed a post-EEN clinical remission rate of 84% (defined by PCDAI<10) and a complete mucosal healing rate of 21%. Furthermore, complete mucosal healing was shown to better predict sustained remission without need for corticosteroids, infliximab, or surgery.55 More recently, a prospective observational study of pediatric Crohn’s disease patients demonstrated similar clinical response rates of 88% for EEN compared to 84% for anti-TNF therapy (p=0.08).56 However, in this study, EEN led to normalization of fecal calprotectin in only 45% of patients compared to 62% on anti-TNF therapy (p=0.001). This latter finding appears to challenge the results of Borrelli et al. which demonstrated a mucosal healing rate of 75%.53 One proposed explanation for this that EEN therapy may be more effective in new-onset disease.

While studies in the pediatric population suggest a benefit of EEN as a dietary therapy for IBD, similar data in the adult population are lacking. Two early randomized controlled trials comparing corticosteroids to EEN in adult CD patients demonstrated improved CDAI scores57 (n=95; EEN 41%, corticosteroids 72%, p<0.05) and improved remission rates58 (n=107; EEN 55%, corticosteroids 74%, p<0.01) with corticosteroids compared to EEN. Another randomized controlled trial including two different fat formulations of EEN compared to corticosteroids also showed improved remission rates with corticosteroids (corticosteroids 79% vs. EEN 20% and 52%, p<0.001).59 Furthermore, a recently updated systematic review of 27 studies included a meta-analysis of 8 trials comparing various types of enteral nutrition (EN) to corticosteroids in both pediatric (n=29) and adult (n=194) CD patients.60 Overall, there was no difference in remission rates between EN and steroids (RR 0.77, 95% CI 0.58-1.03). However, subgroup analysis by age showed that adults had a remission rate of 45% with EN compared to 73% with steroids (RR 0.65, 95% CI 0.52-0.82), and children had a remission rate of 83% with EN compared to 61% with corticosteroids (RR 1.35, 95% CI 0.92-1.97). It should be noted that more patients withdrew on EEN compared to corticosteroids, and children may be more adherent to EEN therapy than adults since it is given via naso-gastric tube during sleep.51 This factor may account for the differences seen between the pediatric and adult populations.

Studies on EEN for the treatment of ulcerative colitis are lacking. One small clinical trial randomized patients with moderate-severe UC to receive polymeric total enteral nutrition or total parenteral nutrition (TPN) for their nutritional support in addition to medical therapy.61 This study showed no significant difference in readmission rate and colectomy rate between the two groups. However, enterally fed patients had less frequent and milder adverse events (9% vs. 35%, p=0.046) and less postoperative infections (p=0.028).

Other Defined Diets and Dietary Interventions
Other diets that have been proposed to have a potential therapeutic role in the treatment of IBD include the specific carbohydrate diet (SCD), gluten-free diet, anti-inflammatory diet, and the low-fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet.7,9 It should be noted that most of these diets have not been evaluated in a randomized trial, and only anecdotal benefits have been reported.

The SCD includes only monosaccharides contained in fruits and vegetables and excludes disaccharides and polysaccharides contained in simple sugar and wheat-containing products.7,9 It restricts carbohydrates and processed foods,9 likely making it difficult to maintain adherence in the long-term. The SCD was initially used to treat celiac disease and proposes that undigested complex carbohydrates enter the colon and ultimately lead to intestinal injury through overproduction of bacteria, yeast, and mucus.7 A recent online survey of 417 respondents (47% with CD, 43% with UC, 10% with indeterminate colitis) demonstrated a perceived clinical improvement with the SCD.62 Prior to starting the SCD, 4% of patients reported clinical remission compared to 33% at 2 months and 42% at 6 and 12 months. Abdominal pain was present in 80% of patients before starting the SCD, and this proportion decreased to less than 10% at 12 months. Another study by Cohen et al. used capsule endoscopy to prospectively evaluate both clinical and mucosal responses to the SCD.63 Nine pediatric CD patients completed the trial after 10 were enrolled. There were significant improvements in Harvey-Bradshaw Index (p=0.007), PCDAI (p=0.011), and Lewis score (p=0.012). Despite these studies showing positive associations, a more recent study of 7 pediatric patients on the SCD for a median of 26 months showed no association with mucosal healing.64

Similar to the SCD, there has been limited investigation into the gluten-free diet in IBD patients, but gluten sensitivity is likely common among IBD patients. One single-center study of 102 IBD patients (55 CD, 46 UC) reported gluten sensitivity in 23.6% and 27.3% of CD and UC patients, respectively.65 A recent cross-sectional study investigated the gluten-free diet using a gluten-free diet questionnaire in 1647 IBD patients participating in a longitudinal internet-based cohort.66 The findings showed that among 314 (19.1%) participants who attempted a gluten-free diet, 65.6% reported symptomatic improvement and 38.3% reported fewer or less severe IBD flares. The anti-inflammatory diet (IBD-AID) is based on the SCD and eliminates refined sugar, gluten, and select starches.7 Clinical studies on this diet are lacking, except for a small case series of 11 patients who all reported symptom reduction with decreased bowel frequency after 4 weeks.67

The low-FODMAP diet reduces the amount of poorly-absorbed carbohydrates that are digested by gut bacteria to produce gastrointestinal symptoms.7 With the significant impact of functional gastrointestinal symptoms on patients with IBD,68,69 the low-FODMAP diet has been considered as a dietary intervention in IBD patients, especially in symptomatic patients with quiescent IBD.

However, few studies have investigated the low-FODMAP diet in IBD. One study of 32 patients with quiescent IBD and functional GI symptoms showed that challenge with fructan, a fermentable carbohydrate, led to exacerbation of pain, flatulence, and fecal urgency.70 Another prospective study investigating the low-FODMAP diet in IBD (n=30), in addition to irritable bowel syndrome and celiac disease, showed improvement in Rome III criteria across all subjects, including IBD patients.71 Another study used a prospective survey to assess clinical response to a low-FODMAP diet and showed symptomatic improvement in 78% at week 6 with improved stool consistency (p=0.002) and frequency (p<0.001) compared to baseline.72 A recent meta-analysis and systematic review of 319 IBD patients (96% in remission) demonstrated significant improvement with the low-FODMAP diet in diarrhea (OR 0.24, 95% CI 0.11-0.52, p=0.0003), bloating (OR 0.10, 95% CI 0.06-0.16, p<0.00001), abdominal pain (OR 0.24, 95% CI 0.16-0.35, p<0.00001), and nausea (OR 0.51, 95% CI 0.31-0.85, p=0.009).73 Lastly, one small study examined the low-FODMAP diet in patients after colectomy (5 J-pouch, 2 ileorectal anastomosis) and found symptomatic improvement in 5 out of 7 patients (p=0.02).74

Finally, it should be noted that older clinical trials have investigated fish oil supplementation as a potential diet-related IBD therapy.75-79 An initial double-blind, placebo-controlled, cross-over trial of fish oil supplementation with omega-3 fatty acids showed no significant difference in clinical activity of CD and UC patients.75 Two additional randomized controlled trials demonstrated no statistically significant benefit in ulcerative colitis disease severity based on histopathologic scores or mucosal cytokine levels76 and in rate of corticosteroid-free remission.77 However, a randomized controlled trial of an oral supplement enriched with fish oil, soluble fiber, and anti-oxidants was associated with improved clinical response and decreased corticosteroid requirement in 121 patients with UC compared to placebo (p<0.001).79

CONCLUSION
As we learn more about the role of diet in IBD, signals from the available literature have demonstrated potentially positive and deleterious effects of several different dietary factors. Animal studies and human studies on risk associations suggest a possible protective role for omega-3 fatty acids, amino acids, plant polysaccharides, vitamin D, fiber, fruits, and vegetables. High total fat, red meat, omega-6 fatty acids, food additives, and a general Western diet may have potentially harmful effects. Exclusive enteral nutrition has been shown to be effective in inducing remission in pediatric CD, but is often impractical. Other defined dietary interventions in IBD have not been well studied and are not yet supported by a strong framework of scientific evidence. But perhaps this does not really address the most pertinent and practical matter of how to counsel patients in day-to-day practice. To this end, another defined diet not discussed previously in this review may play a key role—the Mediterranean diet—a non-restrictive diet with inclusion of potentially protective and exclusion of potentially harmful dietary factors.7 A clinical trial to assess this diet in IBD patients is currently underway (NCT03058679). In the meantime, we might consider recommending the Mediterranean diet to our IBD patients, if not for its potential effects on IBD, then for its well-established benefit on cardiovascular risk.80


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From the Pediatric Literature

Colonoscopy in Children with Abdominal Pain

June 2019 • Volume XLIII, Issue 6

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Recurrent abdominal pain (RAP) of childhood is a common reason for referral to pediatric gastroenterologists. Most causes of RAP are functional in nature and it is essential to determine which children with RAP would benefit from endoscopy. The authors of this study from Brisbane, Australia looked at the diagnostic yield of pediatric patients with RAP who subsequently underwent a colonoscopy.

This study consisted of a 4-year retrospective analysis of patients with RAP who underwent colonoscopy at a large, tertiary children’s hospital. Patients were included in the study if they had undergone a colonoscopy for abdominal pain and if the abdominal pain fit criteria for RAP (defined as occurring for at least 2 months, being present for several times weekly, and affecting activity). Medical records for included patients included endoscopic findings, including histology, C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and tissue transglutaminase IgA antibody titers.

In total, 652 colonoscopies were performed, and 10% (total of 68) of these procedures were done for the indication of abdominal pain. All 68 patients met Rome IV criteria for RAP. The median age for pediatric patients undergoing colonoscopy for abdominal pain was 12 years (range 2 – 16 years), and 65% of these patients were female. Further analysis demonstrated that 10% of these 68 patients (total of 7) had endoscopic disease (Crohn disease, colonic polyps, or microscopic colitis). Rectal bleeding in the setting of RAP was significantly associated with the presence of colonic polyps, and no patient with RAP and no secondary symptoms had any GI pathology. The presence of abnormal histology was significantly associated with elevated fecal calprotectin levels and/or elevated serum inflammatory markers although this effect disappeared on multiple regression analysis used to evaluate the significance of secondary indications of endoscopy (such as rectal bleeding) and histologic findings.

This study strongly suggests that colonoscopy is not indicated in pediatric patients with isolated RAP and no other symptoms. Avoiding endoscopic procedures in such clinical settings will improve patient safety, reduce over-testing, and reduce healthcare costs.

Singh H and Ee L. Recurrent Abdominal pain in children: Is colonoscopy indicated? Journal of Pediatric Gastroenterology and Nutrition 2019; 68: 214-217

FROM THE PEDIATRIC LITERATURE

MicroRNAs and Necrotizing Enterocolitis

June 2019 • Volume XLIII, Issue 6

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Necrotizing enterocolitis (NEC) is defined as an inflammatory condition of the gastrointestinal system which mainly affects premature infants and is associated with a high mortality rate. The cause of NEC is multi-factorial (likely a combination of infectious, vascular, and intestinal permeability issues), and early diagnosis would be helpful in order to start therapy and to prevent disease progression. MicroRNAs (miRNAs or small, non-coding RNAs) have been shown to be potential markers of intestinal inflammation, and the authors of this study evaluated the miRNA profiles of premature infants to determine if NEC could be diagnosed early in order to provide expeditious treatment.

A miRNA analysis occurred across 4 groups of infants which included premature infants with proven NEC (Bell stage II or higher), infants with sepsis (who had elevated C-reactive protein levels and had received parenteral antibiotics), infants with suspected sepsis but who ended up with other disease processes instead (heart failure, anemia, etc.), and healthy control infants. Microarray analysis for miRNA from plasma specimens was performed at the initial time of proven NEC and sepsis evaluation. Samples for miRNA on healthy control infants were obtained in the first 6 weeks of life. Potential miRNA biomarker for NEC were selected if they were associated with a greater than two-fold elevation in expression and with a significantly statistical difference in expression between NEC and non-NEC cases. Using this criteria, 7 potential miRNA biomarkers were noted, and polymerase chain reaction was done to quantify the amount of expression of these specific miRNAs between the 4 study groups in a case-control manner. Finally, a cohort of consecutive patients with NEC, sepsis, and non-NEC/non-sepsis were evaluated to determine the 3 highest potential miRNA biomarkers.

The case-control study had 50 infants that were compared between the 4 groups, and four of the 7 potential miRNAs had high enough levels of expression for detection (miR-1290, miR-1246, miR-375, and miR-619-5p). Significantly more copies of miR-1290, miR-1246, and miR-375 were found in patients with NEC compared to the other groups, and these same miRNAs decreased significantly between day 0 and day 1 of patients with NEC. Finally, ROC curve analysis showed that plasma miR-1290 at the initial time of NEC presentation provided the most accurate diagnosis regardless of NEC severity (>220 copies / microliter; sensitivity 0.83, specificity 0.92, PPV 0.60, and NPV 0.98). When miR-1290 levels of greater than 650 copies / microliter were considered, the specificity increased to 0.98 with a PPV 0.75, and when this initial miR-1290 level at time of NEC diagnosis was combined with an elevated C-reactive protein level above 15.8 mg/dL one day later, it was determined that this level of miR-1290 had a sensitivity 0.83, a specificity 0.96, PPV 0.75, and NPV 0.98. No significant correlation was noted between miR-1290 and gestational age or postnatal age in any of the infants. The authors conclude that miR-1290 has the potential to be a very good biomarker for detecting NEC early in its development. It remains to be seen how feasible it is to use such as potential biomarker in other hospital systems especially in regards to cost and timing of lab result returns.

Ng P, Chan K, Yuen T, Sit T, Lam H, Leung K, Wong R, Chan L, Pang Y, Cheung H, Chu W, Li K. Plasma miR-1290 is a novel and specific biomarker for early diagnosis of necrotizing enterocolitis – biomarker discover with prospective cohort evaluation. Journal of Pediatrics 2019; 205: 83-90.

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