Nutrition Issues In Gastroenterology, Series #171

Moo-ove Over, Cow’s Milk – The Rise of Plant-Based Dairy Alternatives

January 2018 • Volume XLII, Issue 1
Meagan Bridges

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Consumer demand for alternatives to dairy is on the rise, and with it, an ever-expanding array of plant-based products from which to choose. This is especially evident when considering milk substitutes. Each type of non-dairy milk offers a unique nutritional profile, with a wide range of values for protein, carbohydrates and fat, along with vitamins and minerals. In this article, we review which non-dairy beverages are gaining in popularity and how these options compare nutritionally to cow’s milk.

The Rise of Plant-Based Milks

When choosing milk, it is no longer simply a matter of whole, low-fat, or skim. Now more than ever, consumers can choose from a plethora of plant-based “milks” derived from a variety of sources, including nuts, seeds, legumes, and cereal grains.

Worldwide sales of non-dairy milk alternatives more than doubled between 2009 and 2015, reaching $21 billion – a reflection of both consumer demand and the burgeoning array of products to meet that demand. Meanwhile, consumption of cow’s milk has dropped 13 percent in the U.S. over the last five years.1

Plant-based milk substitutes are essentially suspensions of dissolved and disintegrated plant material and extracts in water. Homogenization and thermal treatments are used to improve the suspension and stability of the product. They are made to visually resemble cow’s milk and often include the word “milk” in the beverage name. Specific nutritional properties depend on the plant source, processing, and fortification. The most widely available plant-based milks in the U.S. are identified in Table 1.

The increasing popularity of non-dairy milks can be attributed to many factors. More and more people are consuming non-dairy alternatives, whether due to an allergy, lactose intolerance or adherence to a vegan/plant-based diet. Still others are concerned over saturated fat levels, hormone content, and antibiotic use in dairy cattle. But with an ever expanding array of options, the dairy aisle can end up being a place of utter confusion, especially when weighing not only taste, texture, and other sensory attributes of non-dairy milks, but also the nutritional qualities of these beverages and how they compare to cow’s milk.

How Do Plant-Based Milks Compare to Cow’s Milk?

Dairy foods are often good sources of important nutrients, including protein, vitamin D, calcium, and phosphorus. As some plant-based milks are very low in these nutrients, consumer awareness is important when dairy-free alternatives are used as a direct replacement for cow’s milk in the diet. For example, of all the non-dairy alternatives, only soy milk naturally contains protein in an amount comparable to cow’s milk (8 g per 8 oz. cup). By contrast, almond milk – one of the most popular non-dairy options among consumers – only contains 1 g of protein per 8 oz. cup.

Moreover, every gram of protein is not created equally, and it is important to evaluate the quality of protein when comparing plant-based milks to cow’s milk. Protein quality is based on amino acid composition, digestibility, bioavailability, and specific protein-derived components. Protein from animal sources is generally of higher quality than plant-based protein due to its more “complete” array of amino acids.2 Cow’s milk contains both whey and casein proteins, which have high biological value given their “usability” by the body. While soy protein is also recognized for its high biological value among plant sources, its usability when derived from soy milk has not been extensively studied.3 Most other proteins found in plant-based milks are not complete and do not offer the full array of essential amino acids.

While non-dairy alternatives do not offer exact nutritional equivalency to cow’s milk, they can be fortified with certain nutrients – especially calcium, vitamin D, and vitamin B12 – to make them more comparable. In fact, many fortified plant-based milks are marketed as having equal or greater amounts of calcium and vitamin D than cow’s milk. However, it is important to recognize that the bioavailability of such nutrients varies significantly among products and in many cases is not precisely known.3

By the same token, while the quantity of most micronutrients has been established for cow’s milk, similar information is not available for most non-dairy beverages. In fact, only figures for calcium and vitamin D are consistently reported for non-dairy milks on the USDA’s Food Composition Databases; figures on phosphorus, zinc, thiamin, niacin, vitamin B6, folate, vitamin E, vitamin K, and other micronutrients are often missing.4 Table 2, which compares the nutritional profile of popular plant-based milks to 2% cow’s milk, omits these particular vitamins and minerals, as most of this information is not yet readily available.

In addition to protein and vitamin/mineral content, added sugar is another variable that can vary widely among plant-based milks and depart drastically from cow’s milk. While unsweetened versions have as few as 25 calories per cup, most non-dairy milks are sweetened with added sugars (such as rice syrup, barley malt, or cane sugar) to make them more palatable. Many sweetened and/ or flavored non-dairy milks contain up to 20 g of sugar, compared to 12.5 g of naturally occurring lactose in 2% cow’s milk.

Finally, consumers should be aware of any additives used to emulsify and stabilize plant- based milks. Some leading nut milks, for example, contain carrageenan, a thickener and emulsifier derived from seaweed that has recently been implicated in some preliminary (though far from conclusive) studies on ulcers, inflammation, and other GI complications. Other non-dairy milks can be thickened with sunflower lecithin or a variety of gums. Learn more about the specific properties of the most popular plant-based milks below.

Soy Milk

Likely the most recognizable among dairy-free alternatives, soy milk is the “original” replacement for cow’s milk, first appearing on shelves in the U.S. in the 1950s. Made by soaking, crushing, cooking, and straining soybeans, it is the only milk alternative that naturally contains the same amount of protein as a cup of cow’s milk – 8 grams – along with omega-3 fatty acids and fiber. Most manufacturers also fortify soy milk with vitamins A, D, B12, and calcium. In addition, soy milk can be a good source of manganese and magnesium.

Interestingly, when considering the manufacturing process, soy milk is likely the “least processed” out of all plant-based milks. At the same time, soy is one of the top three genetically modified organisms (GMOs) in the U.S., with 94% of all soybeans in the country being genetically engineered.5 Most mainstream brands, however, use certified non-GMO ingredients.

In recent decades, soy foods have garnered increasing attention for the amount of isoflavones they contain. These phytoestrogens are being extensively studied for their potential health effects ranging from heart disease and breast cancer prevention to bone mineral density reduction in post-menopausal women. Current evidence, however, is far from conclusive, and much remains to be learned about these compounds.6

Of additional note, soybeans do contain high levels of phytic acid, a compound sometimes referred to as an “anti-nutrient,” which is not destroyed or reduced during the conventional manufacturing process for soy milk.7 Phytic acid has a high affinity for binding minerals such as calcium, iron, magnesium, and zinc and can render these nutrients unavailable for absorption. This effect, however, only occurs when such minerals are ingested simultaneously with phytic acid.

Almond Milk

Almond milk is made from ground almonds and water. It is quickly gaining in popularity, especially among those avoiding soy due to allergies or other health concerns. It is perhaps best known for being low in calories, typically between 30 and 50 per 8 oz. cup (unsweetened), or about one-third the calories of 2% cow’s milk. Sweetened varieties, however, can contain up to 90 calories per cup and 16 g of sugar.

Nut milks in general tend to be highly diluted with water. While this allows them to be relatively lower in calories, this also means that they supply minimal amounts of the nutrients typically found in nuts, including protein, manganese, magnesium, and copper. A major drawback of almond milk is that the protein content from the almonds is strained out of the milk along with the pulp; hence, it contains very little protein – usually only 1 g per 8 oz. cup, compared to 8 g in cow’s milk.

Through fortification, almond milk can offer a comparable amount of vitamins and minerals as cow’s milk – and in some cases, can offer more. However, it is still devoid of most B vitamins, essential fatty acids, and many trace elements such as zinc and copper. One unique aspect of almond milk is its high vitamin E (alpha tocopherol) content, with one cup offering up to 10 mg, or 50% of the daily value for adults.

Rice Milk

There are not many advantages to rice milk over other plant-based milks, but it is likely the most hypoallergenic of all non-dairy alternatives. Though usually derived from boiled brown rice and brown rice starch, it has no fiber and a thin consistency. It has considerably less protein than cow’s milk (only 1 g per 8 oz. cup) and a very small amount of natural calcium, though most brands are calcium-fortified and enriched with vitamins A, D, and B12. It is also low in fat; however, some manufacturers do add vegetable oil as an emulsifier and stabilizer.

Rice milk generally tastes sweeter than cow’s milk, owing to the addition of sweeteners (usually brown rice syrup) and vanilla. It is also significantly higher in carbohydrates.

Oat Milk

Oat milk is made from oat groats (oats that have been cleaned, toasted, and hulled), water, and potentially other grains and beans, such as triticale, barley, brown rice, and soybeans. It has a mild flavor and is slightly sweet. Its consistency is similar to that of 1% or skim milk.

Oat milk is low in overall calories, cholesterol, and saturated fat. It is higher in fiber than other milk alternatives, with 2 g per cup or sometimes more, depending on whether oat bran has been added. It also contains iron, vitamin E, and folic acid. In addition, it offers 4 g of protein per cup, which is relatively higher than most other non-dairy alternatives. At the same time, naturally occurring sugars give this beverage a higher carbohydrate content.

Depending on the manufacturer, oat milk could be another viable option for people with nut and seed allergies. It is important, however, to read the label for added ingredients that could be allergens.

Coconut Milk

Made from grated and squeezed coconut meat, this high-calorie, high-fat beverage is not for drinking straight-up but is usually reserved for cooking, especially in southeast Asian cuisine. It is often found canned and in the ethnic foods section of the grocery store. It has a natural, creamy thickness with a mild nutty flavor.

A 1-cup serving of canned raw coconut milk contains 445 calories and 48 g of fat, of which 43 g are saturated. Recently, however, manufacturers are now offering “coconut milk beverage,” which is essentially coconut milk that has been diluted with water, to appeal to consumers who seek to drink it more regularly. While this type of diluted coconut milk has far fewer calories and much less fat, it also has very little protein – less than 1 g per 8 oz. cup. This version of coconut milk is usually found in cartons (not cans) in the dairy aisle.

Whether concentrated or diluted, coconut milk offers medium-chain triglycerides and a relatively high amount of potassium. If fortified, it can serve as a good source of vitamin D and can also supply up to 50% more calcium than dairy milk. In addition, coconut milk contains fiber and iron, two notable departures from cow’s milk.

Hemp Milk

Though unlikely to ever gain the same kind of popularity as soy or almond milk, hemp milk is considered ideal for people who cannot consume gluten, nuts, and/or soy. It can also be a viable option for those who are on a starch-limited diet and/or must avoid oligosaccharides.

Hemp milk is made from the hulled seeds of the industrial hemp plant, which includes varieties of Cannabis sativa that are low in the psychotropic substance tetrahydrocannabinol (THC) and are grown for food and textile uses. It has an earthier flavor that may be off-putting to some consumers and/or lead them to buy the sweetened versions.

Hemp milk naturally contains more protein than other non-dairy alternatives, but at 2-3 g per 8 oz. cup, it is still not a particularly good source. It does offer a three-to-one ratio of omega-6 to omega-3 essential fatty acids, including around 1,000 mg of alpha-linolenic acid. Other nutrients include magnesium and phytosterols, as well as some calcium, fiber, iron, and potassium.

Pea Milk

Pea milk is one of the newer dairy-free milk alternatives, with only one major manufacturer currently in the U.S. but a second one gearing up to introduce its own line soon. Made from yellow field peas, this beverage is poised to gain more popularity, owing largely to its naturally high protein content (at least 7 g per 8 oz. cup). During manufacturing, yellow peas are milled into flour, which is then processed to separate the protein content from the fiber and starch, and the protein is then further purified and blended together with water and other ingredients. This is a departure from most nut-based milks, in which the protein content is removed and never reintroduced.

Like most other non-dairy alternatives, pea milk is fortified to contain 150% more calcium than cow’s milk. Moreover, its taste and consistency is actually very close to cow’s milk. An added benefit: yellow peas are easy and inexpensive to grow, so pea milk carries a much lower water footprint than almond milk and a much smaller carbon footprint than cow’s milk.8

Cashew Milk

With only 60 calories per cup and no saturated fat or cholesterol, unsweetened cashew milk is often considered a good option for those looking for a creamier alternative to almond milk without the fat and calories of canned coconut milk. It is made by blending water-soaked cashews with water.

Like almond milk, after the pulp is strained away, most of the protein content and naturally occurring vitamins and minerals in cashews ends up being lost. Through fortification, however, cashew milk can offer close to 50% more calcium than cow’s milk. Fortified cashew milk can also be an excellent source of vitamin D. In addition, one 8 oz. cup contains 50% of the recommended daily value for vitamin E.

Flax Milk

With a similar nutrition profile to that of almonds, flax milk is low in calories (around 25 kcal in 1 cup of unsweetened) and very little protein. Flax milk is made commercially by combining cold-pressed flax oil with water, thickeners, and emulsifiers. Flax milk has the additional benefit of 1,200 mg of omega-3 fatty acids (alpha-linolenic acid) per 8 oz. cup. It is also fortified with calcium, vitamin D, and vitamin B12, though not to the same degree as some other non-dairy alternatives.

Flax does contain a very high amount of phytoestrogens – over three times that of soy – but it is unclear how much remains in the oil after the seeds are pressed. And again, the potential health effects (both positive and negative) of these compounds are still being extensively researched.

Potato Milk

Potato milk is another newcomer to the non-dairy milk scene. It is not widely available at grocery stores, but it can be ordered online. Commercially, it is usually found in powdered form. Like rice milk, potato milk is high in carbohydrates but low in protein, though it is usually fortified with calcium and vitamins. It is also a good option for those who may have a soy or nut allergy, as well as those following a gluten- and/or casein-free diet, although consumers should read the label to check for potentially allergenic additives.

In addition to providing as much calcium as cow’s milk, potato milk provides more iron than many other non-dairy alternatives.

CONCLUSION

A growing number of consumers are opting for plant-based milk substitutes, either for medical reasons or as a lifestyle choice, and as a result, the current generation of plant-based milks continues to expand. Table 3 outlines the pros and cons of the various types of non-dairy milk alternatives. The nutritional profile of each type of “milk” depends not only on the plant source, but also the manufacturing process and the degree of fortification. These factors are especially important when considering the protein, vitamins, minerals, and sugar in each serving. Most non-dairy milk alternatives are fortified to provide a reasonable amount of calcium and vitamin D, although amounts of other micronutrients are often unknown. Besides taste and texture, protein and added sugars are perhaps the most widely variable attributes among plant-based milks. Consumer awareness, therefore, is important when plant-based substitutes are used to fully replace cow’s milk in the diet.

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A Special Article

Arsenic Levels in Celiac Patients

January 2018 • Volume XLII, Issue 1
Runa Diwadkar Watkins,Anca Safta,Dana Hong,Elaine Lynne Leonard Puppa,Samra Sarigol Blanchard

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For persons with celiac disease, wheat, barley and rye trigger an autoimmune response in the small intestine, specifically destroying the villi of the duodenum and triggering systemic inflammation. To avoid this immune response, people with celiac disease substitute rice and rice products for wheat, barley and rye. Concerns regarding arsenic levels in rice have prompted the celiac community to question whether increased rice consumption puts them at an increased risk for arsenic toxicity. Some studies have suggested children may be at greater risk than adults. The purpose of this study was to evaluate the risk for increased arsenic levels in persons with celiac disease.

Background:

For persons with celiac disease, wheat, barley and rye trigger an autoimmune response in the small intestine, specifically destroying the villi of the duodenum and triggering systemic inflammation. To avoid this immune response, people with celiac disease substitute rice and rice products for wheat, barley and rye. Concerns regarding arsenic levels in rice have prompted the celiac community to question whether increased rice consumption puts them at an increased risk for arsenic toxicity. Some studies have suggested children may be at greater risk than adults. The purpose of this study was to evaluate the risk for increased arsenic levels in persons with celiac disease.

Methods:

A retrospective chart review of 60 charts was performed for patients seen at a Mid-Atlantic celiac clinic between July 2012 and June 2014. Arsenic levels in biopsy-proven pediatric and adult celiac patients were reviewed. Serum arsenic levels were compared to established normal values; the length of time patients were adherent to a gluten free diet was recorded. Pediatric celiac patients were compared to adult celiac patients.

Results:

Thirty-nine patients had arsenic levels reported. The duration of time between diagnosis to laboratory collection of arsenic levels ranged from four months to 10 years. The mean duration between diagnosis and laboratory collection was 2.35 years for the pediatric group and 3.31 years for the adult group. All patients had normal serum arsenic levels.

Conclusions:

Rice consumption did not increase risk for arsenic toxicity in a retrospective study of serum arsenic levels for patients with biopsy proven celiac disease, irrespective of the duration of gluten free diet.

Runa Diwadkar Watkins, MD1 Dana Hong, MD1 Elaine Lynne Leonard Puppa, RN, Med, MSN1 Anca Safta, MD2 Samra Sarigol Blanchard, MD1 1Department of Pediatrics, University of Maryland, Baltimore, MD 2Department of Pediatrics, Wake Forest University, Winston-Salem, NC

INTRODUCTION

Celiac disease is an autoimmune enteropathy triggered by gliadin proteins found in wheat, barley and rye, commonly referred to as glutens. The disease is characterized by increased intestinal permeability, systemic inflammation and damage to the villi of the small intestine resulting in impaired nutrient absorption.1 The prevalence of celiac disease in the United States is approximately 1:133 individuals.2 However, the majority of persons in the United States remain undiagnosed.2 Typical symptoms include dyspepsia and diarrhea.3,4 Atypical cases may present with a variety of symptoms including short stature, fatigue, rash, anemia, folate deficiency, osteoporosis, arthralgias and myalgias, migraine, peripheral neuropathy and seizure disorder.4 The only treatment for celiac disease is strict elimination of any exposure to the gliadin proteins, as gluten consumption as low as 20 ppm (1/4 tsp flour) may trigger the autoimmune response.5

Wheat, barley and rye constitute the staple grains of the United States. Although quinoa, amaranth, corn and other grains that do not contain gluten have recently come into the market, rice remains the staple grain of the celiac diet in most parts of the world. A 2012 Consumer Report article detailed concerns over arsenic levels in food in general, and rice in particular.6 In addition, the Food and Drug Administration (FDA) began its own investigation into the levels of arsenic in rice in 2012.7 Concerns over the quality of rice and results of accumulated consumption over time began to emerge from the celiac community.8-12 A 2014 study estimated that rice-based foods contained potentially dangerous levels of arsenic with consumption of 0.45-0.46 µg per kg bodyweight.13 Patients in our practice began to express concerns for the level of arsenic they were consuming, not just as rice itself, but also in their baked goods and other gluten free foods that contained rice flour and rice starch as a primary ingredient.

Arsenic is a metallic trace element widely distributed in the environment as a result of natural and human activity.14 Its organic forms are believed to be essential to many forms of mammalian life.15 The human body rapidly eliminates organic arsenic compounds such as those found in seafood.16 However, the inorganic forms of arsenic are more problematic. The World Health Organization (WHO) categorizes inorganic arsenic as a class I human carcinogen.17,18 Long-term exposure can lead to arsenicosis, a condition of arsenic toxicity due to chronic exposure. Arsenicosis can manifest itself in diseases involving the skin, cardiovascular, nervous, hepatic, hematologic, endocrine or renal systems.

Arsenic compounds occur in soils, and contamination can be widespread in the environment. Volcanoes disperse arsenic containing ash. Metal smelting, burning fossil fuels, pesticide production and use, and drilling of water wells may also mobilize arsenic in the soil.6-7,19 Ground water dissolves the mineral from the soil creating a variety of salts across a wide range of conditions.20

For most people, diet is the largest source of exposure to arsenic with mean dietary intakes of total arsenic of 50 -60 mcg/day. Intake of inorganic arsenic ranges from 1-20 mcg/day when rice and/ or infant rice cereal are included in the diet. Rice contains the highest level of inorganic arsenic and arsenic concentrations ranging from 0.05 to 0.4 mcg/g of rice.7

Arsenic accumulation in the rice plant increases markedly under flooded conditions due to the soluble nature of arsenic salts. Arsenic levels vary throughout the world with highest arsenic contamination found in ground water affecting Bangladesh, India, Vietnam, Thailand, and Nepal. Contamination of water is largely due to heavy industry contaminants. Within the United States, rice grown in the south-central US contains higher average total arsenic concentrations compared to California.15 Brown rice contains higher levels of arsenic because the arsenic tends to concentrate in the area near the surface of the grain, the area polished off to create white rice. 21

Children have dietary arsenic exposure from 2 to 3 times greater than that of adults and may be the most vulnerable.22 Considering rice and rice based foods contain high levels of inorganic arsenic, pediatric celiac patients may be a particularly high-risk category.23 In these patients, rice and rice based foods are the main edible substitutes of gluten based products.

The American Academy of Pediatrics (AAP) in November 2014 advised pediatric patients to reduce exposure to arsenic in rice, in response to FDA advisory group which conducted a risk assessment regarding acceptable levels of arsenic in drinking water and diets.24 The AAP recommended interim advice was directed, in particular, toward infant rice cereal, which is used as a thickening agent in feedings for infants and older children, and as a bland introductory food during weaning. The North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) in 2015 published a consensus statement that rice contains high levels of inorganic arsenic and its intake during childhood is likely to affect long- term health. The recommendation was to limit the intake of inorganic arsenic as long as possible and reduce intake of inorganic arsenic exposure from food by including a variety of grains such as oat, barley, wheat and maize in the diet.

Chronic and continued exposure to arsenic achieves steady-state concentrations in blood and urine as well as arsenic accumulating in hair and nails.25 Urinary arsenic reflects arsenic excretion but may not reflect tissue burden. Blood arsenic levels better demonstrate both recent exogenous exposure and an individual’s total internal arsenic burden.25

METHODS

A retrospective chart review of celiac clinic patients with arsenic orders placed between July 2012 and June 2014 was conducted. Physicians obtained routine nutritional and serologic markers to monitor the nutritional status and antibody levels of their patients diagnosed with celiac disease. Blood arsenic levels were ordered in conjunction with annual nutritional and serology follow up in established celiac patients or within six months for newly diagnosed celiac patients as part of routine care.

Blood arsenic level was selected as a marker to limit the number of extra procedures. The value of evaluating blood or urine arsenic has been shown to be equivocal in detecting chronic exposure and body’s burden of the toxin.25-26 Chronic and continued exposure to arsenic achieved steady state concentrations in blood and urine. However, urine arsenic levels reflect arsenic excretion and not actual tissue burden.14 The blood arsenic levels may be a better indicator of recent exogenous exposure and tissue burden.

The review identified sixty unique patients on a gluten free diet from the University of Maryland Medical Center Division of Pediatric Gastroenterology and Nutrition. Inclusion criteria included an order for blood arsenic levels and a diagnosis of celiac disease with confirmatory small bowel biopsy. Demographics, diagnoses, method of diagnosis, date of diagnosis and lab values for arsenic level were reviewed for each patient. Four patients were excluded for lack of follow up visit and 15 patients were excluded as the laboratory studies were ordered but not resulted in the patient chart. Of the remaining 41 patients, the diagnosis of celiac disease was made by biopsy of small bowel on esophagogastroduodenoscopy (EGD) for 39 patients as recommended by NASPGHAN. The arsenic levels from lab panels of the 39 patients who met inclusion criteria were reviewed.

RESULTS
Demographics

Thirty-nine patients, ages ranging from 5 to 68 years of age, met the inclusion criteria for review. The mean age for the group was 20 years of age with a bimodal distribution. Twenty-two patients were pediatric patients, defined as less than 18 years of age. The median age of reviewed patients was 10 years old for the pediatric group and 30 years old for the adult group.

RESULTS

The span for duration of time from diagnostic biopsy to blood arsenic collection ranged from 4 months to 10 years. The mean duration period from diagnosis to collection of arsenic levels was 2.35 years for the pediatric group and 3.31 years for the adult group. All patients had normal serum arsenic levels (Table 1). Seven patients had rice exposure of greater than 6 years and the arsenic levels did not differ from the other patients with shorter exposure. This pilot study found no abnormal levels of serum arsenic in patients diagnosed with Celiac Disease, eating a gluten-free diet. Longer exposure to a rice containing diet, determined by an earlier age of diagnosis of Celiac Disease, demonstrated no increased risk of arsenic accumulation for either pediatric or adult celiac patients.

DISCUSSION

Although significant speculation regarding the potential risk of high arsenic exposure in persons can be found in the literature regarding persons with celiac disease due to their higher rice consumption on a gluten free diet, no published literature is available to substantiate the risk. Bioavailability of arsenic from rice can be very high due to the ability of rice to sequester arsenic absorbed from soil and water.24-26 Existing arsenic levels in rice are often exacerbated by contaminated cooking water.20,27 The American Academy of Pediatrics, FDA and NASPGHAN committee on nutrition recommends limiting the intake of rice in diet and to introduce variety of grains including oats, wheat and barley in vulnerable populations.7,24,26,28 This limitation of rice intake by introducing variety of grains is not possible for celiac patients who have restricted diets where oats are limited and wheat, barley, or rye and oats are eliminated.4

This pilot study suggests that celiac patients who are on an exclusive gluten free diet may not need to have arsenic levels checked along with their other follow up laboratory studies. We did not see any abnormal serum arsenic values for celiac patients who were on exclusive gluten free diets for a longer duration of time. This study highlights the need for clinicians to be aware of the concerns that parents of celiac patients may be facing in the dietary restrictions but no further work up is recommended based on this limited set of data from the pilot study.

This study should be interpreted within the context of its limitations. First, because of the retrospective design, we could not perform blood arsenic levels at time of diagnosis and later after therapy with a gluten free diet for comparison. Second, the gluten free diet of each celiac patient did not account for varied intake in amount of rice consumption for each patient or the origin of the rice. Variations existed in the definition of normal range of arsenic levels between lab facilities that were used to define cut off values. Standardization of laboratory collection at the same resulting facilities would eliminate this variability in comparison of values. Lastly, the power of the study can be improved if an increased number of subjects were included. Future studies should focus on improving the shortcomings as highlighted above. Newer concerns have also suggested arsenic levels possibly being higher in urine samples in those with a strictly gluten free diet. This value was not tested in our study, but would need to be considered in future studies as well.

Most studies of arsenic levels are laboratory based and do not allow for the complex interaction of systems involved in human digestion. Several other modifying effects from the environment influence the human body’s ability to detoxify arsenic that may have influenced the results of this study. Folate and folic acid supplements have demonstrated the ability to lower blood arsenic levels in persons exposed to high levels of arsenic in the drinking water.29 Arsenic, therefore, presents a greater threat to persons who are folate deficient. Likewise, antioxidants from brassicas and other vegetables have also shown protective effects in vitro and been hypothesized to provide a protective effect in the human diet.16 The soil microbiome is known to degrade inorganic arsenic and the human microbiome has demonstrated a similar effect in vitro.16,30 Based on these findings and interpretations, it is not useful to obtain nor follow serum arsenic levels in those with Celiac Disease.

CONCLUSION

In conclusion, the serum arsenic levels were found to be normal in our patients with Celiac Disease. Adherence to a strict gluten free diet did not pose a risk of elevated serum arsenic levels. It is suggested that elevated serum levels of arsenic is correlated with acute toxicity, which did not occur in our cohort. We strongly recommend that patients with Celiac Disease do use high quality rice products and future studies may point to checking urine arsenic levels after being on a strict gluten free diet for a long period of time.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIS #183

Part I Enteral Feeding Barriers: Pesky Bowel Sounds & Gastric Residual Volumes

January 2019 • Volume XLIII, Issue 1
Carol Rees Parrish,Stacey McCray

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Enteral nutrition (EN) is an effective way to nourish patients; however, many barriers prevent consistent and effective delivery of EN in the hospitalized patient. Clinicians must focus on interventions that will make our patients comfortable while their EN is infusing. Part I of this four part series critically evaluates two of the most common barriers to EN: the use of bowel sounds to assess readiness for EN and gastric residual volumes to assess tolerance of EN. Strategies to manage such obstacles in the clinical setting will be provided.

Upcoming in the series:

  • Part II Enteral Feeding: Eradicate Barriers with Root Cause Analysis and Focused Intervention
  • Part III Jejunal Feeding: The Tail is Wagging the Dog(ma): Dispelling Myths with Physiology, Evidence, and Clinical Experience
  • Part IV Enteral Feeding: Hydrating the Enterally-Fed Patient—It Isn’t Rocket Science.

Carol Rees Parrish MS, RDN Nutrition Support Specialist, Digestive Health Center, University of Virginia Health System, Stacey McCray RDN Coordinator, Nutrition Support Training Programs, University of Virginia Health System, Digestive Health Center, Charlottesville, VA

INTRODUCTION

Enteral feeding is an effective way to nourish those patients unable to meet nutritional needs by mouth alone. However, many barriers exist in the hospital setting that interfere with the delivery of the prescribed EN (Table 1). Confirming our clinical experience, many studies have demonstrated that patients routinely receive only 45-65% of EN ordered,1-5 and only 84% was achieved in a recent study that set out to ensure a targeted level of EN was delivered.5 To overcome this track record, we must carefully examine each aspect of EN delivery for potential barriers to adequate nutrition support. Many current practices surrounding the provision of EN are not evidenced-based, nor physiologically sound. One of the most common reasons for EN to be held is “gastrointestinal (GI) intolerance.” Many reports of ‘GI intolerance” are based on unproven monitoring techniques and years of past assumptions about how the GI tract works. While it is true that hospitalized patients can have significant GI issues, little evidence exists to support many of the practices used to “monitor” tolerance to EN. Developing a successful EN regimen requires the following:

  • Full understanding of normal GI anatomy and physiology
  • Knowledge of current evidence behind the practice of enteral nutrition
  • Clinical experience as a bedside practitioner 

The goal of this four part series is to review basic GI anatomy and physiology, discuss how this relates to EN, identify common barriers to EN, and identify strategies to overcome these obstacles. With a better understanding of the GI tract and normal GI function, the clinician will be better equipped to address the root cause of EN delivery barriers and intervene appropriately to improve provision of EN. Part I critically evaluates two of the most common barriers to EN: the use of bowel sounds to assess readiness for EN and gastric residual volumes to assess tolerance of EN. 

BOWEL SOUNDS

Auscultation of bowel sounds (BS) has historically been used to assess bowel function and readiness for oral diet or EN. Despite widespread use, the practice of auscultating BS has never been validated as a marker of GI function; hence its clinical value remains largely unstudied and subjective. In fact, no evidence exists supporting the correlation between bowel sounds and peristalsis, or the need to wait for BS prior to EN initiation.6 To the contrary, two studies have demonstrated that there is a great deal of inter-rater variability among physicians when listening to BS, and that auscultation of BS are unreliable as an indicator of peristalsis and GI function.7-8

Enhanced Recovery after Surgery (ERAS) protocols are multimodal peri-operative protocols aimed at enhancing organ function and decreasing surgical complications resulting in earlier hospital discharge. Most ERAS protocols include early initiation of an oral diet (often post-op day 1). Assessment of BS is not included in any ERAS protocols. This is in contrast to conventional care protocols that hold oral and EN until ‘bowel function returns’—most often assessed by BS or passage of gas. The recent implementation and advancement of ERAS protocols demonstrate that early oral or EN is not only possible, but beneficial to patients. ERAS protocols have demonstrated.9-11

  • Earlier return of bowel function & decreased incidence of post-op ileus
  • Less nausea (through prophylactic nausea medication) 
  • Decreased complication rates and shorter hospital length of stay
  • Earlier resumption of normal activities
  • Increased patient satisfaction
  • Significant cost savings

In summary, experience from ERAS protocols suggests that there is no benefit to using BS as an indicator of GI function and it should be removed as a potential barrier to nutrition supports goals.

ASSESSMENT OF GASTRIC RESIDUAL VOLUMES

Gastric residual volumes (GRV) for decades have been used to ‘measure’ tolerance of EN. A recent nursing survey of 582 nurses in 5 major hospitals found that 89% of nurses would terminate EN for GRVs > 300mL.12 However, this practice is counterintuitive to normal gastric anatomy and physiology. The stomach is a reservoir and the idea that having some gastric residual is abnormal or a problem contradicts its physiologic role.

It is important to bear in mind that a GRV in an enterally-fed patient is not only comprised of EN (i.e. what goes in is not the only thing that comes out). The volume of endogenous secretions (salivary and gastric secretions) that pass through the stomach daily is approximately 2-4 liters (Table 2). Remember, when any volume is put into the stomach, the stomach responds by adding its own gastric juices as part of its physiologic role.13,14Borgstrom demonstrated a 3-5 fold dilution of a test meal from stomach into duodenum over a 4 hour period—500mL/625kcal test meal diluted to a volume of 1500-2500mL.15The total daily volume of endogenous secretions, oral intake, EN, medications, and water flushes can be > 6 liters per day (∼ 230mL/hr) above the pylorus alone. With this volume in mind, one might argue that standard GRV thresholds (60-150mL) are less than endogenous secretions, and therefore, by definition, emptying must be occurring. When evaluating the significance of GRV, all the components contributing to that volume should be considered. 

In addition to the physiologic aspects of GRVs, there are practical and institutional limitations, as well. No standard definition of a GRV exists because the volume that constitutes a significant GRV has never been prospectively studied in a randomized fashion. EN is often held based on an arbitrary number chosen by the hospital or found in textbooks. There is little agreement on how frequently GRV should be checked and whether the GRV should be returned to the stomach (and, if so, how much should be returned?).16 The location of the tip of the feeding tube in the stomach will also affect the amount of GRV. For example, a PEG tube placed high in the stomach may not produce a significant residual because it sits above the air-fluid level of dependent gastric contents. Conversely, a nasogastric tube may produce more GRV simply due to its position in the stomach (see section on pooling effect below).

Gastric Emptying and the Pooling Effect

Normal gastric emptying is quite swift. Liquid emptying is preserved even in severe gastroparesis.17 However, liquids empty from the stomach by receptive relaxation and gravity; therefore, the supine positioning of many hospitalized patients is not optimal for gastric emptying. In the supine position, the anatomy of the stomach is such that the fundus is in the most posterior/superior/left portion and the antrum is in the anterior/inferior/right portion. When the patient is supine or semi-recumbent, liquids can collect in the fundus because it is posterior. Hence, when a patient is supine or at low backrest elevation, the stomach “drapes” over the spine, and with the addition of gravity, gastric secretions may pool in the most dependent portion. When the patient turns to the right side down position, liquids move past the spine to the more anterior antrum and thus can pass into the duodenum. In the upright position, the fundus empties into the more dependent body and antrum and into the duodenum. Therefore, the stomach generally empties best when the patient is on the right side when lying flat or semi-recumbent, or when the patient is fully upright. For radiology photo images illustrating this concept, see also the 2008 article in the Practical Gastroenterology series on GRVs.18

Most nasogastric feeding tubes fall into the most dependent part of the stomach, the fundus, which is not contractile and furthest from the pylorus. Aspirating a GRV from the fundus may retrieve a much greater volume than from the antrum. Although anecdotal, one intervention that is used at UVAHS should a patient’s residual be checked and be elevated beyond what the team is comfortable with, is to put the patient on their right side (while semi-recumbent) for 15-20 minutes, after which the residual is rechecked. Taking advantage of gravity by turning patients on their right side where the pylorus is located (while maintaining backrest elevation at 30 degrees or greater), may enhance liquid emptying from the stomach, and decrease the amount of GRV detected. For more information on this topic, ask your radiologist about how they perform a barium swallow (not to be confused with a modified barium swallow).

Back to GRVs

Monitoring of gastric residuals is often thought to reduce the risk of aspiration and pneumonia in higher risk, critically ill patients. However, several studies have shown that increasing the threshold for gastric residuals (up to 400-500mL) did not increase the incidence of pneumonia.19,20 Several studies have also shown that raising the level of GRV and decreasing the frequency (or eliminating checks altogether) results in more EN received21,22 without significantly increasing the incidence of ventilator associated pneumonia. The use of GRVs to prevent aspiration pneumonia suggests that only those patients who are enterally fed are at risk for aspiration. Do we check GRVs in patients on oral diets during the day, but supplemental EN overnight? What about patients receiving parenteral nutrition (PN) or IV fluids (often our sickest patients)? Some studies have shown that patients receiving PN have a higher rate of pneumonia than those enterally-fed.23,24

Despite the lack of evidence to support monitoring GRVs, a great deal of nursing time is spent on this task, and patients miss a significant amount of EN for what may be a clinically unimportant (and arbitrary) reason. At least one study has also shown that frequent GRV checks may lead to more frequent clogging of feeding tubes.25 Williams, et al. also concluded that reducing the frequency of residual checks saves nursing time, decreases risk of contamination of feeding circuit, and minimizes risk of body fluid exposure.26 Ultimately, not checking GRV allows the nurse more time with their patients to focus on steps that have been shown to decrease aspiration pneumonia (good oral hygiene, backrest elevation, etc.), while allowing patients to meet important nutrition goals.

Time To Move On?

In 2016, the American Society for Enteral and Parenteral Nutrition (ASPEN) and the Society for Critical Care Medicine (SCCM) jointly came out with practice guidelines questioning the practice of checking GRVs. Their conclusions can be summarized as follows:27

  • GRVs should not be used as part of routine care to monitor ICU patients receiving EN. 
  • For those ICUs where GRVs are still utilized, holding EN for GRVs < 500mL in the absence of other signs of GI intolerance* should be avoided. *GI intolerance is defined as:  
    “Vomiting, abdominal distention, complaints of discomfort, high NG output, high GRV, diarrhea, reduced passage of flatus and stool, or abnormal abdominal radiographs.”

While GRVs are not an effective way to monitor tolerance to EN, it is still extremely important to monitor hospitalized patients for signs and symptoms of impaired gastric emptying which is common in the hospital setting. Clinicians should be aware of circumstances that put patients at risk for gastroparesis or altered GI function and develop an individualized plan accordingly. It is crucial to pay attention to abdominal symptoms such as distention, complaints of fullness, tenseness, guarding, firmness, bloating, pain, nausea or vomiting. Patients should also be monitored for constipation, especially in those on narcotics. If your institution does continue to check GRVs, see Table 3 for suggestions to intervene. Finally, see Appendix I for one institution’s justification to phase out routine GRV checks.

Additional Considerations Physiologic Response to Enteral Feeding Initiation and the Ileal Brake

An initial increase in GRV has been documented the first few hours of EN initiation, but this effect subsides rather quickly.28 Kleibeuker provided 15 healthy volunteers with 200mL/hr of EN for 450 minutes (7.5 hours).28 GRVs were checked every 30 minutes beginning at 120 minutes of EN infusion. The author found the highest GRVs occurred at 120 minutes, then decreased with continued infusion. 

The ileal brake is a feedback mechanism within the ileum that regulates the passage of food through the gut.29 When the distal intestine identifies nutrients that seem to have escaped absorption higher up in the small bowel, a signal is sent to slow peristalsis (including gastric emptying).30,31 Therefore, it is not uncommon for patients to have an increase in nausea or other GI symptoms upon initiation of jejunal feedings if nutrients escape to the ileum.

In either circumstance above, if patients experience increased GRVs or an increase in nausea upon initiation of feeding, a brief decrease in rate with a slower advancement may help this transition. Use of a scheduled antiemetic for a few days can help also. However, patients should be able to quickly advance to goal flow as these mechanisms subside.

A Word About Backrest Elevation

While there is little evidence to support GRV checks, there is clear evidence available to support a decreased aspiration risk when backrest elevation (BRE) is maintained.32-39BRE of < 30 degrees is one of the most modifiable risk factors consistently and strongly associated with aspiration, especially in bedbound patients with altered sensorium or impaired swallow. This seemingly simple (but underutilized) intervention is not easy to accomplish. Two studies reported that critical care nurses consistently over-estimated the BRE level.37,40 Another study found that nurses self-reporting of BRE were consistent with observed levels of 28 degrees for intubated patients.41 In all of these studies, actual BRE fell far short of the recommended 45 degrees regardless of the nurses’ perceptions. A summary of studies evaluating BRE in hospitalized patients can be found in Table 4.

There are a number of things that clinicians can do to help ensure that backrest elevation is maintained. First, educate all members of the team that they share this responsibility—it really does take a village. Education should not be a one-time event, but should be ongoing at regular intervals (e.g. quarterly). Note that it is not necessarily accurate to use the head of bed gauge since the gauge measures the level of the head of bed and does not measure the patient’s level of BRE. For those who slide down in the bed, a technique might include elevation of the HOB to approximately 20-30 degrees, then changing the angle of the whole bed to assure BRE (i.e., reverse trendelenberg). Physician orders for backrest elevation may help with compliance. If not already a part of routine order sets, any member of the healthcare team can request such an order from the physician or nurse practitioner. Finally, regular monitoring of institutional practices is necessary, as adherence with guidelines fluctuates over time. 

SUMMARY

EN is an effective way to nourish patients unable to meet their nutritional needs, particularly in the acute inpatient setting. However, for EN to be effective, patients need to receive the goal (“dose”) intended. Many barriers exist in the hospital setting that thwart patients from meeting key nutrition goals, without good evidence to support holding EN for these issues. Instead of perpetuating the myth that EN causes complications, clinicians must focus on the underlying conditions and interventions that will make our patients comfortable while their EN is infusing. This article specifically addresses bowel sounds, gastric residual volumes and backrest elevation, and provides the reader with an opportunity to reevaluate how one approaches these barriers in order to maximize nutrient delivery in the enterally-fed patient.

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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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Medical Bulletin Board

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.

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