Page 71 – Practical Gastro

A 42 year old male expatriate from Yemen was referred to the gastroenterology outpatient clinic with a six-month history of intermittent rectal bleeding. He had daily bowel movements but noted occasional rectal bleeding. There was no history of diarrhea, abdominal pain, weight loss or fever. His physical examination was unremarkable and baseline laboratory investigations were normal. Colonoscopy revealed a 5-6 mm sessile polyp in the rectum with surrounding inflammation marked by erythema and loss of vasculature (Figure 1). The remainder of the examination to the terminal ileum was normal. The polyp was removed using a biopsy forceps without any complications.

Histology showed colonic mucosa with mixed inflammatory cell infiltrate, composed of plasma cells and eosinophils surrounding the crypts in the lamina propria (Figure 2). An egg of Schistosoma mansoni, with tapered anterior end and lateral spine near the posterior end, was also seen. This is shown at higher magnification in Figure 3. Schistosomal proctitis was diagnosed and was subsequently treated with praziquental.

Schistosomiasis is a trematode infection caused by blood fluke, Schistosoma, which is endemic to many parts of Africa, Asia and South America. It affects 200 million people worldwide and causes 200,000 deaths each year.¹ Studies have shown that its prevalence is increasing in Europe and the United States due to an increasing number of travelers and immigrants to and from these areas.² Infection in humans, the definitive host, is due to contact with fresh water snails, which act as intermediary host. There are three major species of Schistosomas that infect humans: S. haematobium, S. mansoni and S. japonicum. S. haematobium is associated with urogenital pathology while S. mansoni and S. japonicum cause intestinal and hepatic infection. S mansoni, the main colonic pathogen, resides in the mesenteric veins around the colon where it produces large number of eggs. Some of the eggs make their way to colonic lumen and are cleared in the stool. Others get deposited in the colonic mucosa causing ulceration and polyp formation due to cell mediated immune response and granulomatous reaction. This in turn leads to the main symptoms of colonic schistosomiasis i.e. abdominal pain, bloody diarrhea and tenesmus.³ Colonic schistosomiasis can be diagnosed by finding eggs in stools in acute cases or in tissue biopsies in chronic cases where egg excretion is scant. Schistosomal polyps are seen mainly in patients from endemic areas with chronic disease. The rectum is the preferred site for these polyps but they have been reported in the sigmoid and transverse colon as well.⁴ Treatment of schistosomiasis is with the antibiotic Praziquental, with the usual dose of 40-60mg/Kg in divided doses.

Gastroenterologists and primary care physicians should keep Schistosomasis in mind as one of the possible etiologies when evaluating patients with colorectal symptoms and exposure to endemic areas.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #141

Trophic Agents in Treatment of Short Bowel Syndrome

John K. DiBaise,

Carol Rees Parrish

An important goal when treating the short bowel syndrome (SBS) patient who requires parenteral nutrition or fluid support is to reduce dependency on this support and, whenever possible, to eliminate its use altogether. There is great interest in the use of growth factors in patients who have been unable to achieve enteral independence during the adaptive period despite optimization of diet and medical management. A number of pharmacological agents have been demonstrated to induce trophic properties on the intestinal epithelium. In Part V of our series on SBS, we will focus on somatropin, a recombinant human growth hormone, and teduglutide, a recombinant human glucagon-like peptide-2 analogue, the currently approved trophic factors available for use as aids to wean parenteral support in SBS.

An important goal when treating the short bowel syndrome (SBS) patient who requires parenteral nutrition or fluid support is to reduce dependency on this support and, whenever possible, to eliminate its use altogether. There is great interest in the use of growth factors in patients with SBS who have been unable to achieve enteral independence during the adaptive period despite optimization of diet and medical management. A number of pharmacological agents have been demonstrated to induce trophic properties on the intestinal epithelium. In Part V, the final part of this series on SBS, we will focus on somatropin, a recombinant human growth hormone, and teduglutide, a recombinant human glucagon-like peptide-2 analogue, the currently approved trophic factors available for use as aids to wean parenteral support in SBS.

John K. DiBaise, MD, Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ. Carol Rees Parrish MS, RD, Nutrition Support Specialist, University of Virginia Health System Digestive Health Center of Excellence, Charlottesville, VA

INTRODUCTION

An otherwise healthy 45 year-old man underwent laparoscopic cholecystectomy for acute cholecystitis. His postoperative course was complicated by an undetected vascular injury causing widespread bowel necrosis requiring extensive resection leaving him with about 90 cm of jejunum anastomosed to his transverse colon. He has been on home parenteral nutrition (PN) since September 2011. Previous attempts to wean him from the PN have stalled at 4 nights per week despite adherence to aggressive dietary and pharmacologic strategies. Although he has experienced no complications from the PN, and is otherwise doing well, he desires to be off PN due to its untoward effects on his quality of life.

Are there any other non-surgical treatment options that may allow him to further wean and potentially eliminate his need for PN?

While life saving, PN use in short bowel syndrome (SBS) is associated with a reduction in quality of life and a number of complications arising from not only the PN, but also the catheter used to infuse the PN. These complications may include catheter-related bloodstream infections and venous thrombosis, metabolic bone disease, liver disease, and renal failure (See Part I in this series). An important goal when treating the SBS patient who requires parenteral support (i.e., PN or intravenous fluids [IVF]) is to reduce dependency on this support and, whenever possible, eliminate its use altogether. PN requirements decrease as the bowel adapts following resection allowing greater nutrient and fluid absorption. Over 50% of adults with SBS can be weaned completely from PN within 5 years of diagnosis.^1,2 In contrast, the probability of eliminating PN use is < 6% if not successfully accomplished in the first 2 years following the individual’s last bowel resection.¹ A number of clinical factors may serve as useful predictors of the success of eliminating the use of PN in SBS (Table 1). The presence of a colon and the remaining length of functional small bowel are the most critical factors. Permanent need of PN generally occurs when there is < 50-70 cm of small bowel with colon-in-continuity or < 100-150 cm of small bowel when the colon is absent.¹

Following the 2 — 3 year period of greatest intestinal adaptation after massive resection, a homeostatic/ maintenance stage begins where no further spontaneous intestinal adaptation is thought to occur. Intestinal failure is frequently considered permanent when PN is required beyond this stage. There is great interest in the use of growth factors in patients with SBS who have been unable to achieve enteral independence during the adaptive period despite optimization of diet and medical management. The current understanding of the adaptation process has led to the study of hormones, nutrients, and growth factors in experimental models and in humans with SBS. A number of pharmacological agents have been demonstrated to induce trophic properties on the intestinal epithelium in animal models of SBS. These encouraging reports have been followed by conflicting reports of efficacy in humans regarding the enhancement of intestinal absorption, adaptive changes to the gut and utility in PN weaning. This review will focus on somatropin (Zorbtive™; Serono Inc., Rockland, MA), a recombinant human growth hormone, and teduglutide (Gattex®; NPS Pharmaceuticals, Bedminster, NJ), a recombinant human glucagon-like peptide-2 analogue, as they are both Food and Drug Administration (FDA)-approved for use as aids to wean parenteral support in SBS patients.

Growth Hormone

Growth hormone (GH) has been shown to promote crypt cell proliferation, mucosal growth, collagen deposition, and mesenchymal cell proliferation via insulin-like growth factor-1 and suppressor of cytokine signaling-2. Enhanced intestinal absorption has repeatedly been demonstrated in animal models of SBS, while there have been conflicting reports in humans. In 1995, Byrne et al. reported on 47 patients, most of whom had a colon- in-continuity, treated with a combination of growth hormone (GH), oral glutamine and an optimized SBS diet for 3 weeks in a controlled inpatient-like setting followed by continued use of the diet and glutamine.³ With follow-up for as long as 5 years, they showed that 40% of patients could be weaned completely from PN while another 50% could make significant reductions in their PN use.⁴ With these reports, the concept of intestinal rehabilitation was introduced.^5,6 In a more recent uncontrolled, prospective case series, Zhu and colleagues used a similar treatment program and demonstrated very similar, long-lasting results.⁷ ? A phase III prospective, randomized, placebo- controlled trial conducted at 2 centers was subsequently performed. Forty-one PN-dependent SBS patients (most with colon-in-continuity) were enrolled and studied in an inpatient-like setting for 6 weeks; 2 weeks of diet and medication (i.e., antidiarrheal and proton pump inhibitor) optimization and PN stabilization followed by a 4-week treatment period. Patients were randomized into 3 groups: somatropin (0.10 mg/kg subcutaneously once daily) with glutamine, somatropin without glutamine, and placebo with glutamine. A significant reduction was seen in both groups treated with GH in PN requirements (the primary endpoint), including PN volume, PN energy and frequency of PN infusions at the end of the 4-week treatment period (Table 2). The extent of reduction, however, was greatest in the group receiving somatropin in combination with glutamine.⁸ PN reduction remained significantly reduced during a 12-week observation period in the somatropin with glutamine group only; importantly, a weight loss of about 5 kg was also observed in this group. Although tolerated, peripheral edema and musculoskeletal complaints were common in the somatropin treated groups. On the basis of this evidence, and the safety of the treatment program, the FDA approved the use of somatropin in December 2003 as a short-term (4 weeks) aid for PN weaning in patients with SBS. To date, somatropin has not been approved by the European Medicines Agency for this indication.

Despite the reports of success with GH, 3 randomized, controlled nutrient balance studies found conflicting evidence with respect to nutrient and wet weight absorption^9-11 using this combination of somatropin and glutamine (but without diet or conventional medication optimization). This has led to a considerable amount of skepticism surrounding the long-term benefits of this approach and its clinical use remains controversial.¹² Additionally, side effects of somatropin including peripheral edema, arthralgias and carpal tunnel syndrome are significant, further limiting its adoption into clinical practice. Concern exists about a potential increased risk of colorectal cancer in patients receiving somatropin if required to be administered over a longer period of time.¹³ Finally, there is also concern about the feasibility of replicating the results of the pivotal trial in an ambulatory setting without the same daily monitoring and counseling provided. Clearly, admitting a patient for 4 weeks to optimize diet, hydration and medical therapy and administer somatropin would be rather challenging in the present healthcare environment.

Contraindications, Precautions and Costs Associated with Somatropin Use

Somatropin is contraindicated in patients with active neoplasia and in those who are acutely critically ill. It has been associated with acute pancreatitis, impaired glucose tolerance, type 2 diabetes mellitus, carpal tunnel syndrome and arthralgias. In the U.S., the cost of a 4-week course of somatropin is approximately $20,000.²⁸ An economic analysis of healthcare costs associated with GH use estimated a 2-year savings of $85,474 assuming that 34% of GH-treated patients eliminated PN use within 6 weeks of treatment and 31% remained PN-free after 2 years.29 However, remember that patients in the clinical trial were studied in an inpatient setting (albeit not hospital), and received daily visits and education/counseling; costs not factored into the dollar amount mentioned above. How the use of this agent will translate into the ambulatory setting where visits and supervision will not be as intensive is unknown. It has not been widely adopted into clinical practice more than a decade after its approval. Furthermore, the role of repeated course(s) or prolonged treatment with somatropin requires additional study.

Glucagon-like Peptide-2

Glucagon-like peptide-2 (GLP-2), secreted from distal small intestine and proximal colonic mucosal L-cells in response to luminal nutrients, plays an important role in intestinal adaptation. GLP-2 administration induces epithelial proliferation in the stomach, small bowel and colon by stimulating crypt cell proliferation and inhibiting enterocyte apoptosis, increases absorptive capacity and inhibits gut motility and secretion.^14-18 In a small, open-label trial investigating the effects of GLP-2 in humans with SBS, 8 patients received 400 µg GLP-2 subcutaneously twice daily for 35 days.¹⁹ Of the 8 patients studied, 4 had a portion of colon-in- continuity and were receiving PN while the other 4 did not have a colon and did not require PN. An increase in overall energy absorption, decrease in fecal wet weight, slowing of gastric emptying and nonsignificant trend toward increased jejunal villus height and crypt depth were demonstrated.

Teduglutide, a recombinant, degradation-resistant, longer acting GLP-2 analogue, was shown in an open- label study to be safe, well-tolerated, intestinotrophic and significantly increased intestinal wet weight absorption, but not energy absorption in 16 SBS patients with an end- jejunostomy or a colon-in-continuity.²⁰ Teduglutide was then studied in two phase III multinational, randomized, double-blind, placebo-controlled trials that included a total of 169 PN or parenteral fluid-requiring SBS patients in an outpatient setting (Table 2). A habitual diet was followed by patients in both trials. Notably, only about one-half of the subjects used antidiarrheal and antisecretory medications during the studies. In the first study, 83 SBS patients were separated into 3 treatment arms (placebo, 0.05 mg/kg/d and 0.10 mg/kg/d administered subcutaneously once daily) and treated with the study medication for 6 months following a PN optimization period. PN weaning was the primary endpoint (20% reduction by week 20 and maintained to week 24). Teduglutide was found to be safe and well tolerated; however, only the lower teduglutide dose significantly reduced PN requirements (46% for 0.05 mg/kg/d versus 6% for placebo), and 3 patients were completely weaned from PN.²¹ There was a strong trend towards overall reduction in fluid volume at the end of treatment in the teduglutide treated groups compared to placebo (2.5 L/wk vs. 0.9 L/wk, respectively; P=0.08). Parenteral energy intake, while much lower than baseline, was not significantly different from placebo at the end of 24 weeks of treatment (P=0.11). Villus height, plasma citrulline concentration and lean body mass were significantly increased in the teduglutide groups compared to placebo; no evidence of dysplasia in the intestinal samples was detected.²² After stopping teduglutide at the end of the 24 week treatment period, some patients (15/37) required an immediate increase in their fluids while others (22/37) seemed to maintain their fluid requirements and body weight.²³ Indicators of sustained fluid reduction and maintenance of body weight included a longer length of the remaining small bowel and the presence of at least a portion of colon, lower body mass index at baseline, and lower PN volume reduction while on teduglutide (i.e., they were already receiving lower volume of parenteral support at baseline).

During long-term (an additional 28 weeks) treatment of 52 patients from the original 24-week study, at week 52, 68% of the 0.05-mg/kg/d and 52% of the 0.10-mg/ kg/d dose group had a ≥ 20% reduction in PN, with a reduction of 1 or more days of PN dependency in 68% and 37%, respectively.²⁴ Those treated with the lower dose showed continued decrease in parenteral volume requirements (4.9 L/wk); 4 patients achieved complete independence from PN. Overall, it appears that long-term treatment is associated with continued improvement.

The second trial compared the lower dose of teduglutide to placebo administered for 6 months in 86 adult SBS patients and utilized a more aggressive PN weaning strategy (10-30% vs. 10% reductions at 2-weekly intervals and starting at week 2 vs. week 4.²⁴ Once again, a significant benefit of teduglutide over placebo was seen (Table 2). Those receiving teduglutide were more than twice as likely to respond to therapy (63% versus 30%, P=0.02). The mean reduction in PN volume after 24 weeks was 4.4 L in the teduglutide group compared to 2.3 L in the placebo group. Fifty-four percent of those receiving teduglutide reduced at least 1 PN infusion day/week compared with 23% for placebo. No subjects were completely weaned from PN at the end of 24 weeks of treatment. In a preliminary report from a 2-year extension study, 65 patients (74%) completed the study. Of the 30 patients treated for 30 months with teduglutide, 28 (93%) made significant reductions in their parenteral support with a mean decrease of 7.6 L/wk, and 21 (70%) eliminated at least 1 infusion day.²⁶ A total of 15 of the 134 (11%) patients treated in both phase III studies and their extension studies achieved enteral autonomy.²⁷ Most of these patients had a portion of colon-in-continuity and lower baseline PN/IVF requirements. Due to the small numbers, a formal statistical analysis for predictive factors was not possible.

The most frequent gastrointestinal side effects reported in both trials included abdominal pain, nausea, stomal changes (in those with an ostomy), abdominal distension and peripheral edema; resolution occurred with treatment continuation or temporary discontinuation in most instances. Data from the extension studies suggest a tolerable safety profile with abdominal pain, injection site reactions and stomal complaints being most common (24). Although anti- teduglutide antibodies have been demonstrated in the blood of treated patients, they appear to be non- neutralizing and have not been shown to decrease the effect on PN volume reduction (25). Thus, it appears that long-term teduglutide treatment is associated with acceptable tolerability and continued improvement. On the basis of the data from these two pivotal trials, teduglutide was approved by the United States FDA in December 2012 and by the European Medicines Agency in 2012 (Revestive®; Nycomed, Zurich, Switzerland) for SBS patients as a long-term aid to PN weaning.

Contraindications, Precautions and Costs Associated with Teduglutide Use

The only contraindication to teduglutide use is active GI neoplasia. In patients with active, non-GI neoplasia, use should only be considered if benefits outweigh the risks. Precaution is necessary, however, due to a number of potential adverse effects including increased fluid absorption and the potential for fluid overload; the potential to increase drug absorption requiring dosage reduction and drug monitoring when using medications with narrow therapeutic window or require titration (e.g., benzodiazepines, opioids, psychotropics), and the risk for acceleration of neoplastic growth within the gut requiring periodic colonoscopic surveillance before and during its use (6 months before, 1 year after, and at least every 5 years thereafter). Additional monitoring for gastrointestinal obstruction, gallbladder, biliary and pancreatic disease (amylase, lipase, alkaline phosphatase and total bilirubin before and every 6 months while using) is also advised as part of the risk evaluation and mitigation strategy (REMS- https://www.gattex. com/hcp/rems.aspx) program required of prescribers (see Table 4 for one institution’s monitoring form). Given the average annual cost of $295,000 associated with teduglutide use in the U.S., appropriate patient selection will be important to determine the proper place for this therapy in the management of the PN- requiring SBS patient. Of note, in the U.S., the cost to the individual is generally much lower as a result of insurance coverage and patient support programs that provide financial assistance for out-of-pocket expenses. One other interesting predicament that may need to be considered, particularly in those patients weaned entirely from PN support while using teduglutide, is that there may be a potential for insurance denial of coverage of continued use of teduglutide since the patient is no longer using PN; letter writing and/or phone calls to the insurance company may be needed in this situation. It is important to recognize that the reduction in costs associated with PN use as weaning progresses will offset some of the cost associated with the use of teduglutide. Finally, some clinically important outcomes that defy accounting may come in the form of a dramatically improved quality of life as a result of decreased stool output, preserved hepatic function due to less PN dependence, and even an intestinal transplant avoided. Although these outcomes are difficult to quantify, to SBS patients and the clinicians who care for them, they are worthy goals.

Practical Approach to PN Weaning

The eligibility criteria used in the phase III clinical trials only provide a guide to aid in determining which patients should be considered for trophic factor use. At present, these agents should not be used in the pediatric population outside of the setting of a clinical research study. Suitable patients include those with SBS who have neither obstructive nor active GI malignant disease and who are dependent upon PN or IVF support despite optimization of diet, oral fluids and adjunctive medications (See Part II, III, IV A & B of this series). They should also be nutritionally optimized and in fluid balance. Furthermore, the patient should be motivated with a desire to reduce or discontinue the parenteral support. The presence/absence of a colon and length of the remaining small bowel do not necessarily factor into the selection of appropriate candidates and virtually any bowel anatomies can be considered. Table 3 lists factors to consider when determining whether to enlist a trophic factor in the care of the patient with SBS.

Prior to weaning, regardless of the use of a trophic factor, it is important for the SBS patient to recognize that the ‘trade-off’ to not being on PN is the need to take several medications orally and increase the amount of food and fluid ingested daily. Major lifestyle changes and increased out-of-pocket expenses are generally required. Consequently, patient education regarding the care plan (e.g., diet and drugs to be used and PN weaning plan) and ongoing support is important to enhance compliance. This is best done in the setting of a multidisciplinary practice with healthcare providers experienced in the care of SBS patients.

Before PN weaning begins, as previously mentioned but important to reemphasize, the SBS patient’s diet, fluid intake and conventional antidiarrheal and antisecretory medications should be optimized. Additionally, certain criteria should be met before reducing PN that include meeting the daily calorie and fluid intake goals established for the patient. Frequent follow-up is necessary with subsequent PN reductions based on tolerance as determined by the development of symptoms, hydration status, electrolytes and weight.30 A useful approach to monitor hydration status is to maintain the urinary sodium concentration > 20 mEq/L and daily urinary volume > 1 L (on PN free nights) and enteral balance (oral fluid intake minus stool output) between 500 and 1000 mL/d. Monitoring stool and urine output is cumbersome, however, SBS patients attempting to wean PN tend to be highly motivated. Providing the patient with tools to measure both stool and urine as well as a diary to record this information for review and discussion at the office, via e-mail, or over the phone is helpful.31

Once daily subcutaneous injection is required for the use of either somatropin or teduglutide. As injection site reactions are relatively common, rotating the injection site among the abdomen, thigh and upper arm is recommended. The injection should be administered at about the same time each day. The patients should be aware of the precautions necessary with the use of these medications and be instructed on the proper monitoring for complications and what to do/whom to contact should a problem occur. There are no data on the use of these agents in the presence of octreotide, biologic agents or immunosuppressant therapies.

PN reductions can be made by either decreasing the days that PN is infused/week or by decreasing the daily PN infusion volume equally throughout the week (e.g., 10%-30% reduction).30 Patients tend to prefer the former; however, dehydration is less of a potential concern with the latter. The teduglutide studies used the latter approach while the phase III somatropin study used the former approach. An optimal interval for making PN reduction decisions has not been defined. At most, in the ambulatory setting, once weekly would seem appropriate while acknowledging that this needs to be individualized. A recent report recommended obtaining laboratory studies weekly with an office visit monthly until parenteral requirements are stable, after which the frequency of monitoring and visits can be reduced.31 Once PN infusions are < 3 d/week, a trial of PN discontinuation is suggested. Although the occasional patient may successfully discontinue PN without the gradual weaning strategy, this approach is not recommended for the SBS who has been receiving PN for an extended period of time.

Oral micronutrient supplementation becomes necessary as PN is weaned and levels require periodic monitoring. Electrolyte supplementation, usually magnesium and/or potassium and sometimes bicarbonate, may also be needed and require monitoring. The frequency of monitoring will depend upon the stage of PN weaning and the presence of existing or prior deficiencies.30 Periodic laboratory monitoring will need to continue indefinitely, even in those weaned completely from PN.

CONCLUSION

An important goal in the treatment of SBS is to improve enteral autonomy, thereby reducing and, occasionally, eliminating the need for PN or IVF support. Following optimization of diet, hydration and conventional
pharmacological strategies (and occasionally surgical reconstructive procedures), the use of trophic factors has the potential to bring about further reductions.

The currently available agents include somatropin, a recombinant human GH, and teduglutide, a recombinant human GLP-2 analogue. Both agents, while quite different in terms of duration of use, cost and adverse
effects, have been shown in randomized, placebo-controlled trials to facilitate weaning from parenteral support. Long-term safety and efficacy, timing of administration in relation to the onset of SBS, optimal patient selection for use, duration of treatment and cost effectiveness of both somatropin and teduglutide strategies will require further study.

FRONTIERS IN ENDOSCOPY, SERIES #18

Avoiding Misses and Near Misses: Improving Accuracy in EUS

David L. Diehl,

Douglas G. Adler

Even expert endoscopists can miss significant lesions during an EUS examination. In this article, we discuss the challenging aspects of EUS, analyze potential causes for misses and near misses in EUS, and suggest how the endosonographer can minimize these occurrences.

David L. Diehl MD¹ Douglas G. Adler MD, FACG, AGAF, FASGE² 1Geisinger Medical Center, Department of Gastroenterology and Nutrition, Danville, PA² Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT

“Real knowledge is to know the extent of one’s ignorance.” – Confucius

“The first step in avoiding a trap is knowing of its existence.” – Thufir Hawat (Dune, Frank Herbert)

INTRODUCTION

Endoscopic ultrasound (EUS) has proven to be an indispensable tool for diagnosis and management of a wide variety of disorders. Mastery of EUS takes considerable time, dexterity, effort, and perseverance. A steady and wide-ranging caseload of EUS procedures is critical for maintaining competence and the development of new skills in this field. Even expert endoscopists can miss significant lesions during an EUS examination.

One of the most challenging aspects of EUS is that scope manipulation is driven by the real-time gray-scale images on the EUS screen, and not the view on the color video monitor used for standard endoscopic procedures. Evaluation and interpretation of ultrasound images are unfamiliar to most endoscopists, particularly in the United States, because formal training in transabdominal ultrasound imaging is not part of their GI curriculum, as it might be in Europe or Asia.

Manipulation of the echoendoscope is driven by the images on the EUS monitor, and the usual “up, down, left, right” movement will not produce the same effect as it would on the endoscopic video monitor. Mastery of the movements necessary to optimize EUS imaging is “as much done by the cerebellum as by the cerebrum”, and for real experts, the scope movements seem to be commanded subliminally.

Obtaining comprehensive EUS images of a given area of interest takes practice and skill, but the influence of factors that cannot be controlled by the endoscopist should not be underestimated. A patient’s body habitus, luminal anatomy, and the anatomic variations that can be encountered from one patient to another must be factored in to the ability of any endosonographer to arrive at the correct diagnosis. It must be recognized that the ability of EUS to visualize lesions is imperfect, even in the hands of the most experienced endosonographer. There are many potential pitfalls for EUS and EUS- FNA, which have been exhaustively summarized.1

Adverse effects (AEs) of EUS are remarkably low, even with the addition of fine needle aspiration. However, missing a diagnosis of malignancy remains one of the most feared complications of EUS. In distinction to ERCP, in which AEs are often acts of commission (for example, actively doing things that cause pancreatitis or a perforation), AEs in EUS are most commonly acts of omission (“missing things”).

It should be stressed that all EUS operators are human, and thus imperfect. Even the most skilled and experienced endosonographer can miss a clinically significant lesion.

The consequences of missing a cancer diagnosis are among the most difficult in all of procedural gastroenterology. However, missing other findings (even non-malignant ones), can result in increased health care costs and patient discomfort or inconvenience and can create medicolegal issues for physicians. We recognize that EUS, like all human endeavors, is an imperfect science and that even the most experienced endosonographer can miss a critically important finding. In this article, we will analyze potential causes for “misses and near misses” in EUS, and suggest how the endosonographer can minimize these occurrences.

Patient Dependent Factors in EUS Imaging of The Pancreas

Certain patient-dependent factors may have a significant impact on the ability to visualize the pancreas (Table 1). In patients with increased intra-abdominal fat, pancreatic imaging may be very challenging, as the pancreas might be hyperechoic due to fatty infiltration, or be atrophic which could be related to diabetes and/or metabolic syndrome. Fatty infiltration of the pancreas can occur in patients with a normal body habitus as well. Dense shadowing from inflammation, scarring, or calcifications in chronic pancreatitis can leave large portions of the pancreas, typically the head and genu, unseen. In the immediate period following acute pancreatitis, inflammatory changes can mask significant findings or be misinterpreted as a mass. EUS evaluation of the pancreas is often pursued in cases of idiopathic recurrent acute pancreatitis, but many endosonographers will wait for several weeks prior to doing a diagnostic EUS to allow these inflammatory changes to clear. Performing EUS of the pancreas in the time period just after an episode of acute pancreatitis can often be a fruitless endeavor.

Usually the presence of a biliary stent does not interfere with the ability to see a pancreatic mass with EUS, although in unusual cases, ultrasonographic shadowing in the pancreatic head from a biliary stent may make it difficult to see or fully delineate a small mass lesion. The literature is mixed on the influence of pancreatic cancer staging accuracy with or without a biliary stent in place.^3,4 Three studies have looked at cytologic yields of EUS-FNA of pancreatic masses after a stent has been placed. The concern is that cytology yields could be diminished due to the aforementioned stent effect (which could affect targeting of tissue for FNA sampling), or that false positive cytology could result. One of the 3 studies demonstrated a diminished yield of FNA in the presence of a stent,⁵ while another showed more indeterminate results if the biliary stent was placed less than 1 day prior to EUS.⁶ The third study compared EUS FNA in patients who had previously received metal or plastic biliary stent.⁷ The yields were very high and comparable in both groups (all patients had stents). A single false positive FNA was found in a patient with a plastic stent).

One of the few available studies to analyze factors accounting for missed pancreatic masses was the No EndoSonographic detection of Tumor (NEST) study.7 In this retrospective analysis, 9 expert endosonographers retrospectively identified 20 patients in whom a pancreatic neoplasm was missed. The goal was to try to understand factors that led to the missed diagnosis. Twelve of the 20 missed malignancies had EUS features of chronic pancreatitis, again emphasizing the limitations of EUS in this setting. Three patients had diffusely infiltrating carcinoma, which was not mass forming. Other unusual causes of missed pancreatic neoplasms were “prominent ventral dorsal split” in two patients and recent acute pancreatitis in one patient.

We have encountered cases of “invisible” pancreatic masses, in which only a caliber change of the bile and/ or pancreatic ducts was the sole clue to the presence of malignancy (Figure 1).⁸ In other cases, the mass is “isoechoic” and subtle. An example of a patient with pancreatic adenocarcinoma that mimicked the usual difference in echogenicity seen between the dorsal and ventral anlagen in the uncinate process is shown in Figure 2. In this patient, the mass lesion was missed and the images were initially interpreted as showing a normal uncinate process.

The “Hidden” Areas in Pancreatic Imaging

Given the relationship of the pancreas to the adjacent stomach and duodenum, the entire gland can be reproducibly imaged by EUS. However, the endosonographer must assure that the whole pancreas has, in fact, been imaged. While this sounds simple, in practice this can sometimes be hard to do and it can often be difficult to be sure that one has seen the entire pancreas.

The distal extremity of the pancreatic tail, often in very close approximation to the splenic hilum, can be easily overlooked or incompletely imaged, particularly if another finding has caught the eye (Figure 3). Even concerted attempts to evaluate the entire tail can result in an incomplete examination in some patients.

The pancreatic neck (near the region of the portal confluence) is an area that some feel is seen better with the linear echoendoscope⁹ although data on this point is limited and it is wholly acceptable to view this area with a radial scope. When using a radial scope, some feel that this region may be better imaged by tracing the pancreas back from the pancreatic head, rather than pushing the scope forward from the pancreatic body towards the head of the pancreas.

The uncinate process may be hard or impossible to reach in some patients due to variations in gastric or duodenal anatomy, and, again, it can be difficult to ensure that the entire uncinate process has been seen. Inability to visualize all parts of the pancreas must be distinguished from reporting that “nothing abnormal was seen in the pancreas”, even though these two disparate concepts seem similar.

Operator Dependent Factors in EUS Imaging

There are also endoscopist related factors that may factor into the quality of an EUS examination (Table 2). Operator experience is probably the most important one. The variation in EUS imaging from patient to patient and the wide range of anatomic locations that must be familiar to the endosonographer are unlike any other facet of advanced endoscopic practice. The endoscopist must maintain an organized approach to EUS imaging to prevent missing pathologic findings.

Doing a so-called “directed examination” i.e. performing EUS just to FNA a pancreatic mass that was identified on a pre-procedure CT scan without thoroughly evaluating the rest of the gland, may lead to missing important additional findings, such as liver metastases, the presence of ascites, malignant adenopathy, and other important pathology (Figures 4,5).

Competence and comfort in using both the radial and linear echoendoscope is vital to procedural success as one or both instruments may be required in a single patient. For example, the mediastinum is often easier to fully scan with the radial instrument than the linear, which requires careful, staged rotation to perform a complete exam (Figures 6,7). With experience, and the willingness to spend a little more time, a comprehensive examination can be conducted with the linear echoendoscope.

Endosonographer, (Attempt To) Know Thyself

In studying learning, social psychologists have identified factors that can influence perception of visual information. A person’s motivational state in regards to their wishes and preference can influence their processing of visual stimuli.¹⁰ Humans often “see what they want to see”, despite clear objective findings. An example might be the endosonographer minimizing the findings on EUS because, for example, he doesn’t “want the patient to have cancer”, or has already concluded that the findings are not consistent with malignancy (Figure 8). An endosonographer who is overscheduled may also minimize a particular finding because of the additional time burden associated with performing a fine needle aspiration. Overscheduling can also lead to rushing or distraction that could result in a missed lesion.

Another psychological phenomenon that could influence the quality of an EUS examination is the so-called “Dunning-Kruger effect”.¹¹ This describes a cognitive bias in which unskilled individuals mistakenly overestimate their abilities in a given field. Their very lack of skill leads them to fail to recognize that they lack skill, and tends to inflate their perception of their own competence. In another way of phrasing it, they “don’t know what they don’t know.”

An EUS trainee who works with an expert that provides active proctoring (rather than passive teaching) may be less likely to fall victim to this effect. One example of active proctoring would be to help the student learn how to find relevant anatomy, and then the mass, which is the target of the examination, rather than just positioning the endoscope at a mass and then relinquishing the endoscope to the trainee so that he or she can perform the FNA. However, also according to the Dunning-Kruger effect, the expert who finds EUS “easy” may mistakenly assume that it must be “easy” for others and, in turn, may be a less effective teacher because of this.

Recognize When Imaging is Less Than Optimal

Document any limitations in your ability to conduct a complete examination. Some patients have gastric and/or duodenal anatomy makes it very challenging to position the echoendoscope properly in order to obtain adequate images. Obvious situations that can preclude complete EUS examination include gastric bypass surgery or anatomy after reconstructive surgery (Billroth I or II, pancreaticoduodenectomy, etc.). An asymptomatic mild post-bulbar stenosis may make it impossible to safely advance the echoendoscope to the deep duodenum. Gentle dilation of a post- bulbar duodenal stricture with a 14mm or 15mm TTS balloon can frequently make the difference in obtaining complete pancreatic imaging. We have also encountered cases in which initial deep duodenal intubation was achieved early in the examination, but subsequently could not be achieved. The reason for this phenomenon is unclear, but we suspect insufflated air in the stomach and proximal small bowel changes the orientation of the patient’s anatomy in a dynamic way that makes repeated deep intubation difficult.

It is good to get into the habit of adequately documenting the EUS anatomy with endosonographic images, although no standard of care exists as to how many images should be obtained and exactly what structures must be photographed, and individual practice varies widely. Of note, some sites performing EUS do not have the ability to record EUS images and this should not be considered a violation of the standard of care either. With newer EUS consoles, there is the capability of transferring DICOM (digital imaging and communications in medicine) images to the hospital- wide PACS (picture archiving and communication system), and this has proven invaluable, for example, at multidisciplinary tumor board meetings.

Annotated photos illustrate what the endosonographer was seeing, because almost no one else is likely to be able to make definitive sense of the EUS images after the fact. Insufficient visualization is a reality of EUS, and should be appropriately documented.

Recognize When Repeat or Complementary Imaging is Required

Further imaging may be necessary if adequate endosonographic imaging is impossible, felt to be incomplete or inadequate for any reason, or for any of the other reasons mentioned above (Figure 9). In some cases, a repeat EUS will prove useful, for example, if initial FNA is negative but the index of suspicion is high for malignancy, repeat EUS FNA is generally warranted.¹² Complementary imaging with CT or MRI may also be a good option in some cases. A “cancer until proven otherwise” approach is prudent when one is an EUS specialist. One must realize that the patients referred for pancreatic EUS imaging will be part of a pool “enriched” for patients harboring pancreatic neoplasia, so a high index of suspicion is the best approach. This can apply to patients referred for a CT read simply as “fullness of the head of the pancreas”, a slightly elevated CA 19-9, or even idiopathic acute pancreatitis. It is better to expect to find cancer than to be surprised by it.

CONCLUSION

Practitioners of endoscopic ultrasound never cease to be amazed at the ability of this modality to visualize and access structures in the chest, abdomen, and pelvis, and have a good sense as to when it will be helpful. One of our roles is to educate our colleagues on how EUS is an indispensable diagnostic modality, and is having a larger role in therapeutics as well. However, we must honestly confront the limitations of EUS in any given patient or anatomical situation, and recognize how to handle this. Those who understand the art of EUS realize that we have arrived here by “standing on the shoulders of giants”, and we must lend a shoulder for those that follow us who want to learn endoscopic ultrasound.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #94

Mucosal Healing as an Emerging Therapeutic End-Point in Inflammatory Bowel Disease

Annalisa Aratari

In the last few years mucosal healing (MH) has emerged as an important therapeutic goal for patients with inflammatory bowel disease. Growing evidence suggests that MC can improve patient outcomes and potentially alter the natural course of the disease. In this article, we discuss the important questions that remain to be answered. How should MH be defined? What is the impact of current treatments in healing mucosal lesions in CD and UC? What is the real impact of MH on the clinical course of IBD? In other words, is MH a valid surrogate end-point of disease outcome?

In the last few years mucosal healing has emerged as an important therapeutic goal for patients with inflammatory bowel disease. Growing evidence suggests that mucosal healing can improve patient outcomes and, potentially, can alter the natural course of the disease. However several questions remain to be answered: a validated definition of mucosal healing is lacking, the effect size of different drugs is difficult to assess because of different definitions, different study design, and different timing of endoscopic evaluation and, finally, the evidence that mucosal healing has a high positive predictive value for long-term good clinical outcome is still limited. For these reasons it is still uncertain how mucosal healing should be used in everyday clinical practice. Future studies are needed to answer the most important question if mucosal healing should be systematically assessed in all patients and if treatment strategies should be targeted to achieve complete mucosal healing.

Claudio Papi MD, Giovanna Condino MD, Giovanna Margagnoni MD, Annalisa Aratari MD, Gastroenterology & Hepatology Unit, S Filippo Neri Hospital, Rome, Italy

INTRODUCTION

The management of inflammatory bowel disease (IBD) has traditionally been aimed at improving symptoms and little attention has been focused on healing of mucosal lesions. Nevertheless mucosal healing (MH) has been always considered important in ulcerative colitis (UC), but not in Crohn’s disease (CD). In fact, since the 1960s, clinical studies suggested that the long-term outcome in UC patients after a steroid course was more favorable in patients who achieved both clinical and endoscopic remission compared to those who achieved only clinical remission.¹ Up to the late 1990s, other observational studies reported the lack of a similar correlation in patients with CD. In particular, these studies described the absence of a clear impact of the mucosal lesions healing on relapse rates in CD patients with steroid-induced clinical remission.² These observations led clinicians to limit their CD treatment focus to symptomatic improvement and remission, therefore abandoning the idea that MH could affect the natural course of the disease.

The attitude of clinicians towards MH changed drastically when anti-TNFα drugs entered the IBD clinical practice. For the first time, in fact, it was thought possible to achieve a rapid and possibly sustained healing of mucosal lesions also in CD.³ Since then, the interest on MH, in both UC and CD, grew so much that, nowadays, there is a trend towards considering MH a relevant end-point in clinical trials and a desirable goal in clinical practice and some authors have suggested that future studies should focus on MH as primary outcome measure.⁴

Over the last years, accumulating evidence suggest that MH is prognostically relevant. In a Norwegian population-based cohort, MH was found to have a significant impact on the long-term outcome of both CD and UC.⁵ Observational studies and subgroup analyses of randomized controlled trials in CD indicate that MH is associated with lower relapse rates, higher corticosteroid-free remission rates, reduced hospitalizations and reduced need of surgery at least in the medium term.^6-8 Moreover, achieving MH may reduce the risk of relapse after infliximab (IFX) therapy is stopped.⁹ Also in UC MH has been associated with a more favorable outcome such as reduced risk of relapse, fewer hospitalizations and lower colectomy rates.^10-13 Moreover, the persistence of mucosal inflammation, even in the absence of symptoms, has recently been associated to an increased risk of colorectal cancer in UC; therefore, to address medical treatments beyond clinical remission, could lead to possible reduction of incidence of cancer.¹⁴

Although compelling arguments suggests that MH may be associated with improved disease outcome, the most important question for clinical practice is if we should systematically assess MH in all patients and target our treatment strategies to achieve not only clinical remission but also complete healing of endoscopic lesions. Several questions may arise from this issue: How should MH be defined? What is the impact of current treatments in healing mucosal lesions in CD and UC? What is the real impact of MH on the clinical course of IBD? In other words, is MH a valid surrogate end-point of disease outcome?¹⁵

Definition of Mucosal Healing

There is a wide range of possible endoscopic lesions in IBD but, to date, there is no standardized definition of MH.

In CD, MH has be defined in a simple and pragmatic manner as “absence of ulcerations at follow-up endoscopy in patients who had ulcerations at baseline”.⁶ This definition may be simple for clinical practice but it is too rigid and does not consider patients with substantial endoscopic improvement but with persistence of some mucosal lesions. Endoscopic scores, such as the Crohn’s Disease Endoscopic Index of Severity (CDEIS) or the Simple Endoscopic Score for Crohn’s Disease (SES- CD) are generally restricted to clinical trials. They are complex to calculate, require training and expertise and are not suitable for routine clinical practice.¹⁶ Moreover these scores were initially conceived, as continuous- variable systems and no agreement on cut-off values to define MH exist. In fact, in various studies, different cut-off values for the CDEIS and SES-CD have been used for defining MH.16

For UC, there are several endoscopic scores. All are quite similar, but none of them has ever been properly validated.¹⁷ One of the most used is the Mayo Endoscopic Score that combines 5 variables (erythema, vascular pattern, friability, bleeding, erosions, and ulcerations) in a 4-point scale, as follows: 0=normal or inactive disease; 1=mild disease (erythema, decreased vascular pattern, mild friability); 2=moderate disease (marked erythema, absent vascular pattern, friability, erosions); 3=severe disease (spontaneous bleeding, ulcerations).¹⁸ The International Organization of Inflammatory Bowel Disease (IOIBD) has proposed a definition of MH in UC as “absence of friability, blood, erosions, ulcers in all visualized segments^“.¹⁷ This definition corresponds to a Mayo score comprised between 0 and 1 and is simple to use in clinical practice.

A precise definition of MH would be of critical importance. In order to be useful in clinical terms, any definition should carry a prognostic value, in particular, it is discussed whether the definition of MH should be reserved solely for those cases of complete healing of mucosal lesions or whether, less strictly, MH could be defined as a clear improvement of mucosal lesions but without complete mucosal restitutio ad integrum. In a retrospective study on a large cohort of CD patients treated with IFX, no difference in the long-term need of major abdominal surgery was observed in patients that achieved complete MH (absence of ulcerations) or partial MH (clear improvement of mucosal lesions, but still with ulcerations).⁶ Similarly in UC, a sub-study of the ACT 1 and ACT 2 trials showed that early MH with IFX was associated with a reduced risk of colectomy within 1 year, but the colectomy-free survival was similar in patients who achieved complete MH (Mayo Score = 0) or partial MH (Mayo Score ≤ 1).¹² Taken together, these observations suggest that a distinction between complete and partial MH may not be relevant in clinical terms but further studies are needed.

Current Treatments for IBD and Mucosal Healing

Several drugs currently used in the management of IBD are capable of inducing MH in different clinical settings of disease location and severity. However the effect size of different treatments and the duration of the effect (short-term or sustained MH) are difficult to assess because of different definitions, different study designs, and different timing of endoscopic evaluation.¹⁹

Aminosalicylates are the first line treatment for mild to moderate UC. Their efficacy in inducing and maintaining clinical remission has been demonstrated in several randomized controlled trials.^20,21 Several data prove the capacity of both oral and topic aminosalicylates in inducing also MH in mild to moderately active UC. In several studies using different oral 5-ASA doses and formulations, and considering different definitions of MH at different time points, the percentage of patients achieving endoscopic remission ranged from 25% to 70%.¹⁹ In a recent meta-analysis involving 3,977 patients treated with oral 5-ASA and 2,513 patients treated with rectal 5-ASA, the overall rate of MH, according to different definitions, was 36.9% in patients receiving oral 5-ASA and 50.3% in patients receiving rectal 5-ASA.²² Optimising oral dose and combining oral and topical aminosalicylates may result in an increased rate of endoscopic remission in the short-term, up to 75%-80% or approximately 30% when MH is defined as completely normal mucosa (Mayo score = 0).^{10, 23-24}

Corticosteroids are the gold standard for the treatment of active moderate to severe IBD. Despite their excellent capacity to induce rapid symptomatic improvement and clinical remission in the short-term, it has been known for a long time that these drugs have a little impact on mucosal lesions. Historical trials showed that approximately one third of patients with CD and UC with corticosteroid-induced remission achieve also endoscopic remission^{1, 25} and similar rates of clinical and endoscopic remission have been recently reported in a prospective study on 157 UC patients receiving their first steroid course.¹¹

Immunomodulators azathioprine (AZA) and 6-Mercaptopurine (6MP) are usually considered effective in inducing MH in CD, even though it is well known that these drugs take a long time to achieve their potential benefits. However, evidence for AZA- induced MH in CD is very limited, deriving from few small studies performed in different clinical settings in which rates of MH, defined with different criteria, range from 36% to 70% within 12-42 months of continuative treatment.^26-28 Recently, the SONIC study investigated the effect of a combination of AZA plus IFX vs. AZA or IFX monotherapy in moderate to severe CD patients, immunosuppressive or biologic naïve. The primary outcome was steroid-free remission at week 26 and MH was a secondary end-point evaluated in a subgroup of 309 patients who were assessed endoscopically at baseline and after 6 months of therapy. MH was achieved in only 16.5% of patients receiving AZA monotherapy.²⁹ As far as UC is concerned, data are very limited. In a small prospective study in patients with steroid dependent UC, 55% of patients receiving AZA achieved clinical and endoscopic remission within 6 months.³⁰ Taken together these data suggest that AZA and 6MP may induce MH in a variable proportion of patients with CD and UC but the slow action of these drugs is the major limitation.

In the last 15 years, the advent of anti-TNFα agents has raised treatment expectations beyond symptomatic remission. In fact, the first observations suggested that, compared to conventional therapies, anti-TNFα agents were very effective in inducing and, possibly, in maintaining MH.³ Nevertheless, MH in anti-TNFα treated patients has not been systematically studied and data are available from subgroup analysis of RCTs and observational cohort studies.

In CD, subgroup analyses of RCTs suggest that scheduled IFX every 8 weeks can induce MH in approximately 30% of patients in the short-term, 50% in the long-term, and sustained MH (short and long- term) in approximately 30% of patients.^{8, 29} Real life experiences report similar data.⁶ Scheduled adalimumab (ADA) maintenance (40 mg every other week) can induce and maintain complete MH in approximately 25% of patients.³¹

In UC, scheduled IFX every 8 weeks can induce and maintain MH in approximately 30% to 50% of patients according to the definition of MH (Mayo score = 0 vs. Mayo score ≤ 1).^13,32 Studies with ADA in UC report a short-term MH in approximately 40% of patients and one year MH in approximately 25% of patients.^{33, 34} Real life experiences with ADA in UC report partial MH (Mayo score ≤ 1) in approximately 50% of responders and complete MH (Mayo score = 0) in approximately 25% of patients after a median of 11 months.³⁵

Is MH a Valid Surrogate End-Point of Disease Outcome?

Although evidence suggests that MH may improve disease outcome in terms of sustained remission and reduced complications, hospitalization and surgery, it is a surrogate end-point of disease course and an important point for discussion is to establish if MH is a valid surrogate end-point of disease outcome. A surrogate end-point is an outcome measure that per se has not a direct clinical importance but reflects a clinically relevant outcome. The greatest potential for the validity of a surrogate end-point is when the surrogate is in the only causal pathway of the disease process and the therapeutic effect on the true outcome is mediated through its effect on the surrogate.³⁶ It is difficult to find this ideal setting in a complex and multifactorial disease such IBD and, therefore, surrogate end-points could yield misleading conclusions.¹⁵

Apart from the difficulties establishing the validity of MH as a surrogate end-point of disease outcome, there are other debated issues; first of all whether histology should be included in the evaluation of MH. Although theoretically appealing, the prognostic relevance of histological healing has not been extensively evaluated but some data suggest that histological healing is relevant in UC as microscopic inflammation, even without gross endoscopic lesions, is predictive of disease relapse in patients who are in clinical and endoscopic remission.^37,38 Moreover, some studies indicate that ongoing microscopic inflammation is an independent risk factor of colorectal cancer in long-standing UC.^39,40 Although the effect of different drugs on microscopic inflammation in UC has not been extensively studied, histological healing may be, theoretically, the ultimate therapeutic goal in UC. Conversely, in CD, comes the issue of the appropriateness of MH as a relevant end- point in the treatment of a disease that is typically transmural. A lesson about the inadequateness of superficial healing in a transmural condition, we learnt from fistulizing CD, where it has clearly emerged how the closure of fistulas’ external orifices can be achieved despite the persistence of the fistulous tracks.⁴¹ For this reason, the concept of MH in CD is evolving towards a more complex model of intestinal healing with the elaboration of an instrument, the so-called Lemann score, which should enable an assessment of the cumulative structural bowel damage.⁴² The score includes not only endoscopy but also cross-sectional imaging techniques and, in the near future, it could be used in clinical trials and observational studies to measure the progression of bowel damage over time and to assess the effects of treatment on the progression of bowel damage.

Take Home Messages

1. In the last years the therapeutic goals of IBD have
  
  changed from mere control of symptoms towards
  
  long-term strategies aimed at affecting the natural
  
  course of the disease and MH is an emerging end-
  
  point in this setting.
  
  Although accumulating evidence suggests
  
  that MH is associated with improved disease
  
  outcome, it remains a weak surrogate end-point
  
  of disease course and further studies are needed
  
  to prospectively assess the impact of MH on long-
  
  term clinical outcomes.
  
  There is currently no standardized definition of
  
  MH and further studies are needed to develop
  
  and validate a definition of MH that carries a clear
  
  prognostic value.
  
  It is still uncertain how MH should be used in
  
  clinical practice. Although corticosteroids-free
  
  remission remains the first therapeutic goal in IBD,
  
  appropriate use and optimization of conventional
  
  and biological strategies may results in short and
  
  sustained MH in a variable proportion of patients.
  
  The most important question for clinical practice is
  
  if we should systematically assess MH and target
  
  our treatment strategies to achieve MH in all IBD
  
  patients.
  
  MH is likely not ready to be the primary therapeutic
  
  end-point in clinical practice, but it should be
  
  considered in decision-making. If the optimal
  
  management of a patient in clinical remission
  
  but with persistent endoscopic lesions is unclear
  
  (there are no prospective studies showing that
  
  escalation of therapy or switching to an alternative
  
  agent is associated with better outcomes in this
  
  setting), assessment of MH may be useful to select
  
  patients in sustained clinical remission in whom
  
  withdrawal of immunosuppressive or biologic
  
  therapy could be considered minimizing the risk
  
  of relapse.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #8

Update In Pediatric Gastroparesis

Eduardo D. Rosas-Blum,

Essam M. Imseis,

Richard W. McCallum

There is a robust body of evidence for the etiology and management of adult gastroparesis, but limited in the pediatric population. Pediatric gastroparesis is usually overlooked and can remain untreated for a long period of time. The aim of this review is to provide the most up to date evidence on the spectrum of pediatric gastroparesis, emphasize the differences from the adult setting as well as extensively address management approaches and treatment recommendations.

Gastroparesis is characterized by delay in gastric emptying in the absence of mechanical obstruction. The etiology and management of gastroparesis have been well studied in adults, but limited in the pediatric population. Most common identifiable etiologies of pediatric gastroparesis include: post-viral illness, drug side effects, post-surgical complications, diabetes mellitus, and mitochondrial disease. The most common symptoms are usually age-dependent. Nausea and abdominal pain are more common in older children and adolescents, while vomiting is more common in younger children. The gold standard for diagnosing gastroparesis remains gastric emptying scintigraphy, although normal values in children are limited. Treatment includes dietary modifications, pharmacotherapy, and gastric electrical stimulation, maintenance of nutrition, attention to glucose control, and psychological aspects.

Eduardo D. Rosas-Blum¹* Essam M. Imseis²* Richard W. McCallum³ 1Paul L. Foster School of Medicine, Texas Tech University Health Science center at El Paso. Department of Pediatric, Division of Gastroenterology, Hepatology, and Nutrition 2University of Texas Health Science Center at Houston, Department of Pediatric, Division of Gastroenterology, Hepatology, and Nutrition ³Paul L. Foster School of Medicine, Texas Tech University Health Science Center at El Paso, Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition *These authors contributed equally to this work.

INTRODUCTION

Gastroparesis is characterized by delay in gastric emptying associated with upper gastrointestinal symptoms without mechanical obstruction.¹ The care for these patients is often complex, difficult, and frustrating.² In adults, the most common etiologies are secondary to complications from diabetes or surgical interventions³ as well as “idiopathic”. The gold standard for the diagnosis of gastroparesis is a scintigraphic gastric emptying study.⁴

There is a robust body of evidence for the etiology and management of adult gastroparesis, but limited in the pediatric population. Pediatric gastroparesis is usually overlooked and can remain untreated for a long period of time.^5,6 In children, the most common identifiable causes for gastroparesis are secondary to viral illness or complications of a surgical intervention.⁷ The aim of this review is to provide the most up to date evidence on the spectrum of pediatric gastroparesis, emphasize the differences from the adult setting as well as extensively address management approaches and treatment recommendations.

Etiology and Pathophysiology

The normal gastrointestinal function is complex and depends on coordination between the smooth muscles, enteric, and central nervous systems. The most common gastrointestinal dysfunctions associated with adult gastroparesis include: impaired gastric accommodation, postprandial antral hypomotility, pyloric dysfunction, duodenal dysmotility, dysfunction of the autonomic nervous system, and visceral hypersensitivity.⁸ However, in infants and children there are developmental aspects which are superimposed on these recognized abnormalities.

Delayed gastric emptying occurs very frequently in premature infants^9-11 (< 28 weeks gestation) as the normal gastric emptying gradually matures with age. At 32 weeks gestation, the gastric emptying patterns are similar to older infants, children, and even adults.1,¹⁰ In normal term infants, expressed breast milk leads to faster gastric emptying compared to formula. Also, larger volume feedings are associated with a slower gastric emptying rate.¹⁰

In two large pediatric studies examining the etiology of gastroparesis, no recognized cause was found in up to 70% of cases (idiopathic). The identifiable causes included: viral gastroenteritis (18%), drug side effects (18%), post-surgical complications (12.5%), mitochondrial disease (8%), and diabetes mellitus (2%-4%).¹ Recognized pathogens associated with post-infectious gastroparesis include: parvovirus- like agents, Lyme disease, and rotavirus.¹² In the vast majority of post-viral gastroparesis, the emptying delay tends to improve or resolve spontaneously over days to several months.^12,13 At the time of presentation, identifying a virus may be problematic but a preceding gastroenteritis-like illness can be elicited from the family. Therefore, this raises the question whether so called “idiopathic” gastroparesis represents a latent post- gastroenteritis neuronal injury; this type of gastroparesis also spontaneously resolves. In adults, there have been many reports of histological abnormalities associated with gastroparesis which include: depleted or reduced numbers of interstitial cells of Cajal,^14,15 degeneration of the myenteric plexus combined with loss of ICC¹⁶ myopathic gastroparesis,¹⁷ stomach muscular layer eosinophilia,¹⁸ and lymphocytic myenteric ganglionitis.¹⁹ There have been no similar reports in pediatric gastroparesis based on our research of the literature.

Post-surgical gastroparesis has been described as a complication for antireflux surgery.²⁰ The main cause is an accidental injury to the vagus nerve which is an infrequent complication. Infrequently, patients with autoimmune diseases (i.e. systemic scleroderma) can present with delayed gastric emptying.^7,21 Mitochondrial disorders are often associated with intestinal dysmotility disorders. Screening for mitochondrial disorders involved serum levels of lactate or pyruvate, while confirmation can be accomplished by sequencing of the mitochondrial DNA or/and muscle or liver biopsy. In a small study looking at patients with mitochondrial disorders, delayed gastric emptying had poor response to prokinetic therapy.²² Patients with hypertrophic pyloric stenosis have been extensively followed up. To date, there is no evidence of increased gastroparesis following the surgical correction (pyloromyotomy).^23,24

Pseudo-obstruction is a rare but well described entity (familial or acquired) characterized by deficiency in the smooth muscles or nerves of the gastrointestinal tract. Gastroparesis is present in some of these patients as part of the diffuse involvement of the gastrointestinal tract, and particular attention needs to be paid to assessing the gastric emptying in children being considered for a subtotal colectomy for refractory constipation, in addition to histologically assess the resected colon smooth muscle histology.

Pediatricians often encounter infants with regurgitation or “reflux”. Gastroesophageal reflux (GER) of infancy is a normal physiologic event that requires no therapy and generally improves over time. Empiric treatment of GER for these infants is generally not recommended if this GER is without complications, but a subset of infants with GER may also have significantly delayed gastric emptying for which prokinetic therapy may be helpful.²⁵

Other important distinction from gastroparesis is cyclic vomiting syndrome (CVS), which is characterized by intense and stereotypical episodes of emesis. Patients with CVS usually are asymptomatic between episodes, without complains of abdominal pain or postpandrial distress, and have normal gastric emptying.

Clinical Symptoms of Gastroparesis

In children, presenting symptoms of gastroparesis appear to be different from those noted in adults.^5,26 In infants with gastroparesis, vomiting appears to be the most prevalent presenting symptom while both vomiting and abdominal pain are more commonly noted in young children between 1 and 10 years of age. Like adults, adolescents report more abdominal pain and nausea than younger children, but the incidence of nausea in adolescents still remains less than that which is noted in adults with gastroparesis. Nausea is quite common in adults with gastroparesis ? noted in more than 80% ? and is more common in diabetic gastroparesis than idiopathic gastroparesis. Vomiting is also more commonly noted in adults versus adolescents and is noted in 60% and 90% of idiopathic and diabetic gastroparesis in adults.²⁷ Other symptoms present in children with gastroparesis include early satiety and weight loss which are present in approximately 25% of children of either gender. Bloating is less common and reported in fewer than 10% of children. One apparent reason for this age-related symptom difference in children may be the inability of infants and young children to express and describe symptoms of abdominal pain and nausea.

Gender differences also appear to be more pronounced in adults with gastroparesis. In adults, gastroparesis is predominantly noted in females which comprise approximately 80% of patients.²⁸ When analyzed as a single group, children with gastroparesis appear to be nearly equally divided between male and female gender. However, male-female incidence appears to change with age at diagnosis. Gastroparesis appears to be slightly more common in male children (<12 years of age) who comprise over 61- 72% of patients in this age group.5, 26 Adolescents with gastroparesis tend to be overwhelmingly female and comprise approximately 3/4 of patients in this age group. This is consistent with current theories related to explaining female susceptibility to gastrointestinal motility disorders in adults through the hormonal changes experienced after puberty.

The presence of comorbid conditions has been noted in children with gastroparesis. Unlike adults, non- psychiatric comorbidities are commonly noted in children diagnosed with gastroparesis with 38% of children suffering from some other major neurologic disorder? seizure disorder, cerebral palsy, developmental delay, or prematurity. Psychiatric symptoms have been noted in adults with gastroparesis with higher depression and anxiety scores on psychological testing and rates of depression exceeding 60%.^3,29 In one study in children, only 28% of children with gastroparesis were noted to suffer from psychiatric disorders which included attention-deficit hyperactivity disorder, depression, anxiety, bipolar disorder, or other behavioral problems.⁵

Based in our literature review, an association between gastroparesis and pervasive developmental disorders, attention deficit and hyperactivity disorder (ADHD), or Down’s syndrome in children is not evident. Rumination syndrome is an entity that needs to be clearly differentiated from nausea and vomiting of gastroparesis, and gastric emptying in rumination is generally normal. Finally, there is an overlap between adolescents with eating disorders (anorexia, bulimia) and gastroparesis, and in this setting, identifying the diagnosis and instituting appropriate treatment is a challenging problem.

Diagnosis

Gastroparesis is a condition of delayed gastric emptying without evidence of mechanical obstruction and is typically associated with symptoms of nausea, vomiting, abdominal pain, early satiety, or bloating. It is imperative that mechanical obstruction (i.e. hypertrophic pyloric stenosis, intestinal webs, malrotation, duodenal atresia, anular pancreas, etc.) be considered and ruled out when necessary, particularly in young children or children with severe or significant symptoms.

Gastric emptying may be recognized as early as the 12th week of gestation possibly coinciding with increased amniotic fluid volume and the development of the suck reflex in utero. The percentage of fetuses that demonstrate normal gastric emptying also appears to increase in frequency in late gestation.³⁰ Gastric emptying appears to play a critical role in the developmental process and gastroparesis can be suspected if there is an abnormality in the normal process of growth or developmental milestones.

The gold standard for diagnosing gastroparesis remains gastric emptying scintigraphy. In this test, the solid or liquid contents of a test meal are radiolabelled so the amount of radiolabelled food remaining in the stomach at specified time intervals can be used to compute the rate of gastric emptying. A recent consensus statement in adults favors a 4 hour gastric emptying scintigraphy scan over a shorter 2 hour scan since the sensitivity of the test appears to improve with a 4 hour duration.³¹ While consensus exists regarding adult normative values, normal values in children are limited. A small study in infants and children revealed a gastric emptying of 32-64% one hour after ingestion of radiolabelled milk and 44-58% in children receiving radiolabelled milk feedings.³² In children 5-10 years of age, the time to empty half of a child-friendly Rice Krispie™cake technetium 99m-radiolabelled meal was 107.2 minutes. Most pediatric centers use consensus- defined adult normal values published using a standardized meal consisting of egg-whites, toast, jelly, and water or as appropriate for age. Using this adult protocol, gastric emptying is defined as normal if less than 90%, 60%, 30%, and 10% of the test meal remains in the stomach 1, 2, 3, and 4 hours following ingestion. In children as in adults, vomiting or an inability to ingest the test meal and its radiolabelled tracer must be noted since either of these may affect baseline and residual tracer counts noted during scintigraphy.

Wireless capsule motility testing (SmartPill™) is another modality that has been used to detect gastroparesis. This device is an orally ingested 26mm X 13mm non-digestible pill taken following ingestion of a standard test meal. b5 measure luminal pressure, pH and temperature throughout the entire GI tract and is thereby able to quantitate rates of gastric emptying, small bowel transit and colonic transit. While this device is currently FDA approved for use in adults, it is not approved for use in children. There are inherent challenges in this age group as the smart pill is difficult to swallow in younger children and normal values are not well-established. Nevertheless, there is limited data supporting its use in children. In a small study of 22 symptomatic children age 8-17 years old, wireless motility capsule testing was well tolerated with no adverse events and had 100% sensitivity and 50% specificity in detecting gastroparesis when compared to a 2 hour scintigraphic gastric emptying study.³³ Its major asset is being able to measure small bowel and colon transit thus providing a total profile of gut transit to assist in therapeutic decisions without use of radiation. In this limited pediatric study, the capsule was also found to have greater sensitivity in detecting abnormalities of small bowel motility when compared with antroduodenal manometry, perhaps because the capsule asseses the entire small bowel actively.

Breath testing is another means of assessing gastric emptying in children. In breath testing, orally ingested food is enriched with naturally occurring 13-carbon. A number of 13-carbon enriched substrates are utilized such as radiolabelled 13C-octanoic acid for solids and 13C-sodium acetate for liquids. After ingestion, these 13-carbon substrates are rapidly metabolized in the liver upon leaving the stomach and following their absorption in the duodenum. After oxidation in the liver, these isotopes are excreted from the blood into the exhaled breath. The rate of gastric emptying is the rate limiting step in excretion of this compound in exhaled breath.³⁴ As a result, quantitative measurement of this 13-carbon dioxide can help in determining the rate of gastric emptying. Multiple studies have validated its use in adults. Small studies in children of various ages seem to support a role for breath testing in analysis of gastric emptying in children. For example, use of radiolabelled 13C-octanoic acid breath testing did reveal good correlation with scintigraphy in assessment of gastric emptying of solids in 25 children 5 to 10 years of age.³⁵ Use of breath testing in small studies of both premature infants and term infants also demonstrates a potential role for 13-carbon breath testing with reproducibility and correlation with other methods including scintigraphic testing.^36,37 The major benefit is that the patient does not have radiation exposure and also it can be repeated multiple times to assess the response to treatment. This method is now FDA approved for use in adults only. In gastroparesis, where there is accompanying small bowel bacterial overgrowth (SIBO) in more than 50% of patients, there is a concern that this SIBO can interfere with metabolism and absorption of 13C-octanoic acid thus changes the calculations required for assessment of gastric emptying by breath testing. Hence its future role in adults with gastroparesis remains unclear; for now is it not approved in children.

Treatment

The management of gastroparesis can be complex (Figure 1). Initial efforts should correct fluid and electrolyte abnormalities since correction of these derangements can assist with management of gastroparesis.^38,39 Hyperglycemia is often noted in exacerbations of diabetic gastroparesis. Hyperglycemia can delay gastric emptying and contribute to symptoms of gastroparesis in both idiopathic and diabetic gastroparesis.⁴⁰ It is accepted that acute hyperglycemic states (serum glucose >250mg/dl) will delay gastric emptying and is a major contributor of nausea and vomiting in the newly diagnosed diabetic where an infection (often urinary) may be the trigger. Correcting this hyperglycemia may therefore also enhance gastric emptying. Chronic gastroparesis related to diabetes takes up to 5-10 years to evolve.

Dietary Management

Dietary modification is a key first step in the management of gastroparesis. In children as in adults, small frequent meals may be helpful in managing gastroparesis. Low fat, low fiber foods can also be helpful in managing gastroparesis since fat and fiber can retard gastric emptying and since fiber may be associated with an increased risk of bezoar formation in individuals with gastroparesis. Blenderized foods and ingestion of liquids during meals may also be helpful since gastric emptying of solids may be slower than liquids. A study in adults with diabetic gastroparesis revealed that a low particle size diet consisting of “foods” that were mashable with a fork” resulted in improvement in symptoms as well as more significant improvement in rates of gastric emptying when compared to a control group taking a low fat, low fiber diet.⁴¹

Dietary management of infants can be difficult due to their dietary restrictions, but there may be some strategies that may be helpful. In infants who are predominantly fed commercial formula, a small study of 6 infants revealed a significant difference and more rapid gastric emptying when those infants were fed infant formula containing high medium-chain triglyceride versus high long-chain triglyceride formula and when those infants were fed glucose-polymer containing formulas versus lactose-containing formulas.⁴² In separate studies, gastric emptying in infants fed breast milk appeared to be more rapid when compared to infants fed commercial formula.³⁷ There are also some studies that revealed an increased rate of gastric emptying in infants and non-infants when fed a formula containing whey protein or whey hydrosylate, although data regarding protein content in infant formula and rates of gastric emptying are conflicting.^43-45

Pharmacological Management

Since nausea and vomiting are common symptoms in children with gastroparesis, antiemetics may be helpful. Studies supporting their use appear to be limited, and recommendations for antiemetic therapy appear to be largely based on anecdotal experience and the adult literature. Furthermore, while use of antiemetic agents may result in improvement in symptoms in patients with gastroparesis, they do not appear to have beneficial effects on gastric emptying.³⁹ since their main source of action is centrally with the chemorector trigger zone at the floor of the 4th ventricle. Ondansetron, a 5HT-3 antagonist and antiemetic, can be helpful in management of vomiting associated with gastroparesis or other pediatric gastrointestinal disorders, such as cyclic vomiting syndrome, and doses of 4-8 mg every 8 hours are generally recommended in children and adolescents and can be administered orally, intravenously, or rectally if necessary.⁴⁶ Promethazine can be used in children but only with caution. The FDA issued a 2004 black box warning that recommended use of promethazine only in children greater than 2 years of age and only with the lowest effective dose since there have been several reports of respiratory depression and death with use. Furthermore, a more recent FDA warning recommended that injectable promethazine be administered only via the deep and intramuscular route and not into the skin or artery since there may be a risk of gangrene with these routes of administration. Oral and rectal routes of promethazine administration are also treatment options. Other over-the-counter antiemetic with some antiemetic effect include: meclizine, ginger, peppermint drops, and some homeopathic remedies.

With continued symptoms of gastroparesis unresponsive to conservative measures, use of prokinetics may be helpful. Only a few agents exist that can accelerate gastric emptying in children, and there are problems that can arise with use of most of these agents. Since erythromycin is a potent stimulator of gastric contractions, it can be utilized as an “off label” use of the agent. The main mechanism of action is to occupy the motilin receptor in the stomach and mimic the action of motilin. Lower doses of erythromycin are recommended in a range of 1-3mg/kg every 6 to 8 hours, since this can delay tachyphylaxis which occurs with chronic erythromycin use and usually occurs within 4 weeks of starting the medication.⁴⁷ Symptoms of nausea and vomiting can actually be provoked with higher doses of erythromycin most commonly used for infections (10 mg/kg/dose). Prolongation of the QTc and interaction with other inhibitors of cytochrome P-450 3A have been reported to result in cardiac arrhythmias and even death in individual case reports in adults. Azithromycin may theoretically be used as an alternative since it has fewer drug interactions, less incidence of QTc interval prolongation, a longer half- life, and fewer gastrointestinal adverse effects.^48,49 The dose of azithromycin is twice that for erythromycin. Data supporting its use is lacking at this time. Ingestion of oral azithromycin and erythromycin should be used with caution in infants if the exposure occurs in the first 2 weeks of life as the possibility of increasing the risk of developing infantile hypertrophic pyloric stenosis has been reported.⁵⁰

Metoclopramide is an FDA approved drug for gastroparesis in adults but not in children, although it is commonly used in management of children with gastroparesis. While there is a large amount of experience using metoclopramide in adults, the published evidence supporting its use in children is limited. In a small study of 6 post-surgical infants with gastroparesis, metoclopramide more than doubled the rate of gastric emptying but no beneficial effect of metoclopramide was noted in premature infants. There remains some concern over adverse events accompanying long- term use of metoclopramide including a potential risk of tardive dyskinesia and Parkinson-like syndrome. Akathisia, anxiety, hyperactivity, tremor, and sleepiness can develop in the first few days to months after treatment is initiated. These symptoms are completely reversible after decreasing the dose or stopping the medication. A recent 2009 FDA black box warning recommended metoclopramide only for short term use less than 12 weeks. A recent 2015 Canadian federal health warning recommended that metoclopramide should not be used in children less than 1 year of age since they appear to be at higher risk of extrapyramidal symptoms The Canadian recommendation further states that metoclopramide not be used in children greater than 1 year of age unless treatment is clearly necessary. The Canadian report states that the Canadian health department (HealthCanada) has identified only 8 reports of extrapyramidal symptoms suspected of being associated with metoclopramide in children receiving the recommended daily dose. However, the Health Canada warning cites a recent review of the European data that found cases of EPS in children less than 18 years of age treated with metoclopramide with most cases occurring when recommended doses were used. As a result, caution should be emphasized when considering this agent for children, and follow up is essential for monitoring for side effects. The tardive dyskinesia adverse events may be irreversible in some cases.

Less commonly used medications may be necessary when symptoms persist. Domperidone can enhance gastric emptying and may be considered for use in children. An FDA administered IND must be obtained prior to administering this agent. Domperidone is useful where chronic prokinetic therapy is being contemplated or when metoclopramide and erythromycin have resulted in side effects or are not effective. It is a dopamine 2 receptor inhibitor, as is metoclopramide, but it does not cross the blood-brain barrier decreasing the risk for extrapyramidal side effects. Its effects are antiemetic acting centrally and as a prokinetic acting peripherally. Dosing is similar to metoclopramide in adults, starting at 10 mg four times a day but its benefit is lack of significant side effects and dosing can be increase up to 80 mg a day in adolescents. An electrocardiogram needs to be followed to address the rare reports of prolong Q-T intervals.

Baclofen is a γ-Aminobutyric acid (GABA)?B
receptor agonist which increases lower esophageal
sphincter pressure and decreases the transient lower
esophageal sphincter relaxations. In children, Baclofen
significantly improved the gastric emptying compared
to placebo in a trial involving 30 children.⁵¹ In adults,
Baclofen is commonly used for refractory GERD but
there are no randomized trials for its use in gastroparesis.
The baclofen dose in adults is 10 mg four times a day,
while in children is 0.5 mg/kg/dose to a max of 40 mg
a day.

Other agents can also be helpful for management of associated abdominal pain accompanying gastroparesis. Low-dose tricyclic antidepressants or cyproheptadine are also potentially helpful since they have been utilized in other functional abdominal pain disorders such as irritable bowel syndrome and cyclic vomiting syndrome.

Interventional: Surgical and Endoscopic Options

Placement of a gastrostomy tube for venting or jejunostomy for feeding may be helpful in severe cases. Parenteral nutrition may be necessary in severe and refractory cases to help in maintaining nutrition. However, a jejunostomy tube is the recommendation due to severe TPN complications and costs.

Gastric electrical stimulation (GES) has emerged as a reasonable alternative in those with refractory symptoms of gastroparesis or where oral medications are not tolerated or are ineffective; this occurs in approximately 25% of adult patients with gastroparesis. With few good pharmacologic options and with the concerns over adverse drug effects, this approach has recently garnered more support. The history of gastric electrical stimulation and pacing date back to the 1960’s.⁵² In 2000, the FDA approved the Enterra system for humanitarian use in which a surgically implanted pacer delivers high frequency electrical pulses to electrodes placed at the junction of the antrum and body. A recent meta-analysis in adults revealed that gastric electrical stimulation appeared to result in significant improvement in symptoms of gastroparesis in individuals with diabetic and non- diabetic gastroparesis. Improvement in gastric emptying is not a goal.⁵³ Guidelines published by the American College of Gastroenterology in 2013 recommend this approach only for compassionate use in adults or children with refractory symptoms, particularly nausea and vomiting. Some uncontrolled data does exist supporting the use of gastric electrical stimulation in children. In a study of 9 children aged 8-17 years, all 9 children reported symptom improvement and quality of life improvement following gastric electrical stimulation during a follow up of 8 to 42 months.⁵⁴ In another study in 16 children age 4-19 years, there was significant improvement noted in all children with improvements in severity of both nausea and vomiting.⁵⁵ As noted in adults with idiopathic gastroparesis, there was not clear improvement in gastric emptying noted in those children who received gastric electrical stimulation which is consistent with the mechanism of action of GES which is to affect central control of nausea and vomiting via vagal afferents. It is important to remember that abdominal pain is not a target for GES since the main goal is to improve nausea and vomiting.

Surgical intervention may be necessary in cases of severe, symptomatic gastroparesis that appears to persist despite aggressive nutritional and pharmacologic intervention. Use of enteral feeding tubes may be necessary to maintain or improve nutrition, hydration, or metabolic derangements. Placement of these tubes may also allow venting for patients with excessive gastric distention or enteral secretions with simultaneous feedings as in instances where gastrojejunal feeding tubes with gastric and jejunal access are placed. They also permit the administration of medications via the enteral tube which improves the absorption of prokinetics and antiemetics, as well as “other agents” (i.e. antiseizure, pain medication, etc). Current recommendations by the American College of Gastroenterology favor a trial of nasoenteric postpyloric feedings prior to jejunostomy feeding tube placement in individuals with weight loss of more than 10% or refractory symptoms of gastroparesis.³⁹ In 2 large pediatric series, surgical placement of either a gastrostomy or jejunostomy tube was required to aid with management in a small percentage (4%, 19/469) children.^5,26 In one of these series, all five children requiring surgical feeding tube placement were noted to have CNS comorbidities and developmental delays complicating their management.⁵ A large study in adults with gastroparesis reported improvement following jejunostomy tube placement with 39% reporting improved nausea and vomiting, 52% fewer hospitalizations, 56% with improved nutrition, and 81% with improvement in overall health status.⁵⁶) Enteral feeding devices offer good reversible and, in some cases, temporary measures for treating children with severe, complicated gastroparesis who are unresponsive to more dietary or pharmacologic conservative intervention. It should be emphasized that when the patient has reached the stage of requiring a feeding tube, it will be advisable to consider a GES placement for symptomatic control of the nausea and emesis. Also, a jejunal feeding tube approach is preferable from a percutaneous endoscopic Gastro- Jejunal tube placement as it facilitates maintenance and most importantly, smooth muscle biopsy can be obtained at the time of the surgical jejunostomy to assess the ICC and neuronal status.

Intrapyloric injection of botulinum toxin has also been investigated as a potential treatment for gastroparesis due to encouraging results in multiple small series of patients with gastroparesis. A small open-label retrospective study of intrapyloric botulinum injection in children with gastroparesis revealed that approximately two-thirds of children reported improvement in a variety of symptoms and 40% of responders requiring only one injection. The uncontrolled and open-label nature of this study are obvious limitations, and similar encouraging findings have also been noted in uncontrolled open-label adult studies. Two double-blind, placebo-controlled studies examining the effects of botulinum injection in adults with gastroparesis reveal no improvement in symptoms compared with placebo.^57,58 Based on these placebo- controlled trials, botulinum use is not recommended for children or adults with gastroparesis.39 While the use of intrapyloric injection of botulinum toxin is not approved or endorsed, there is interest in its future role since it could be a first-step where a good response to botulinum injection could predict if a pyloroplasty can be beneficial in the long term.

Pyloroplasty has also been used in the management of gastroparesis and has the advantage of less radical alteration of the gastric anatomy compared with gastrectomy.⁵⁹ In one large adult series of 50 patients with gastroparesis, 83% reported symptom improvement following laparascopic pyloroplasty, and there was also significant improvement in gastric emptying noted on scintigraphy with median preoperative T1/2 of 180+/- 73 minutes and postoperative T1/2 of 60+/-23 minutes (p < 0.001). 68% of these patients had previous foregut procedures and/or cholecystectomy and 64% underwent concomitant procedures, such as paraesophageal hernia repair and gastrostomy takedown, at the time of their pyloroplasty. More recently in adults, pyloroplasty is being combined with GES placement with excellent results since gastric emptying can be normalized, a goal not achieved by GES alone.⁶⁰

Partial or subtotal gastrectomy is also a potential treatment for severe, refractory gastroparesis, but larger studies supporting its use are largely confined to adult populations. In one series of seven adults patients with vomiting due to gastroparesis, subtotal gastrectomy with removal of 70% of the stomach and creation of a Roux-en-Y loop of jejunum to prevent reflux gastritis resulted in substantial subjective improvement in all but one of seven patients.⁶¹ A larger series of 62 adult patients with postvagotomy gastoparesis who underwent near-total complete gastrectomy with a Roux-en-Y reconstruction revealed symptom relief in 43% of patients. A high percentage of postoperative complications were also noted in this larger study in 40% of patients and included narcotic withdrawal syndrome (18%), ileus (10%), wound infection (5%), intestinal obstruction (2%), and anastomotic leak (5%). There was also significant reduction in nausea (93% to 50%), vomiting (79% to 30%), and postprandial pain (58% to 30%) following surgery, but there were not significant differences in chronic pain, diarrhea, and dumping syndrome in this study. Gastrectomy should therefore be reserved only for those with severe symptoms unresponsive to other interventions. Data from McCallum et al. indicates that about 3-5% adult patients who failed GES for gastroparesis will require a total gastrectomy. If the patient has a previous gastric surgery (Billroth I or II) or GIS tumor resection, a GES is not recommended as the best approach but rather they should undergo a subtotal gastrectomy.

TAKE HOME CLINICAL PEARLS FOR THE PRACTITIONER

Pediatric gastroparesis is not similar to the adult
gastroparesis. The diagnosis and treatment for
gastroparesis is well established in adult but there
is limited evidence-base literature in the pediatric
gastroparesis.
1. 2. The most common etiologies in pediatric gastroparesis are idiopathic and post-viral. Most gastroparesis in children tends to resolve spontaneously without any treatment implying that many “idiopathic” gastroparesis could be subclinical gastrointestinal infection cases. Also, treating the underlying pathology (infection, hyperglycemia, etc.) will improve the gastric emptying.
2. 3. Symptoms for pediatric gastroparesis include: nausea, vomiting, and abdominal pain. Gastric emptying scintigraphy remains the gold standard to diagnose gastroparesis in children despite the lack of normal values in pediatric patients.
3. 4. The treatment for pediatric gastroparesis should start with dietary modifications. Pharmacological therapy is the second and third line of therapy for persisting pediatric gastroparesis. A GES is the choice of the treatment for those cases refractory to medical therapy.
4. 5. Future research in the etiology and treatment for persistent gastroparesis is very much needed in the pediatric population, particularly focusing on histological changes in neurons, ICC, and smooth muscle of the gastric muscularis propia.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS

Foreward

Richard W. McCallum

Richard W. McCallum, MD FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Department of Internal Medicine, Director, Center for Neurogastroenterology and GI Motility, El Paso, TX

Hello colleagues. I certainly hope the first six contributions in this series, The Clinical Spectrum of Gastrointestinal Motility and Functional Bowel Disorders for the Practitioner, have enhanced your knowledge base, improved the care provided by us and our staff in our practice and given us confidence that we are gaining the credentials to warrant the term “Card Carrying Motility and Functional Gut Expert”. Armed with this new knowledge let’s expand our horizons even further.

Next, we will reach out to our Pediatric Gastroenterology colleagues, who sometimes can feel a little neglected since they are not being specifically catered to by adult GI articles. We address this deficiency with two articles: The first, “Pediatric Biliary Dyskinesia and Sphincter of Oddi Dysfunction” and the second, “Update in Pediatric Gastroparesis”. These cover a large spectrum of GI issues in children and we will continue to re-visit pediatric GI in future articles.

We then turn our attention to “late breaking news”. Since it is an entertainment term, like the Brian Williams saga in the television world, much news can be overstated. Such is the case with Domperidone and the “Doom and Gloom” over less than well-founded and documented statements on cardiac toxicity that I see bandied around. We review this agent in great detail and conclude that it remains the “champagne” of the antiemetic/prokinetic world. We strongly endorse its efficacy and safety and recommend much broader use in your practices.

We then turn our attention to a series of three articles covering the topics of “Gas and Bloating” — “Integrative Medicine” and wait for it…”Herbal Medicine” where we will provide clinical pearls. Sometimes referred to as the “scourge” of our practice, gas and bloating of undetermined origin has a rational algorithm of diagnosis and treatment, the former relying on the judicious use of glucose and fructose breath testing and the latter on knowledge of treating small bowel bacterial overgrowth, utilizing low fructose, FODMAP diets, and food allergy concepts. Here we are under the expert guidance of second year GI Fellow, Dr. Juan Castro.

We then turn to integrative and holistic medicine with one of my GI Fellows, Dr. Christine Yu, who found time in her second year of GI Fellowship to do online training and certification in this field. Balance is the key – apparently to everything – but definitely in regard to brain / gut balance. The challenge is how to integrate “old world” wisdom with new world technology and actually surprise our patients with “old school” genuine patient involvement. Combined with this article I have asked one of my colleagues, a unique individual with a Ph.D in herbal medicine, Dr. Armando Gonzales – Stuart, to teach us how herbal medicines are not “bad news” based on concerns for liver and other toxicity, but actually have a host of great things to offer our patients.

Here at Texas Tech El Paso, on the border with Mexico we appreciate the rich Hispanic heritage and culture. The common use of food supplements in Hispanic families reminded me of the benefits of this approach when balanced with the patients’ own unique personal medical diagnoses and ways to complement our prescription medications for symptoms. Now we can all learn about this aspect of over the counter use for relief of symptoms in our patients.

The Paul L Foster School of Medicine is flourishing here at Texas Tech, El Paso. We graduate our second medical school class in May, at the same time as I am presenting you our second installment of this series.

A final word. I plan to see that great rock band The Eagles in El Paso. Remember the line from their song Hotel California: “you can check out any time you like, but you can never leave”. So you are now committed. Please stay in the classroom of GI Motility and Functional Bowel Disorders with the University of Practical Gastroenterology.

A CASE REPORT

Acute Liver Failure Due to Gemcitabine

William Ferges,Jeanine Chiaffarano,

S. Devi Rampertab,Nakechand Pooran

Gemcitabine induces apoptosis during DNA replication and has been used as a chemotherapeutic agent in various types of cancer. This drug is generally considered to be well-tolerated with mild common side effects including gastrointestinal disturbance, flu-like symptoms and rash. Myelosuppression and abnormalities of liver enzymes, usually mild, transient and reversible, are frequently reported. Gemcitabine has rarely been identified as a cause of acute liver failure (only four cases of cholestatic hepatotoxicity have been reported). This case involves a patient with acute cholestatic liver failure after adjuvant treatment with gemcitabine for pancreatic adenocarcinoma.

William Ferges, M.D., Jeanine Chiaffarano, D.O., S. Devi Rampertab, M.D., Nakechand Pooran, M.D. Rutgers – Robert Wood Johnson University Hospital, New Brunswick, NJ

CASE REPORT

A 48 year-old woman presented to the emergency room with several weeks of intermittent epigastric abdominal pain. She was found to have obstructive jaundice with a mass in the head of the pancreas. Endoscopic ultrasound revealed localized disease and she underwent an uncomplicated Whipple’s resection. Pathology confirmed a moderately differentiated T3N0 adenocarcinoma with local invasion into the duodenal wall and peripancreatic soft tissues but without lymph node involvement or encasement of the celiac axis or the superior mesenteric artery. Following the surgery, the patient’s liver enzymes began to normalize with only mild elevations in the alkaline phosphatase and aspartate aminotransferase (AST) (see Table 1). The patient was started on six cycles of adjuvant gemcitabine.

After initiating gemcitabine, she developed abnormal liver enzymes characterized by mild elevations in her bilirubin and transaminases (see Table 1). Due to a concern for a biliary anastomotic stricture, she was evaluated by balloon-assisted endoscopic retrograde cholangiopancreatography (ERCP) and was found to have a normal biliary tree with no evidence of stricture. Chronic hepatitis workup (A, B and C serologies, antinuclear antibodies and smooth muscle antibody) was negative. Computed tomography (CT) scan of the abdomen and pelvis with contrast revealed no signs of disease or liver lesions. She denied alcohol, illicit drug use, and herbal medication exposure. She was continued on her chemotherapy.

After she completed her sixth cycle of gemcitabine, the patient developed worsening cholestasis (see Table 1) and was subsequently hospitalized with liver failure as evidenced by a coagulopathy and development of encephalopathy. Transjugular liver biopsy revealed a hepatic injury in a cholestatic pattern with moderate pericellular fibrosis and steatosis (see Figure 1). This was consistent with drug-induced liver injury felt to be secondary to gemcitabine. The patient’s hepatic encephalopathy was medically managed with lactulose and rifaximin. After a long discussion with the patient and her family regarding her poor overall prognosis, she was discharged with home hospice.

DISCUSSION

Hepatotoxicity due to drugs is a common cause of acute liver failure. It has been estimated that more than half of the cases of acute liver failure referred to tertiary care centers in the United States are due to drug toxicity.¹ In most cases of drug toxicity, the drug is suspected to be the sole cause of liver injury. Drugs are typically divided into two categories: (1) dose-dependent hepatotoxins (predictable toxicity related to the blood level of the medication, the dosage and the duration of intake), an example of which is acetaminophen, and (2) idiosyncratic hepatotoxins whose toxicity is unpredictable and thought to be based upon genetic predisposition, age or environmental factors.²

Idiosyncratic reactions often occur without warning, unrelated to the dosage of the medication. Such hepatotoxins can cause a wide range of histologic changes and can be highly variable in the latent period before the onset of an injury. There are a multitude of different proposed mechanisms of idiosyncratic reactions including disruption of the cell membrane, activation of immune-mediated responses, disruption of bile excretion, activation of apoptosis pathways and inhibition of mitochondrial function.^3,4,5 While drug induced hepatotoxicity is common, the effects are often reversible with withdrawal of the offending agent and supportive care. Only rarely do patients develop acute liver failure.

Gemcitabine is a fluorine-substituted nucleoside analog, which has been widely utilized as a chemotherapeutic agent. This antimetabolite inhibits DNA synthesis during replication resulting in apoptosis of tumor cells. It is typically well-tolerated with only mild side effects including mild gastrointestinal disturbance, flu-like symptoms and rashes. Myelosuppression is one of the more commonly noted side effects of the medication. Elevations in liver enzymes are also commonly reported but are typically mild, transient and reversible. Rarely, gemcitabine can elicit severe idiosyncratic reactions resulting in acute liver failure that may be irreversible.

There have been only four previous reports of acute cholestatic liver failure due to gemcitabine, three of which were fatal.^6,7,8 Of note, one of the fatal cases was suspected to be due to a combination of both gemcitabine and vinorelbine.⁸ A fourth case has been more recently reported by Stellman et al. in which a patient with acute liver failure attributed to gemcitabine had a complete recovery after the medication was withdrawn.⁹ Similar to our patient, the clinical presentation for each of these cases was notable for marked cholestasis. Two of these cases, however, had a mixed hepatocellular and cholestatic pattern of injury. The exact mechanism of injury caused by gemcitabine has not been clearly identified. Another report suggested an alternate mechanism of acute liver failure due to gemcitabine through veno-occlusive disease.¹⁰ (See Table 2)

The time course of the acute liver failure and the histologic findings seen on liver biopsy clearly implicate gemcitabine as the cause of liver failure in our patient. Our patient did not develop acute liver failure until completion of her sixth cycle of gemcitabine, which emphasizes the documented latent period prior to development of acute liver failure. This shines a light on the importance of closely monitoring liver enzymes in patients during and after treatment with gemcitabine.

SUMMARY

Our patient is one of only a few cases of gemcitabine- induced cholestatic liver failure reported in the literature. Drug-induced hepatotoxicity is one of the most common causes of acute liver failure, and must be considered in all treated patients with liver enzyme abnormalities. Although gemcitabine hepatotoxicity usually causes mild elevations in liver enzymes that normalize when the medication is discontinued, cases of fatal cholestatic liver failure have been reported. Careful monitoring of liver enzymes should be performed on all patients treated with gemcitabine given the risk of acute liver failure. Additionally, patients with underlying liver disease may be at greater risk of the potential hepatotoxic effect of gemcitabine and should be monitored more closely.

A CASE REPORT

Colonic Polypoid Ganglioneuroma

Saire Mendoza M.,Parajuli D.

Saire Mendoza M.¹ Parajuli D.² ¹Section of Gastroenterology and Hepatology, Ochsner Medical Center ²Division of Gastroenterology, Hepatology and Nutrition, University of Louisville

INTRODUCTION

Intestinal ganglioneuromas can be found throughout the gastrointestinal tract and have three different presentations. They have been reported to be associated with multiple endocrine neoplasia type IIB (MEN-IIB), even before the GI endocrine neoplasms are diagnosed,¹ and occasionally with Von Recklinghausen’s disease (VRD).^2,3 These benign tumors are the result of submucosal (nerve) plexus hyperplasia in the intestinal wall,⁴ and consist of ganglion cells, nerve fibers and supporting cells. We report a case of a colonic ganglioneuroma found incidentally on screening colonoscopy. Management of these lesions, the risk of gastrointestinal malignancy and further assessment for occult non-gastrointestinal malignancies will be reviewed.

CASE

An otherwise healthy 69 year-old African American male underwent screening colonoscopy. A 1 cm subepithelial lesion, which was not characteristically adenomatous under both white light and narrow band imaging, was seen at the recto sigmoid junction (Figure 1). This lesion was biopsied and tattooed for future location. The initial sample did not yield a pathologic diagnosis thus rectal endoscopic ultrasound was performed. The lesion was noted to be hypoechoic and arising from the submucosa layer (Figure 2). Bite-on-bite cold forceps biopsies were taken and sent for histologic examination. The final pathologic findings were reported as a polypoid ganglioneuroma (Figure 3).

DISCUSSION

Intestinal ganglioneuromatous disease (GN) is divided into three groups.

1. Polypoid ganglioneuromas are small (<2cm), sessile or pedunculated polyps that are endoscopically difficult to distinguish from juvenile, hyperplastic or adenomatous polyps. Microscopically, they are divided into three patterns with disarranged crypt architecture with spindle and nerve ganglion cells within the mucosa being the most common.
2. Ganglioneuromatous polyposis (GP) consists of numerous, often 20 to 40, sessile or pedunculated lesions. There is less demarcation among the contents that make up the ganglioneuromas in this subgroup.
3. Diffuse ganglioneuromatosis (DG) presents as disseminated, nodular, intramural or transmural lesions ranging from 1 to 17cm in size and can lead to segmental bowel strictures; histologically these lesions involve the myenteric plexus. Most of DG cases are associated with MEN-IIB or VRD^3,5,6; and may radiographically resemble Crohn’s disease on barium studies and computed tomography scans ⁷

The largest case series of ganglioneuromatosis was reported by Shekitka et al.³ in 1994 where 43 patients with intestinal ganglioneuromatous disease were followed. While some patients presented with abdominal pain, rectal bleeding or megacolon, many were asymptomatic. However, cases with watery diarrhea secondary to vasoactive intestinal polypeptide secretion and diffuse ganglioneuromatosis involving the colon and rectum have been reported,^8,9 as well as upper GI bleeding from a ganglioneuroma of the duodenum¹⁰ and polypoid GN causing colonic intussusception.¹¹

The prevalence of diffuse ganglioneuromatosis in patients with MEN-IIB syndrome is nearly 100%, and often gastrointestinal involvement predates the development of medullary thyroid cancer.¹ Diarrhea or constipation from diffuse alimentary tract involvement, was reported in a case series of 16 patients with MEN-IIB.¹ DG was found before medullary thyroid carcinoma in 12 of these16 cases. Therefore, the authors concluded that diffuse ganglioneuromatosis heralds the development of endocrine neoplasms, especially medullary thyroid carcinoma, which is the most common and most feared component of the MEN-IIB syndrome.

Around 25% of patients with Von Recklinghausen’s disease have shown some gastrointestinal involvement, mainly neurofibromas and occasionally ganglioneuromatosis.^2,5 In one series, the mean interval between diagnosis of Von Recklinghausen’s disease and the onset of gastrointestinal symptoms related to gastrointestinal neurofibromatosis was approximately 37 years.² Also, the simultaneous finding of diffuse ganglioneuromatosis and associated adenocarcinoma of the colon in patients with VRD⁵ seems to be more related to the high incidence of adenocarcinoma in patients with Von Recklinghausen’s disease¹² rather than secondary to ganglioneuromatosis itself.

Polypoid ganglioneuromatosis and ganglioneuromatosis polyposis do not appear to be associated with systemic disorders such as MEN-IIB or VRD.^3,6,13,14 Shekita et al.³ followed 16 patients with Polypoid GN and, after eight years, 13 were still alive and did not have evidence of MEN-IIB or VRD. Similar findings were obtained for patients with ganglioneuromatosis polyposis, however, two of the three patients had multiple skin tags and cutaneous tumors which were thought to be lipomas. Chan and colleagues⁶ also reported these cutaneous findings in patients with ganglioneuromatosis polyposis.

Intestinal ganglioneuromatosis has also been found in association with adenomatous, hyperplastic and juvenile type polyps.^13,15 However, adenomas do not appear to be the prevailing feature in the setting of ganglioneuromatosis.

CONCLUSION

Three patterns of intestinal glanglioneuromatous disease have been described: polypoid ganglioneuromas, ganglioneuromatous polyposis (GP) and diffuse ganglioneuromatosis. Most cases of diffuse ganglioneuromatosis have been associated with MEN- IIB. The clinical presentation depends on size and location of ganglioneuromas. In diffuse gangliomatosis, gastrointestinal symptoms usually precede the development of thyroid medullary neoplasms and should prompt further diagnostic work up. There is not enough literature to suggest that intestinal ganglioneuromatosis has malignant potential.¹⁷ As such, an aggressive surgical approach in an asymptomatic patient without increased risk of carcinoma may be unnecessary.⁷ In the cases where GN is found along with hyperplastic or adenomatous polyps, current standard colonoscopy surveillance recommendations after polypectomy¹⁶ should be followed.

Abbreviation

VRD: Von Recklinghausen’s disease

Acknowledgement

We thank Dr. Silvia D. Potenziani Pradella from the Department of Pathology and Laboratory Medicine at University of Louisville for contributing images of polypoid ganglioneuromatosis of the colon.

UNUSUAL CAUSES OF ABDOMINAL PAIN, #8

Unusual Causes of Abdominal Pain

Omair Atiq,Lan Peng,Christian Mayorga

Omair Atiq M.D.,¹ Lan Peng M.D.,² Christian Mayorga M.D.,¹ 1Division of Digestive and Liver Diseases, ²Department of Pathology, University of Texas, Southwestern Medical Center, Dallas, TX

CASE

A 48 year old woman presented to the emergency department with chief complaints of abdominal pain, nausea and vomiting for five days. Her abdominal pain was located in the mid epigastrium and right upper quadrant (RUQ). It was constant and burning in nature. The vomiting was approximately three times per day and consisted of watery material and food particles, and she occasionally noticed bright red blood. She also noted having one loose bowel movement which was dark in color. She otherwise denied any fevers, chills, dysphagia, odynophagia or hematochezia.

Her medical history was significant for HIV/AIDS on highly active anti-retroviral therapy (last CD4 count: 51 cells/mcL, viral load: 47377 copies/ml), oral candidiasis, disseminated varicella zoster and anemia of chronic disease. On presentation, her vitals were stable. Her abdomen was soft, non-distended, with moderate tenderness on palpation over her RUQ.

Initial laboratory values revealed WBCs: 3.92×10(9)/L, Hb: 9.0 gm/dL, platelets: 225×10(9)/L. Computed tomography (CT) scan of the abdomen showed concentric wall thickening involving the third part of duodenum and proximal jejunum. Her symptoms did not respond to intravenous antiemetics and analgesics. An esophagogastroduodenoscopy (EGD) showed a normal esophagus and stomach. There was patchy, mildly erythematous mucosa in the duodenal bulb. Upon entering the second portion of duodenum, the mucosa appeared markedly abnormal. There was severe villous blunting, mucosal atrophy, diffuse erythema and scattered erosions (Figures 1 and 2). These changes persisted into the third position of duodenum and beyond. Biopsies were taken for histology and microbiology (Figures 3 and 4).

ANSWER AND DISCUSSION
Enterocolitis Caused by Strongyloides Stercoralis (Threadworm)

The pathology report showed duodenal mucosa with inflammation and significant architecture distortion including villous loss (Figure. 3). Both strongyloides adult (black arrow) and larvae (yellow arrow) are seen within crypts. Mucosal ulcer and eosinophilic and neutrophilic infiltration are present (Figure 4).

The patient was diagnosed with enterocolitis caused by Strongyloides stercoralis. She received a course of ivermectin. Her abdominal pain completely resolved within a week, and she remained asymptomatic at two months after hospital discharge.

Strongyloides stercoralis (threadworm), an unsegmented helminth of class Nematoda, was first described in 1876 when it was identified in the feces
of French colonial troops suffering from diarrhea in Cochin-China.¹ Strongyloides is prevalent in the tropical and sub-tropical regions of the world and is endemic in the southeastern United States. Immunosuppressed patients are at greatest risk because impaired cellular
and humoral immunity alter parasite proliferation, resulting in increased parasitic burden and possible dissemination to other organs. Studies have reported the incidence of strongyloidiasis in patients with HIV to be near 2.5 %.² The most common gastrointestinal (GI) symptoms result from involvement of the upper GI tract and include nausea, vomiting, diarrhea, weight loss, and abdominal pain. Additional manifestations of GI strongyloidiasis include malabsorption, GI hemorrhage, colonic pseudopolyposis, granulomatous hepatitis, biliary obstruction, and eosinophilic ascites. Endoscopic findings include ulcerations, gastritis or duodenitis as evident in our patient. Diagnosis can be made with stool
examination, enzyme linked immunosorbent assay or a duodenal or jejunal biopsy (~90% diagnostic yield). Ivermectin (200 mcg/kg/day) is the first-line agent for treatment, and a course of five to seven days has been
suggested in immunosuppressed patients with systemic disease. Lifelong suppressive therapy may be indicated for both gastrointestinal and pulmonary infections in patients with relapses.³ Intestinal strongyloidiasis is not an uncommon infection in immunosuppressed patients and should be in the differential diagnosis for patients presenting with nausea, vomiting and abdominal pain.

Endoscopy should be considered if symptoms are not resolving with conservative management.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #7

Pediatric Biliary Dyskinesia and Sphincter of Oddi Dysfunction

Aldo Maspons,

Richard W. McCallum

Adult gastroenterologists consider biliary dyskinesia a functional disorder and new research has opened the door for Type 3 sphincter of Oddi dysfunction to be considered as a functional disorder. Pediatric gastroenterologists should follow the lead of our adult colleagues and consider the reclassification of biliary dyskinesia and sphincter of Oddi dysfunction type 3 as functional disorders.

Biliary dyskinesia is a gall bladder disorder in the setting of a normal biliary tree. Adult gastroenterologists consider it a functional disorder, but this is not the case in pediatrics, as it is amongst the most common reasons for laparoscopic cholecystectomies. Sphincter of Oddi dysfunction is a motility disorder in the contraction of the sphincter leading to obstruction of the bile or pancreatic juice.1 New research has opened the door for Type 3 sphincter of Oddi dysfunction to be considered as a functional disorder in adult gastroenterology. Pediatric gastroenterologists should follow the lead of our adult colleagues and consider the reclassification of biliary dyskinesia and sphincter of Oddi dysfunction type 3 as functional disorders.

Aldo Maspons, MD¹ Richard W. McCallum, MD² ¹Division of Pediatrics, El Paso Children’s Hospital/Texas Tech ²Department of Medicine, Division of Gastroenterology, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Pediatric Biliary Dyskinesia

Biliary Dyskinesia (BD) is a gall bladder disorder in the setting of an anatomically normal biliary tree. The clinical manifestations include episodic colicky right upper quadrant pain or epigastric pain triggered by food, associated with nausea and vomiting in the absence of cholilithiasis. The pain is thought to be caused by contraction of the sphincter of Oddi at the time of gall bladder relaxation. The most commonly affected tend to be female patients and/or overweight patients.^2,3

Pediatrics often takes its cues from the adult world in terms of diagnosis and treatments so as to mitigate any potential risks for our society’s most vulnerable citizens. Biliary dyskensia (BD) is an example of a disorder first described in adults and treated operatively with subsequent practice adoption in pediatrics.⁴ BD is considered a functional disorder according to Rome III,⁵ but it is not recognized as a childhood functional disorder.⁶ Despite BD being classified as an adult functional disorder, laparoscopic cholecystectomy has been relied on as the final therapeutic solution.⁷

Diagnostically, a Hepatobiliary Iminodiacetic Acid (HIDA) scan along with an injection of cholecystokinin (CCK) is used to assess gall bladder function by evaluating bile excretion, accumulation, and ejection from the gall bladder. Gallbladder emptying less than 35% along with typical symptoms established by the Rome III Criteria establish the diagnosis of BD.⁵ One study found problems with solely using a HIDA scan to make a diagnosis of BD. Some children who had abnormal ejection fractions on their first scans, later had normal ejection fractions.⁸ Caution must be taken regarding opiate pain medication in the background at the time of the abnormal HIDA scan. This is one example of the problems encountered with extrapolating adult data to fit the needs of pediatric patients. The clinical response to cholecystectomy is subsequently used to confirm the diagnosis of BD if there is no recurrence of pain for 12 months.⁵ HIDA scans and Ejection Fractions should be considered as only one aspect in the decision making process.

The diagnosis of BD has been on the rise and this is seen in the steady rise of laporoscopic cholecystecomy. Mehta et al. describe the trend of cholecystectomies at one of the countries largest children’s hospitals in which from the years 1980-1996, there were no documented cases of BD, but from the years 2005-2008, there were 64 cases, making it the third most common indication for a cholecystectomy, behind complicated obstructive disease, and symptomatic cholelithiasis.²

Their study, much like those of others, demonstrated that histologically, the gall bladder had features of chronic cholecystitis.^8-10 Friesen et al. demonstrated that patients with BD had an increase in mast cell density, which parallels other functional disorders.⁸ When comparing the differences between patients who underwent a cholecystectomy secondary to stones vs. BD, patients with BD had more mast cells in the lamina propria. Mast cell degranulation and the high levels of mast cells within the lamina propria, however, did not correlate with the ejection fraction.

What has been lacking in BD research is randomized control trials with larger groups for analysis. The research data for the diagnosis and treatment is based on retrospective studies with small number sizes. Time of response to surgery has also been limited and mostly to only a few months after surgery. Few studies have looked into long-term follow-up. One such study looked at 2.8 years after surgery³ and demonstrated that 44% of their cohort was symptom free after laporscopic cholecstectomy. Nelson, et al., evaluated 55 patients and compared cholecystectomy to children who did not undergo surgery, but instead were observed in the setting of BD.⁸ At the two-year follow up, 55% of the cholecystecomy group had complete resolution of pain and 55% of the observation group also had complete resolution of pain. Twenty-six percent of the cholecystectomy group and 20% of the observation group had partial resolution of pain. Two years after the original two-year follow-up, there were no differences in the rate of response to pain. This study used long term data to suggest that a non-operative approach may be just as effective as an operative one, which is consistent with the long -term outcome of functional disorders.

The relationship between pediatric functional disorders and gall bladder disease was explored by Chumpitazi et al.¹¹ They found that children with BD may also have concomitant gastroparesis, suggesting a neuroenteric abnormality affecting both biliary and gastric motility. Srinath et al. argue that BD is a safe diagnosis in children in that there are minimal associated complications. This should emphasize, according to them, the need to explore therapies used in treating BD as a functional disorder and there should be less reliance on the surgical routes of care for this disorder where there are complications from such interventions.¹²

Currently, there are no established biliary functional disorders in pediatrics (Table 1).¹³ More research for conservative management has begun to set the stage for Biliary Dyskinesia in Pediatrics to be managed like other functional disorders in Pediatrics-conservatively, medically, perhaps with combination therapy involving psychological aspects to treatment.¹²

Pediatric Sphincter of Oddi Dysfunction

The sphincter of oddi (SO) is located at the duodenal junction of the biliary and pancreatic ducts.⁵ Sphincter of oddi dysfunction (SOD) is a motility disorder manifested as an abnormality in the contraction of the sphincter of oddi (SO)¹⁴ that leads to an obstruction of bile or pancreatic juice.¹ Patients typically have biliary obstructive pain not relieved with cholecystectomy. There are three distinct types of SOD. Type 1 consists of patients with a dilated bile duct and abnormal liver labs. Type 2 consists of patients who have either a dilated bile duct or abnormal liver labs, but not both. Type 3 have neither a dilated duct nor abnormal labs.¹⁵

SOD can present with symptoms that include epigastric pain or right upper quadrant pain that radiates to the back or right shoulder in episodic fashion. It can present as idiopathic pancreatitis, biliary type pain with an intact gallbladder and no gallstone, and present after a cholecystectomy. In addition, SOD has been studied as a possible cause of recurrent abdominal pain in children.¹⁶ Currently in the adult literature, SOD is regarded as a functional disorder,⁵ but not so in the pediatric literature.⁶ There is limited data in pediatrics in regards to the number of studies performed. All studies are retrospective chart reviews and the number of patients is small. Brown et al. and Lemmel et al. found 3 of 38 children and 7 of 29 children with SOD as the cause of recurrent pancreatitis, respectively.^17,18 Varadarajulu et al. evaluated 6 patients, three type II, and three type III over a three year time period.¹ Cheng et al. as a part of a large ERCP series evaluated, six patients with SOD type II, 35 patients with SOD type III over a ten-year period. Chronic abdominal pain and recurrent pancreatitis were the two most common presentations. Post ERCP rates of pancreatitis in these patients ranged from 21-30%.¹⁹ Misra et al. performed a retrospective chart review with telephone follow up.¹⁶ Twelve patients, 9 of which had SOD Type III, underwent SO manomentry and sphinctertomy for treatment. Of the twelve patients, three did not respond. Seven patients at the five-year follow up continued to be asymptomatic. Phone follow up, however, did not include a standardized pain scale assessment.

Sphincter of Oddi Dysfunction is first suspected with the above mentioned clinical presentation. To confirm the diagnosis, the ampulla of Vater is cannulated with an endoscopic rertrograde cholangiopancreatography (ERCP). Sphincter of Oddi manometry is then performed with a low compliance infusion pump system (Figure 1). Basal sphincter of Oddi manometry pressure greater than 40 mm Hg or greater are considered abnormal and based on adult data.¹⁹ Treatment of the SOD consists of a sphincterotomy that is preformed on the biliary and/or pancreatic sphincter, depending on which one is above the adult based normal value. There are no pediatric manometrical based pressure values and therefore, adult values are used. Adult data demonstrates that SOD II is more likely to have manometric demonstrable SOD 55% of the time vs. 28 % of the time in SOD III.²⁰ These procedures are not without risk. Post ERCP pancreatitis rates in pediatrics has occurred in up to 13% of cases.²¹

Recently, Cotton et al. performed the first multicenter, sham-controlled, randomized control trial with a large patient volume involving 214 patients.¹⁵ The results of this study have shifted the dynamic of SOD III. Cotton et al. demonstrated that sphincterotomy was not more effective than a sham ERCP in post cholecystecomy patients with SOD type III.¹⁵ Futhermore, manometrical findings, biliary or pancreatic pressures, were not associated with sphincterotomy outcomes. Given these results, treatment with sphincterotomy for patients with SOD III should be called into question because it was demonstrated that sphincterotomy, which is not without risk, is a procedure no better than placebo.

This recently published trial is being interpreted by adult gastroenterologists as moving SOD into a functional bowel disorder category such as irritable bowel syndrome. Hence, the stage invites SOD III in children to be considered a functional disease with therapy that at the very least should no longer involve an invasive approach. Further studies are needed to determine the pathophysiology of pain and a medical route of therapy. Like other pediatric functional disorders, and much like what is suggested for the treatment of biliary dyskinesia, a therapeutic combination that includes a non-invasive approach should be considered in the management of this disease. This combination of treatment should include psychological techniques to deal with anxiety and visceral sensitivity that are so often a part of pediatric functional abdominal pain.²² In the future we speculate that brain-gut modifying agents may be worthy of treatment trials, e.g. Tricyclics. In addition, treatment with cholinergic therapy addressing colon motility will have a role.

Diet could also be considered another form of
therapy. There already is precedence for this kind of
therapy in irritable bowel syndrome (IBS) with the
FODMAPS diet. Much like the role of the intestinal
microflora in IBS, perhaps it is also playing a role
in SOD. Changing the intestinal microflora is one of
many treatment possibilities for a disease whose current
treatment should be further explored.