Page 48 – Practical Gastro

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

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

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

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

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

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

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

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

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

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

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

Visit FDgard’s Website

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

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

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #22

Diet and Inflammatory Bowel Disease: What is the Role?

Adam S. Cheifetz,

Joseph D. Frasca

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

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

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

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

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

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

Several amino acids have also been investigated for their role in intestinal inflammation. Glutamine and arginine are thought to have immunomodulatory effects¹⁸ and have been shown to improve inflammatory measures in colitis-induced mouse models.^19-22 In addition, histidine, a precursor to histamine, inhibited pro-inflammatory cytokine production in a murine colitis model._²³ Threonine, likely through its beneficial effects on intestinal mucus production, and tryptophan have also been shown to reduce colitis in pig and mouse models.^24,25 Similarly, plant polysaccharides, in addition to fibrous plant products, have largely been shown to have an anti-inflammatory effect.²⁶ The proposed mechanism for this effect is increased production of SCFAs, which act to improve the barrier function and immune tolerance of colonocytes.^27,28 Other plant-based compounds, including curcumin, green tea, fermented grains, and polyphenols have also demonstrated anti-inflammatory properties in various animal models.^10,29,30

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

From the Pediatric Literature

Colonoscopy in Children with Abdominal Pain

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

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

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

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

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

FROM THE PEDIATRIC LITERATURE

MicroRNAs and Necrotizing Enterocolitis

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

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

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

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

Early Detection Of Barrett’s Esophagus And Dysplasia With WATS3D Offers New Solution To One Of The Most Rapidly Growing And Fatal Cancers In The United States

Andrew P. Copland,

Calen A. Steiner

SUFFERN, NY – CDx Diagnostics, innovator of the WATS^3D diagnostic tissue test for the detection and surveillance of Barrett’s esophagus (BE), a known precursor to esophageal adenocarcinoma (EA), recognizes and supports the goals of Esophageal Cancer Awareness Month in helping to educate patients and physicians about the role of screening and surveillance in enabling early detection of this highly lethal cancer. EA is one of the most rapidly increasing and fatal cancers in the United States, but patients should know that advances such as WATS3D in combination with high-definition endoscopes and endoscopic therapies enable improved detection and treatment that can save many lives every year.

WATS^3D is a clinically proven diagnostic test used by gastroenterologists and surgeons for sampling and analyzing esophageal tissue. WATS^3D takes tissue from a greater percentage of the target esophageal surface area than standard forceps biopsy and has been shown to sharply increase the detection of precancerous cells. The Company is proud to play a leading role in preempting EA, and has now processed more than 200,000 WATS^3D tests.

“Gastroenterologists now have the diagnostic and therapeutic tools to help prevent esophageal adenocarcinoma,” said Dr. Anthony Infantolino, a gastroenterologist at Thomas Jefferson MedicalCenter in Philadelphia. “The key is finding precancerous cells before cancer can develop and WATS^3D is a game changer in this area. With a larger tissue sample and advanced computeridentification of unhealthy cells, pathologists can arrive at a diagnosis sooner and with more confidence and agreement about their finding.”

While the United States cancer death rate recently hit 25 years of decline, EA is one of the fastest growing and most fatal cancers in the United States. It is estimated that approximately 17,650 new cases of EA will be diagnosed this year and approximately 16,080 people will die from this disease. In many cases, with raised awareness, screening, physician training and the addition of WATS^3D, EA is now a potentially preventable disease. It joins the growing list of preventable cancers including cervical cancer, melanoma and sporadic colon cancer.

The Key to Preventing Esophageal Adenocarcinoma:

Consultation with a Gastroenterologist or Foregut Surgeon
Detection of Precancerous Cells (Dysplasia)
Removal of Precancerous Cells

WATS^3D has been adopted by nearly 1,000 gastroenterologists and foregut surgeons from leading academic and community centers across the United States and has been clinically proven to increase detection of esophageal dysplasia (ED) and BE by more than 200% and 100% respectively.

“I am so thankful that my gastroenterologist used WATS^3D along with standard forceps biopsy,” said Bob Webb, a patient with chronicgastroesophageal reflux disease (GERD) and BE.“While the standard biopsy results came back negative for precancerous cells, WATS^3D found high grade dysplasia which are precancerous cells that can progress to cancer. My doctor was able to remove these cells, and thanks to WATS3D I feel I have really dodged a bullet.”

“The more than 200,000 WATS performed to date in the United States have spared many Americans from developing EA, a cancer that is frequently fatal,” said Mark Rutenberg, Founder and CEO of CDx Diagnostics. “Esophageal Cancer Awareness Month plays a critical role in further reducing the morbidity and mortality of EA byhelping to educate the public about the well-definedconnection between heartburn and cancer and about the role that screening and surveillance play in early detection and removal of precancerous cells before they can progress to EA. I hope that patients will take Esophageal Cancer Awareness Month as a catalyst to discuss their GERD symptoms with their primary care physician and consult with a gastroenterologist to understand their status and cancer risks.”

To learn more about WATS^3D, visit their website

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #26

Rumination Syndrome in the Setting of a Nissen Fundoplication: Its Atypical Clinical and Diagnostic Features

Zorisadday Gonzalez,

Richard W. McCallum

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Rumination syndrome is a behavioral disorder characterized by the subconscious regurgitation of recently ingested food into the mouth. Although a widely unrecognized disorder, rumination syndrome should be an important consideration in the differential diagnosis of postprandial regurgitation and vomiting resistant to treatment.

Zorisadday Gonzalez, MD, Adult Hospitalist, Presbyterian Healthcare Services, Presbyterian Healthcare Services Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Rumination syndrome is a functional gastrointestinal disorder characterized by effortless regurgitation of recently ingested food back into the mouth within 5-20 minutes of ingestion, followed by re-swallowing or spitting of the food bolus.¹ We report a case of a 20-year old male with history of a Nissen fundoplication as an infant who presented with a three month history of severe postprandial abdominal pain and nausea resulting in significant weight loss. Extensive work-up was unrevealing including numerous imaging, diagnostic, and laboratory studies. A thorough physical examination and history confirmed a diagnosis of rumination syndrome, an atypical presentation given his prior fundoplication history. Although a widely unrecognized disorder, rumination syndrome should be an important consideration in the differential diagnosis of postprandial regurgitation and vomiting resistant to treatment.

Presentation

A 20-year old male presented to the hospital with three months of severe postprandial abdominal pain, early satiety, and intractable nausea resulting in a 20 pound weight loss. The onset of his symptoms were within 5-20 minutes of food ingestion. He denied fevers, diarrhea, dysphagia, melena, hematochezia or change in stool caliber. He denied bulimic behavior and did not desire losing weight. His past medical history was significant for severe reflux as an infant resulting in failure to thrive, and underwent a Nissen fundoplication at that time. As a result of his fundoplication, he was unable to regurgitate food or vomit. His family history was negative for gastrointestinal (GI) malignancy. He had recurrent emergency department (ED) visits with these symptoms and had visited numerous physicians without definite diagnosis. Proton pump inhibitors, opioids, and anti-emetics were ineffective in alleviating his symptoms. He had recently experienced several stressful situations at home. Extensive laboratory testing, upper endoscopy, upper gastrointestinal and small bowel series, computed tomography (CT) angiogram of the abdomen and pelvis, gastric emptying study, and CT of the head failed to explain his symptoms. He refused nasogastric tube feeding. Total parenteral nutritional therapy was initiated to support both hydration and nutrition. He was transferred to the University Medical Center (UMC) at Texas Tech University Health Sciences Center after two weeks without clinical improvement. Physical exam findings were remarkable for postprandial contraction of the rectus abdominis muscle. Following meal intake, the patient was noted to burp and belch as he attempted to ruminate, but he was unsuccessful because of his fundoplication. A jejunostomy tube was ultimately placed in approximation of his fundoplication. Biopsy of antral smooth cells obtained during jejunostomy placement revealed normal number of Cajal cells implying normal gastric emptying. The patient was educated on behavioral therapy and discharged home. At two month follow up, he endorsed marked improvement of his gastrointestinal symptoms with diaphragmatic breathing skills, and his jejunostomy tube was removed. At five months follow up, he reported complete resolution of symptoms and was tolerating food well. He had gained weight and had returned to work and school.

Discussion

Rumination syndrome is the subconscious and effortless regurgitation of recently ingested food from the stomach back into the mouth with subsequent spitting out of the regurgitant or remastication with re-swallowing.¹ Episodes occur within 5-20 minutes after ingestion and symptoms can last up to one to two hours.⁷ These patients often describe their symptoms as vomiting and are therefore incorrectly diagnosed with GERD or another upper gastrointestinal disorder such as gastroparesis or dyspepsia. Furthermore, the presence of additional GI symptoms including abdominal discomfort, nausea, or heartburn does not exclude the diagnosis of rumination syndrome which can further confound the differential diagnosis.⁵ Many of these patients undergo extensive, invasive, and costly testing before a diagnosis is reached. Even though rumination syndrome can imitate GERD or gastroparesis, a careful history can help differentiate the diagnosis. In rumination syndrome, symptoms always occur in the early postprandial period as opposed to GERD or gastroparesis where symptoms occur late postprandially. Additionally, anti-reflux medications do not improve symptoms of rumination syndrome. In gastroparesis, nausea and/or retching usually precede vomiting which is not always the case in rumination syndrome. Another gastrointestinal disorder which can present with effortless postprandial regurgitation is achalasia, although these patients present with dysphagia which is not seen in rumination syndrome. The epidemiology of rumination syndrome is limited because many providers are not aware of this diagnosis and is therefore rarely recognized. Although early observations were mostly described in infants and developmentally disabled patients, it is now recognized in healthy patients of normal intellect and of all ages.⁵ Psychological disturbances have been postulated to play a role around symptom onset of rumination, and therefore a psychiatric evaluation should be considered in patients with a suspected eating disorder.^4,7

The pathogenesis of rumination syndrome is not well understood. The hallmark feature is a coordinated combination of lower esophageal relaxation and increased intra-abdominal pressure coupled with negative intrathoracic pressure.^6,7 This subsequently leads to the reversal of the esophagogastric pressure gradient allowing food to come back up the esophagus and into the mouth. Diagnostic findings on manometry include reflux events associated with an increase in gastric pressures > 30 mm Hg caused by voluntary yet unintentional contraction of the abdominal wall muscles. Although postprandial high resolution impedance pH manometry can support a diagnosis, this test is not required to make diagnosis.⁵ A thorough history and physical examination are key to diagnosing rumination syndrome. Brisk contraction of the abdominis rectus muscle prior to regurgitation can be appreciated on exam. Rumination syndrome has been recognized as its own unique category under functional gastrointestinal disorders and should be diagnosed based on the Rome IV criteria outlined in Table 1.1

Treatment for rumination syndrome consists of reassurance and behavioral therapies including diaphragmatic breathing exercises during and after meals to target abdominal wall contraction and prevent the urge to regurgitate.^2,3 This technique allows for habit reversal, and has been proven to be effective in most patients.⁷ There are no known effective medications in the treatment of rumination syndrome.

Our case was unique in that our patient had a Nissen fundoplication procedure as an infant and was therefore unable to regurgitate or vomit any food. Attempts to regurgitate food only led to severe epigastric pain and nausea which led to fear of eating resulting in significant weight loss. To our knowledge, this is the first case of rumination syndrome in a patient with a prior fundoplication. Interestingly, in a case series of five patients with rumination syndrome whose symptoms had been resistant to medical and psychiatric interventions, Oelschlager et al. reported complete elimination of symptoms in all five patients after performing a Nissen fundoplication.² However, this was a very small sample size and fundoplication is not a recommended treatment for rumination syndrome.

CONCLUSION

Rumination syndrome is a behavioral disorder characterized by the subconscious regurgitation of recently ingested food into the mouth. It is widely unrecognized due to the limited awareness of this condition. Patients with prior fundoplication anatomy may further mask this diagnosis due to their inability to bring up undigested food. A thorough history and physical exam are key in diagnosing rumination syndrome with brisk contractions of the rectus abdominis muscles on exam prior to regurgitation. The mainstay of treatment includes diaphragmatic breathing with behavioral therapy.

FRONTIERS IN ENDOSCOPY, SERIES #52

Hemobilia: Evaluation and Management

Douglas G. Adler,

Taylor Frost

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Hemobilia should be suspected in patients with evidence of upper GI bleeding in the setting of a history of prior hepatobiliary intervention or malignancy. Here we discuss the management of hemobilia which can often be managed conservatively with transfusions and the correction of any underlying coagulopathy. However, in patients with persistent bleeding, angiography with selective embolization is the first line therapy to achieve hemostasis but endoscopic biliary stenting and surgical interventions may be warranted.

Taylor Frost MD, Douglas G. Adler MD, FACG, AGAF, FASGE University of Utah School of Medicine Gastroenterology and Hepatology, Salt Lake City, UT.

CASE VIGNETTE

A 68 year old man with chronic pancreatitis developed splenic vein thrombosis with extensive peripancreatic collateral vessels, including around the pancreatic head and duodenal wall. The patient presented with new jaundice and melena and was referred for ERCP. ERCP was performed and revealed ampullary varices with active hemobilia, consistent with variceal erosion and hemorrhage into the distal common bile duct. (Figures 1 and 2) A fully covered metal stent was placed across the distal CBD to produce tamponade on the bile duct, which stopped the bleeding temporarily. (Figure 3) The patient was referred to surgery for splenectomy, which was performed to good effect. The stent was subsequently removed.

Etiology

As a clinical entity, hemobilia can develop from a wide variety of conditions and has been reported in patients with hereditary architectural vascular disease, auto-immune or inflammatory conditions, and malignancy.^1,2,3,4,5,6 However, historically the vast majority of cases have arisen in patients who suffered from abdominal trauma.7 In recent years, with the advent of percutaneous and endoscopic procedures, there has been a shift over time towards iatrogenic cases, and most cases of hemobilia in the modern era are secondary to interventional procedures.^8,9 Hemobilia has been reported as a complication of many procedures including, but not limited to, percutaneous and transjugular liver biopsy, percutaneous transhepatic biliary drainage and cholangiography, radiofrequency ablation of hepatocellular carcinoma, endoscopic retrograde cholangiopancreatography (ERCP) as well as surgical procedures including laproscopic cholecystectomy, liver resection, and liver transplantation.^10,11,12

Mechanism of Injury

Typically, hemobilia occurs when there is direct trauma to the biliary tree and the hepatic blood supply. This then leads to the formation of a fistula followed by a bleeding event, which is often immediate.^13,14 Delayed bleeding has also been reported in some patients. In cases of delayed hemobilia, the initial trauma of the procedure and subsequent inflammation can lead to the formation of a pseudoaneurysm in an adjacent blood vessel. The pseudoaneurysm can then, due to poor structural integrity, rupture or fistulize at a later date, which effectively expands the time between the initial injury and subsequent presentation of hemobilia.¹⁵ Furthermore, both arterial and venous vessels can be affected and have been implicated as sources of hemobilia.^16,17

Incidence and Presentation

Hemobilia can present on a spectrum ranging from an immediate bleed with hemodynamic compromise to minor upper gastrointestinal bleeding that may not even be noticeable clinically. Furthermore, symptoms may not be temporally related to the inciting event, i.e., the initial trauma may have occurred months prior to symptom onset. To complicate this further, hemobilia can present as an intermittent gastrointestinal bleed, which may further impede accurate diagnosis. Quincke’s triad of abdominal pain, upper gastrointestinal bleeding and jaundice has been described as the classical presenting symptoms but may only be present in 20-30% of patients.⁹ For these reasons, the incidence of hemobilia by procedure type or technique is not well understood.

In a retrospective review of 333 patients who underwent percutaneous biliary drainage, Savader et al. (1992) found that 13 patients developed hemobilia with symptom onset ranging from 1 day to 1.8 years following catheter placement. (Figure 4) However, the incidence of hemobilia in percutaneous procedures has been estimated to range from 2.3 – 3.9% in two moderate sized retrospective reviews of percutaneous biliary drainage and 0.005% in those who underwent percutaneous liver biopsy in a large multicenter retrospective study of 68,276 patients.^18,19,20 Hemobilia following transjugular liver biopsy is relatively rare and has been reported at 0.006% in a retrospective review of 601 patients.²¹

Post endoscopic hemobilia has not been well described in the literature. To our knowledge, there are no large retrospective studies that have examined hemobilia following endoscopy. Of the reported cases, hemobilia appears to most commonly follow biliary stenting and may be more prevalent among patients who received metal stents as compared to those who received plastic stents.^{22,23,24,25,26} (Figure5) Hepatic artery pseudoaneurysm from traumatic stent placement has been reported following biliary stenting and is thought to be the mechanism that promotes hemobilia.15 Otherwise, hemobilia has been reported in patients with malignancy or underlying architectural vascular disease who undergo ERCP.^27,28 To complicate matters further, there are no known risk factors that may aid in the identification of those with an increased likelihood of developing hemobilia as a complication of endoscopy.

Management

Currently, there are three main methods that can be utilized in the definitive treatment of hemobilia: surgical intervention, biliary stenting, and angiography followed by selective embolization. The approach to management may change depending upon hemodynamic stability, the suspected source of bleeding, and the inciting event.

Historically, surgical intervention with segmental liver resection, pseudoaneurysm repair, and/or nonselective arterial ligation was the mainstay of treatment. However, more recently surgery has been reserved to patients with extensive liver trauma, hemodynamically instability, and those who develop hemocholecystitis or have failed alternative therapies.²⁹

Endoscopic biliary stenting has been reported to be successful in the treatment of hemobilia but is often a poor choice for definitive therapy as the location of the bleed must be readily identifiable, extrahepatic, and easily accessible.³⁰ Covered and non-covered self-expandable metal stents have seen some success in the treatment of massive hemobilia that occurs from bile duct varices or primary tumor bleeding due to extrahepatic malignancy.^31,32 In these patients, the stent will generally be left in place for a prolonged period of time (or forever) unless the patient develops another complication such as stent obstruction or cholangitis. It is believed that expandable stents are able to distribute pressure over the communicating venous vessel and thereby provide a tamponade effect to achieve hemostasis.

Angiography with selective embolization was first described in 1976 and now represents the first line therapy to achieve hemostasis as it is noninvasive and has a high success rate with an associated low morbidity.^33,34 Furthermore, angiography with selective embolization is the only intervention that can both delineate the vascular anatomy and the location of the pseudoaneurysm or fistula and guide therapeutic intervention. Although one drawback is that false negative studies may occur if there is intermittent bleeding.¹⁵Embolization is typically achieved through the injection of Gel-foam, polyvinyl alcohol particles or steel coils at the site of the lesion.³⁴ Inadvertent embolization of adjacent arteries leading to fatal ischemic disease has been reported but occurs infrequently.³⁵ A caveat to these treatment modalities may exist in patients who develop hemobilia secondary to percutaneous biliary drainage. In this scenario, success with repeated drain flushing followed by an upsizing of the percutaneous catheter may provide a tamponade effect.³⁶ Regardless of which treatment modality is performed, initial evaluation should be directed at hemodynamic stabilization and resuscitation.

After hemostasis is achieved and the patient is hemodynamically stable, attention is often shifted to the clearance of blood from the biliary tree if clinically indicated. However, in minor hemobilia, patients can often be managed conservatively with the correction of any underlying coagulopathy and volume resuscitation with intravenous fluids or transfusions. In those who experience persistent minor hemobilia without a recognizable vascular lesion on imaging, it is reasonable that ERCP be performed, as there may be an identifiable lesion of the distal biliary tree, which could be amendable to biliary stenting. In patients with minor hemobilia, most intrabiliary blood will dissolve under the influence of flowing bile. However, if intrabiliary blood becomes immiscible it is prone to forming a pure clot, which may lead to biliary obstruction and would warrant nasobiliary drainage or ERCP with sphincterotomy and ductal clearance.³⁷

Hemocholecystitis is a feared complication of biliary obstruction as it may necessitate the need for surgical intervention, which carries an increased risk of mortality. Furthermore, it has been hypothesized that even transient obstruction may favor the reflux of blood clots into the cystic duct. Thus, if biliary ductal dilatation is demonstrated on imaging then decompression through either a nasobiliary drain or endoscopic sphincterotomy with clot extraction should be pursued.³⁶

In instances of major hemobilia, surgical intervention is warranted as this approach allows for the identification and selective ligation of the bleeding vessel. If a bleeding vessel cannot be visualized then nonselective ligation of the hepatic vasculature with intraoperative bleed surveillance may be pursued.³⁸ Nonselective ligation allows for gross localization of the source of hemobilia, which can then guide more precise interventions. In rare instances, both ligation and selective embolization can be insufficient in controlling the bleed and partial hepatectomy may be required.³⁹

Discussion

Hemobilia should be suspected in patients with evidence of upper GI bleeding in the setting of a history of prior hepatobiliary intervention or malignancy. The management of hemobilia will depend upon the presenting symptoms and the acuity of the bleeding itself but should initially focus on hemodynamic stabilization. Hemobilia can often be managed conservatively with transfusions and the correction of any underlying coagulopathy. However, in patients with persistent bleeding, angiography with selective embolization is the first line therapy to achieve hemostasis but endoscopic biliary stenting and surgical interventions may be warranted. Biliary dilatation on imaging may represent obstruction and should warrant biliary decompression with either nasobiliary drainage or ERCP with sphincterotomy and clot extraction. Hemocholecystitis carries an increased risk of mortality and is a feared complication of hemobilia with biliary obstruction. The presence of hemocholecystitis or bleeding unresponsive to less invasive therapies should warrant urgent surgical intervention.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #186

Part IV Enteral Feeding: Hydrating the Enterally-Fed Patient – It isn’t Rocket Science

Andrew P. Copland,

Carol Rees Parrish,

Stacey McCray